Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.

BACKGROUND: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Impact of vincristine-steroid pulses during maintenance for B-cell pediatric ALL: a systematic review and meta-analysis.

The benefit associated with the incorporation of vincristine-corticosteroid pulses in maintenance therapy for pediatric acute lymphoblastic leukemia (ALL) is unclear, particularly in the context of modern intensive therapy. This systematic review and meta-analysis examined the impact of reducing the frequency of vincristine-steroid pulses during maintenance for pediatric patients newly diagnosed with B-cell ALL. Two authors reviewed all eligible studies identified through a comprehensive search, extracted data from 25 publications (12 513 patients), and assessed the risk of bias. We created historical and contemporary subgroups; the latter included trials providing both a version of Protocol III from the early Berlin-Frankfurt-Munster trials and eliminating routine prophylactic cranial radiation. Meta-analysis of event-free survival data suggested no benefit between more frequent or less frequent pulses in contemporary trials (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.85-1.09), which differed significantly from historical trials (HR, 0.79; 95% CI, 0.68-0.91; P = .04). We found no significant impact of reduced pulse frequency on overall survival or relapse risk. There was however increased odds of grade 3+ nonhepatic toxicity in the high-pulse frequency group (odds ratio, 1.31; 95% CI, 1.12-1.52). This systematic review suggests that the previous benefit conferred by frequent pulses of vincristine-steroids in maintenance therapy for pediatric B-cell ALL in historical trials no longer applies in contemporary trials but is associated with toxicity. These results will help guide the development of the next phase of clinical trials in the field of pediatric ALL and question the continued use of pulses in maintenance among patients not in clinical trials, particularly those experiencing toxicity.

Polatuzumab vedotin in previously untreated DLBCL: an Asia subpopulation analysis from the phase 3 POLARIX trial.

In the phase 3 POLARIX study in previously untreated diffuse large B-cell lymphoma, polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intention-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cutoff (28 June 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population, and was superior with Pola-R-CHP vs R-CHOP (hazard ratio, 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3 to 4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP vs R-CHOP in the Asia and global populations in POLARIX. This trial was registered at https://clinicaltrials.gov/ct2/home as # NCT03274492.

How I treat older patients with DLBCL in the frontline setting.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive but potentially curable disease and is most common in older people. Rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard of care for fit patients without cardiac contraindications. In each individual older patient, the potential gains of treatment should be balanced against the risks of treatment-related morbidity and mortality. A simplified comprehensive geriatric assessment or easily performed assessments such as gait speed and grip strength can be helpful to assess the fitness of an older patient. Prephase with corticosteroids, rigorous supportive care including granulocyte colony-stimulating factor prophylaxis and careful monitoring can be important in preventing adverse events. In unfit older patients, a dynamic dosing strategy is often applied. For very old patients (≥80 years) a dose-reduced regimen (rituximab-miniCHOP) is recommended. When anthracyclines are contraindicated, doxorubicin can be replaced by etoposide or gemcitabine. Most frail patients do not benefit from chemotherapy. Further progress can be expected from non-chemotherapy-based therapies, such as bispecific antibodies, antibody-drug conjugates, and immunomodulatory agents. This article provides an overview of first line treatment in older patients with DLBCL and our approach to the management of these challenging cases.

Safety and efficacy of tafasitamab with or without lenalidomide added to first-line R-CHOP for DLBCL: the phase 1b First-MIND study.

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.

Interim PET-guided treatment for early-stage NLPHL: a subgroup analysis of the randomized GHSG HD16 and HD17 studies.

The optimal first-line treatment for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) diagnosed in early stages is largely undefined. We, therefore, analyzed 100 NLPHL patients treated in the randomized HD16 (early-stage favorable; n = 85) and HD17 (early-stage unfavorable; n = 15) studies. These studies investigated the omission of consolidation radiotherapy (RT) in patients with a negative interim positron emission tomography (iPET) (ie, Deauville score <3) after chemotherapy (HD16: 2× doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]; HD17: 2× escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP] plus 2× ABVD). Patients with NLPHL treated in the HD16 and HD17 studies had 5-year progression-free survival (PFS) rates of 90.3% and 92.9%, respectively. Thus, the 5-year PFS did not differ significantly from that of patients with classical Hodgkin lymphoma treated within the same studies (HD16: P = .88; HD17: P = .50). Patients with early-stage favorable NLPHL who had a negative iPET after 2× ABVD and did not undergo consolidation RT tended to have a worse 5-year PFS than patients with a negative iPET who received consolidation RT (83% vs 100%; P = .05). There were 10 cases of NLPHL recurrence. However, no NLPHL patient died during follow-up. Hence, the 5-year overall survival rate was 100%. Taken together, contemporary Hodgkin lymphoma-directed treatment approaches result in excellent outcomes for patients with newly diagnosed early-stage NLPHL and, thus, represent valid treatment options. In early-stage favorable NLPHL, consolidation RT appears necessary after 2× ABVD to achieve the optimal disease control irrespective of the iPET result.

Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy. METHODS: ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete. FINDINGS: Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0-11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8-4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5-74·1] in the VAC/VI group vs 66·8% [57·5-76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58-1·26]; log-rank p=0·44). The most common grade 3-4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified. INTERPRETATION: Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population. FUNDING: The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).

The impact of CHOP versus bendamustine on bone mineral density in patients with indolent lymphoma enrolled in the GALLIUM study.

Standard CHOP treatment includes a high cumulative dose of prednisone, and studies have shown increased fracture risk following CHOP. It is unclear whether reductions in bone mineral density (BMD) are caused by glucocorticoids or by the combination with chemotherapy. Our objective was to determine the effect of obinutuzumab (G)/rituximab (R)-bendamustine versus G/R-CHOP on BMD in follicular lymphoma patients. Patients in this GALLIUM post hoc study were ≥60 years old and in complete remission at induction treatment completion (ITC), following treatment with G or R in combination with bendamustine or CHOP. To assess BMD, Hounsfield units (HU) were measured in lumbar vertebra L1 on annual computed tomography. Furthermore, vertebral compression fractures were recorded. Of 173 patients included, 59 (34%) received CHOP and 114 (66%) received bendamustine. At baseline, there was no difference in HU between groups. The mean HU decrease from baseline to ITC was 27.8 after CHOP and 17.3 after bendamustine, corresponding to a difference of 10.4 (95% CI: 3.2-17.6). Vertebral fractures were recorded in 5/59 patients receiving CHOP and in 2/114 receiving bendamustine. CHOP was associated with a significant greater decrease in BMD and more frequent fractures. These results suggest that prophylaxis against BMD loss should be considered.

Prevention of vincristine-induced peripheral neuropathy by protecting the endothelial glycocalyx shedding.

Vincristine-induced peripheral neuropathy (VIPN) adversely affects the quality of life and treatment continuity of patients. The endothelial glycocalyx (eGCX) protects nerves from harmful substances released from the capillary vessels, but its role in peripheral neuropathy remains unclear. We investigated the impact of eGCX protection on VIPN. Using a murine model of VIPN, we administered nafamostat mesylate to protect the eGCX shedding, and analyzed the eGCX integrity and manifestation of peripheral neuropathy. Nafamostat treatment suppressed allodynia associated with neuropathy. Additionally, nafamostat administration resulted in the suppression of increased vascular permeability in capillaries of peripheral nerves, further indicating its positive influence on eGCX in VIPN model mice. This study provided the importance of eGCX in VIPN. With the potential for rapid clinical translation through drug repositioning, nafamostat may be a new promising treatment for the prevention of VIPN.

Cost-effectiveness of polatuzumab vedotin combined with chemoimmunotherapy in untreated diffuse large B-cell lymphoma.

In patients with treatment-naive diffuse large B-cell lymphoma (DLBCL), the POLARIX study (A Study Comparing the Efficacy and Safety of Polatuzumab Vedotin With Rituximab-Cyclophosphamide, Doxorubicin, and Prednisone [R-CHP] Versus Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [R-CHOP] in Participants With Diffuse Large B-Cell Lymphoma) reported a 6.5% improvement in the 2-year progression-free survival (PFS), with no difference in overall survival (OS) or safety using polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) compared with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We evaluated the cost-effectiveness of pola-R-CHP for DLBCL. We modeled a hypothetical cohort of US adults (mean age, 65 years) with treatment-naive DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of pola-R-CHP and R-CHOP using a range of plausible long-term outcomes. Progression rates and OS were estimated from POLARIX. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year PFS of 69.6% with pola-R-CHP and 62.7% with R-CHOP, pola-R-CHP was cost-effective at a WTP of $150 000 (incremental cost-effectiveness ratio, $84 308/QALY). pola-R-CHP was no longer cost-effective if its 5-year PFS was 66.1% or lower. One-way sensitivity analysis revealed that pola-R-CHP is cost-effective up to a cost of $276 312 at a WTP of $150 000. pola-R-CHP was the cost-effective strategy in 56.6% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in PFS is maintained over time, pola-R-CHP is cost-effective compared with R-CHOP at a WTP of $150 000/QALY. However, its cost-effectiveness is highly dependent on its long-term outcomes and costs of chimeric antigen receptor T-cell therapy. Routine usage of pola-R-CHP would add significantly to health care expenditures. Price reductions or identification of subgroups that have maximal benefit would improve cost-effectiveness.

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.

Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome.

Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate, 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. This trial was registered at www.clinicaltrials.gov as #NCT03054896.

Analyzing the risk factors for disease progression within 2 years and histological transformation in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone as first-line treatment: A 15-year follow-up of patients with advanced follicular lymphoma in JCOG0203.

Follicular lymphoma (FL) is an indolent lymphoma that becomes aggressive due to histological transformation (HT), leading to reduced survival. Patients with FL have different clinical courses and various treatment options. Some patients exhibit shorter survival and experience disease progression within 24 months of diagnosis/treatment (POD24); the optimal treatment remains an unmet needs. Thus, identifying factors that predict shorter survival is essential to stratify treatment and prolong the survival of patients with FL. To analyze risk factors for POD24 and HT in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment, we performed this post-hoc analysis of patients with advanced indolent B-cell lymphoma in a randomized clinical trial wherein six cycles of R-CHOP were administered every 2-3 weeks. The primary analysis showed no differences in outcomes, which enabled the analysis of 248 patients with FL, assigned to two arms. All histopathological specimens from the 300 enrolled patients were reviewed by three expert hematopathologists. Multivariable analysis implicated Follicular Lymphoma International Prognostic Index (FLIPI) intermediate (odds ratio [OR] 2.531, 95% confidence interval [CI] 0.676-9.466) and high- (OR 2.236, 95% CI 0.160-31.226) risks, B symptoms (OR 2.091, 95% CI 0.747-5.851), and grade 3A (G3A) (OR 1.833, 95% CI 0.634-5.299) as risk factors for POD24. Furthermore, multivariable analysis through a median follow-up of 15.9 years implicated G3A (OR 2.628, 95% CI 0.806-8.575) and high-risk FLIPI (OR 4.401, 95% CI 0.186-104.377) as risk factors for HT. However, an analysis limited to the first 10 years revealed that the prognostic factors elucidated from the longer-term analysis had a greater impact on HT. G3A and high-risk FLIPI may independently predict POD24 and HT, thereby informing treatment stratification of patients with untreated advanced-stage FL in future trials, particularly to address the unmet needs of patients with POD24.

Modified R-BAC plus BTK inhibitor regimen in newly diagnosed young patients with mantle cell lymphoma: a real-world retrospective study.

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65 years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42-65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17 months (2-86 months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3-4 lymphopenia and grade 3-4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable.

R-miniCHOP versus R-CHOP in elderly patients with diffuse large B-cell lymphoma: A propensity matched population-based study.

For elderly frail patients with diffuse large B-cell lymphoma (DLBCL), an attenuated chemo-immunotherapy strategy of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-miniCHOP) was introduced as a treatment option as from 2014 onward in the Netherlands. Although R-miniCHOP is more tolerable, reduction of chemotherapy could negatively affect survival compared to R-CHOP. The aim of this analysis was to assess survival of patients treated with R-miniCHOP compared to R-CHOP. DLBCL patients ≥65 years, newly diagnosed in 2014-2020, who received ≥1 cycle of R-miniCHOP or R-CHOP were identified in the Netherlands Cancer Registry, with survival follow-up through 2022. Patients were propensity-score-matched for baseline characteristics. Main endpoints were progression-free survival (PFS), overall survival (OS), and relative survival (RS). The use of R-miniCHOP in DLBCL increased from 2% in 2014 to 15% in 2020. In total, 384 patients treated with R-miniCHOP and 384 patients treated with R-CHOP were included for comparison (median age; 81 years, stage 3-4; 68%). The median number of R-(mini)CHOP cycles was 6 (range, 1-8). The 2-year PFS, OS and RS were inferior for patients treated with R-miniCHOP compared to R-CHOP (PFS 51% vs. 68%, p < .01; OS 60% vs. 75%, p < .01; RS 69% vs. 86%, p < .01). In multivariable analysis, patients treated with R-miniCHOP had higher risk of all-cause mortality compared to patients treated with R-CHOP (HR 1.73; 95%CI, 1.39-2.17). R-miniCHOP is effective for most elderly patients. Although survival is inferior compared to R-CHOP, the use of R-miniCHOP as initial treatment is increasing. Therefore, fitness needs to be carefully weighed in treatment selection.

A phase II Japanese trial of 90-minute rituximab infusion for untreated B-cell lymphoma.

OBJECTIVE: This phase II clinical trial evaluated feasibility and tolerability of 90-minute rituximab infusion and a concentration of 4 mg/mL rituximab infusion in Japanese patients with previously untreated follicular lymphoma or diffuse large B-cell lymphoma. METHODS: Treatment was rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone. In cycle 1, rituximab at a dose of 375 mg/m2 (4 mg/mL) was administered at the standard infusion rate stipulated in the package insert. On confirmed tolerance of rituximab, patients received 90-minute infusion in second and subsequent cycles. The primary endpoint was incidence of grade 3 or higher infusion-related reactions during 90-minute rituximab infusion in cycle 2 of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone. RESULTS: All 32 patients (median age 61.5 years, 16 males, 24 with diffuse large B-cell lymphoma) completed the prescribed six or eight cycles of treatment. One patient withdrew consent after cycle 1, and another developed grade 2 erythema and continued receiving 4 mg/mL at the standard infusion rate for cycle 2. The remaining 30 patients received 90-minute rituximab infusion; 28 (93.3%) completed cycle 2 at the scheduled infusion rate and dosage. No grade 3 or higher infusion-related reactions were associated with a concentration of 4 mg/mL rituximab dose or 90-min rituximab infusion in cycle 2. The most common infusion-related reaction symptoms were pruritus, hypertension and oropharyngeal discomfort. During the study, toxicities and adverse events were as expected, with no new safety signals. CONCLUSION: High-concentration dosing (4 mg/mL) and 90-minute infusion of rituximab are feasible and tolerable in Japanese patients with previously untreated follicular lymphoma or diffuse large B-cell lymphoma. CLINICAL TRIAL NUMBER: JapicCTI-173 663.

Characterising vincristine-induced peripheral neuropathy in adults: symptom development and long-term persistent outcomes.

BACKGROUND: Decades following the introduction of vincristine as treatment for haematological malignancies, vincristine-induced peripheral neuropathy (VIPN) remains a pervasive, untreatable side-effect. However there remains a gap in understanding the characteristics of VIPN in adults. This study presents a comprehensive phenotyping of VIPN. METHODS: Adult patients (n = 57; age = 59.8 ± 14.6) were assessed cross-sectionally following completion of vincristine (months post treatment = 16.3 ± 15.6, cumulative dose = 7.6 ± 4.4), with a subset of 20 patients assessed prospectively during treatment. Patient reported measures (EORTC-QLQ-CIPN20, R-ODS) were used to profile symptoms and disability. Neurological assessment was undertaken using the Total Neuropathy Score and nerve conduction studies. Sensory threshold and fine motor tasks were also undertaken. Comparisons of data between timepoints were calculated using paired-sample t tests or Wilcoxon matched-pairs signed-rank test. Comparisons between outcome measures were calculated with independent sample t tests or Mann-Whitney U tests for non-parametric data. RESULTS: The majority of patients developed VIPN by mid-treatment (77.8%, 7.0 ± 3.3 weeks post baseline) with the prevalence remaining stable by end-of-treatment (75%, 8.1 ± 1.7 weeks post mid-treatment). By 3 months post-completion, 50% of patients still reported VIPN although there were significant improvements on neurological grading and functional assessment (P < 0.05). VIPN presented with sensorimotor involvement in upper and lower limbs and was associated with decreased sensory and motor nerve amplitudes, reduced fine-motor function and increased disability. CONCLUSION: VIPN in adults presents as a sensorimotor, upper- and lower-limb neuropathy that significantly impacts disability and function. Neuropathy recovery occurs in a proportion of patients; however, VIPN symptoms may persist and continue to affect long-term quality of life.

Chemotherapeutic metabolism presenting as a recalcitrant case of hand-foot syndrome and mucositis.

INTRODUCTION: Mercaptopurine (6MP) and methotrexate (MTX) are commonly used for maintenance chemotherapy for acute lymphoblastic leukemia (ALL). These medications have been associated with various side effects such as myelosuppression, colitis, and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side-effects most reported include mucositis, alopecia, xerosis, and pruritus. We report an interesting case of hand-foot syndrome to 6MP in a child on maintenance therapy for B-cell ALL from an alteration in medication metabolism. CASE: We report a 10-year-old male on maintenance chemotherapy for pre-Bcell ALL who presented to the hospital with worsening oral lesions and erythematous, fissured plaques on the palms and soles. Maintenance therapy consisted of IV vincristine and 5-day pulse of steroids every 12 weeks, daily 6MP, and weekly MTX, which were increased to ≥ 150% of standard dosing due to persistent absolute neutrophil counts > 1500. Metabolites obtained on admission demonstrated elevated 6MMP metabolites at 35,761 (normal < 5700). TPMT and NUDT15 enzyme activity were normal and no alterations in genotyping were discovered. OUTCOME: Patient's oral chemotherapy, including both 6MP and MTX, were stopped and allopurinol 100 mg daily was initiated, which lead to overall improvement. DISCUSSION: Clinical findings of acute mucositis and worsening of hand-foot syndrome, in the setting of inadequate myelosuppression in a child on maintenance therapy for ALL should raise concerns to consider altered metabolism pathway leading to toxic metabolite buildup. Allopurinol can play in improving cutaneous manifestation and chemotherapeutic dosing in patients with altered metabolism.

Effect of vincristine on intraocular pressure and tear fluid oxidative stress biomarkers in canine transmissible venereal tumor.

BACKGROUND: The ocular side effects of cancer chemotherapeutic drugs are relatively uncommon. Nonetheless, the ocular system has a potentially high sensitivity to toxic substances. This study proposed a framework to assess the effect of vincristine chemotherapy on intraocular pressure, tear protein, and oxidative stress in canines with transmissible venereal tumor (TVT). METHODS: The study group comprised 10 dogs with TVT, whose diagnosis was based on cytology, and all dogs were treated with vincristine for 4 weeks. Each animal was given a complete ophthalmic examination, followed by a standard Schirmer tear test. Before and 20 min after administering vincristine, intraocular pressure (IOP) was measured in the eyes with a noncontact tonometer. At any of the times mentioned, tear samples were collected using the Schirmer test procedure and were subjected to protein analysis-oxidative stress index (OSI), total antioxidant capacity (TAC), total oxidant status (TOS), nitric oxide (NO), and malondialdehyde (MDA) were determined, and standard statistical analysis was applied. RESULTS: No significant differences were found in protein in tears, but mean Pre and Postinjection IOP revealed a significant decrease in the eyes each week. Also, results indicated significant differences in oxidative stress markers: increased OSI, NO, and MDA, and reduced TAC. CONCLUSION: The importance of an increase in oxidative stress levels in the tears of vincristine-treated patients should be taken seriously, as it appears to play a role in the pathogenesis of eye disease. Therefore, during the treatment weeks prior to prescribing vincristine, eye diseases should be evaluated and considered.