Progression-free Survival In High-risk Patients Research Articles

Ixazomib, Lenalidomide, and Dexamethasone (IRD) Treatment with Cytogenetic Risk-Based Maintenance in Transplant-Eligible Myeloma: A Phase 2 Multicenter Study by the Nordic Myeloma Study Group.

Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib-lenalidomide-dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10-5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10-5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free (p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10-5. Altogether 95% of the patients with sustained MRD <10-5, 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance (p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients.

Role of pembrolizumab in relapsed Hodgkin lymphoma patients

About 10–15% of patients with early-stage and 15-30% with relapsed Hodgkin lymphoma after primary conventional treatment. Despite the approval of novel therapies, autologous stem cell transplantation (ASCT) remains the standard of care in these patients. However, up to half of transplanted individuals may relapse. Pembrolizumab is an FDA-approved monoclonal antibody directed against programmed cell death protein 1 (PD-1), it has received approval for the treatment of solid cancer and showed increased progression-free survival in high-risk patients with relapsed Hodgkin lymphoma receiving autologous stem cell transplantation. This study aims to investigate the role of relapsed Hodgkin lymphoma after using Pembrolizumab. This study was conducted for 80 patients with relapsed Hodgkin lymphoma who received Pembrolizumab and 50 patients had completed treatment with 40% complete response. In conclusion, Pembrolizumab showed a good response in patients with relapsed Hodgkin lymphoma.

Sensitive MRD Detection from Lymphatic Fluid after Surgery in HPV-Associated Oropharyngeal Cancer.

Our goal was to demonstrate that lymphatic drainage fluid (lymph) has improved sensitivity in quantifying postoperative minimal residual disease (MRD) in locally advanced human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) compared with plasma, and leverage this novel biofluid for patient risk stratification. We prospectively collected lymph samples from neck drains of 106 patients with HPV (+) OPSCC, along with 67 matched plasma samples, 24 hours after surgery. PCR and next-generation sequencing were used to quantify cancer-associated cell-free HPV (cf-HPV) and tumor-informed variants in lymph and plasma. Next, lymph cf-HPV and variants were compared with TNM stage, extranodal extension (ENE), and composite definitions of high-risk pathology. We then created a machine learning model, informed by lymph MRD and clinicopathologic features, to compare with progression-free survival (PFS). Postoperative lymph was enriched with cf-HPV compared with plasma (P < 0.0001) and correlated with pN2 stage (P = 0.003), ENE (P < 0.0001), and trial-defined pathologic risk criteria (mean AUC = 0.78). In addition, the lymph mutation number and variant allele frequency were higher in pN2 ENE (+) necks than in pN1 ENE (+) (P = 0.03, P = 0.02) or pN0-N1 ENE (-) (P = 0.04, P = 0.03, respectively). The lymph MRD-informed risk model demonstrated inferior PFS in high-risk patients (AUC = 0.96, P < 0.0001). Variant and cf-HPV quantification, performed in 24-hour postoperative lymph samples, reflects single- and multifeature high-risk pathologic criteria. Incorporating lymphatic MRD and clinicopathologic feature analysis can stratify PFS early after surgery in patients with HPV (+) head and neck cancer. See related commentary by Shannon and Iyer, p. 1223.

Integrated strategies for chemotherapy cycles in nasopharyngeal carcinoma patients: Real-world data from two epidemic centers guiding decision-making.

Two cycles of induction chemotherapy (IC) followed by 2 cycles of platinum-based concurrent chemoradiotherapy (CCRT) (2IC+2CCRT) for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is widely adopted but not evidence-confirmed. This study aimed to determine the clinical value of 2IC+2CCRT regarding efficacy, toxicity and cost-effectiveness. This real-world study from two epidemic centers used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses. The enrolled patients were divided into three groups based on treatment modality: Group A (2IC+2CCRT), Group B (3IC+2CCRT or 2IC+3CCRT) and Group C (3IC+3CCRT). Long-term survival, acute toxicities and cost-effectiveness were compared among the groups. We developed a prognostic model dividing the population into high- and low-risk cohorts, and survivals including overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) were compared among the three groups according to certain risk stratifications. Of 4,042 patients, 1,175 were enrolled, with 660, 419, and 96 included in Groups A, B and C, respectively. Five-year survivals were similar among the three groups after PSM and confirmed by IPTW. Grade 3-4 neutropenia and leukocytopenia were significantly higher in Groups C and B than in Group A (52.1% vs. 41.5% vs. 25.2%; 41.7% vs. 32.7% vs. 25.0%) as were grade 3-4 nausea/vomiting and oral mucositis (29.2% vs. 15.0% vs. 6.1%; 32.3% vs. 25.3% vs. 18.0%). Cost-effective analysis suggested that 2IC+2CCRT was the least expensive, while the health benefits were similar to those of the other groups. Further exploration showed that 2IC+2CCRT tended to be associated with a shorter PFS in high-risk patients, while 3IC+3CCRT potentially contributed to poor PFS in low-risk individuals, mainly reflected by LRRFS. In LA-NPC patients, 2IC+2CCRT was the optimal choice regarding efficacy, toxicity and cost-effectiveness; however, 2IC+2CCRT and 3IC+3CCRT probably shortened LRRFS in high- and low-risk populations, respectively.

Ixazomib in the treatment of relapsed multiple myeloma

Ixazomib (NINLARO, Takeda Pharmaceutical Company Limited) is the first oral proteasome inhibitor which approved in combination with lenalidomide and dexamethasone (IRd) for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib is a boron-containing selective and reversible proteasome inhibitor that have high antitumor activity with excellent safety. This combination was approved based on the results from the phase 3, double-blind, placebo-controlled TOURMALINE-MM1 study, which demonstrated a 35% improvement in progression-free survival (PFS) for IRd versus placebo-Rd: median: 20.6 vs 14.7 months; hazard ratio (HR): 0.74, P = 0.012. PFS was improved in both high-and standard-risk cytogenetics subgroups with median PFS in high-risk patients 21.4 vs 9.7 months (HR 0.54; P = 0.021) and in standard-risk patients 20.6 vs15.6 months (HR 0.64; P = 0.007). The addition of ixazomib to Rd regimen was associated with minimal additional toxicity. Common grade ≥3 adverse events with ixazomib include gastrointestinal adverse events, rash, and thrombocytopenia. No significant inhibition of neuronal cell survival protease HtrA2/Omi was noted in response on ixazomib treatment in vitro that explains its minimal clinical peripheral neuropathy. The present review addresses the current knowledge regarding the clinical use of ixazomib in relapsed myeloma patient and the prospects for further expansion of therapeutic indications.

Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle–Invasive Bladder Cancer

Transcripts from the four genes encoding cyclin D1, MCM7, TRIM29, and UBE2C have previously been included in gene expression signatures for outcome prediction in stage Ta/T1 urothelial carcinomas. We investigated the prognostic value of the protein expressions in Ta/T1 urothelial carcinomas patients. We used four different tissue microarrays (TMAs) with a total of 859 Ta/T1 urothelial carcinomas from Danish, Swedish, Spanish, and Taiwanese patient cohorts with long-term follow-up. Protein expression was measured by IHC, and antibody specificity was validated by Western blotting. We found the expression of cyclin D1, MCM7, TRIM29, and UBE2C to be significantly associated with progression to muscle-invasive bladder cancer (log-rank test; P < 0.001) in the Danish training cohort (n = 283). Multivariate Cox regression analysis identified cyclin D1 (P = 0.003), TRIM29 (P = 0.001), and UBE2C (P < 0.001) as independent prognostic markers. The prognostic value of the four proteins was validated in a joint validation cohort from Sweden, Spain, and Taiwan (n = 576). Computer-assisted image analysis of the prognostic markers produced results comparable to those obtained by manual scoring. Finally, a four-protein maximum-likelihood classifier was trained on the Danish training cohort and applied to the validation cohort. The four protein markers may help optimize treatment of patients with Ta/T1 bladder cancer. Additional prospective studies are needed for further validation of their clinical relevance.

Early Response to Methotrexate, Vincristine and Procarbazine Chemotherapy-Adapted Strategy for Primary CNS Lymphoma: Omitted Radiotherapy for Patients Achieving Complete Response in Interim Analysis.

AbstractAbstract 2719The aim of this study was to evaluate treatment outcomes and prognostic factors of high-dose MVP (methotrexate, vincristine and procarbazine) chemotherapy and response adapted intensification therapy in primary central nervous system lymphoma (PCNSL). We evaluated the expression of Epstein-Barr virus (EBV)-encoded RNA in tissue and pretreatment EBV-DNA in whole blood. Forty patients with PCNSL who treated with high-dose MVP chemotherapy were retrospectively reviewed. Additional radiotherapy or autologous stem cell transplantation were performed for the patients who could not achieve complete response (CR) at interim response (Figure 1). The median age was 55 years. CR rate was 50.0% and objective response rate was 80.0%. Two-year overall survival (OS) was 59.8% and 2-year progression free survival (PFS) was 47.1%. Grade 3 or 4 neutropenia was seen in 19 of 40 (47.5%) patients and thrombocytopenia was developed in 13 (32.5%) patients. Treatment-related mortality was occurred in 4 patients. Delayed neurotoxicity was occurred in 4 patients. Poor performance status, elevated cerebrospinal fluid protein level and whole blood EBV-DNA positivity showed inferior OS (P=0.036, P=0.022, P=0.013, respectively, Figure 2). We detected whole blood EBV-DNA in 10 (29.4%) of 34 patients. It was related with poor OS and PFS in high risk patients according to International Extranodal Lymphoma Study Group scores (P=0.015, P=0.027, respectively). This study suggests that high-dose MVP chemotherapy without intrathecal chemotherapy and response adapted strategy may be an effective regimen for the newly diagnosed PCNSL. Whole blood EBV-DNA positivity could predict the inferior outcome in high-risk patients. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Novel Agents to Improve Outcome of Allogeneic Transplantation for Patients with Multiple Myeloma

Over the last few decades therapy for multiple myeloma has improved remarkably. In particular, the introduction of novel agents has allowed improved response rates prior to, and after, stem cell transplantation with extension of progression-free survival in high-risk patients. Nevertheless, most patients relapse, leaving multiple myeloma an incurable disease. Despite being the only treatment option that has real curative potential, allogeneic transplantation has not shown its superiority to autologous transplantation due to its high morbidity and mortality rates. This review highlights how novel agents might help to reduce treatment-related mortality and to improve tumor control prior to and post-allogeneic stem cell transplant, which will hopefully result in significantly improved long-term disease control, and maybe a cure following this treatment modality.

Androgen-deprivation therapy does not impact cause-specific or overall survival after permanent prostate brachytherapy

To determine if androgen-deprivation therapy (ADT) has an impact on cause-specific, biochemical progression-free, or overall survival after prostate brachytherapy. From April 1995 through June 2002, 938 consecutive patients underwent brachytherapy for clinical Stage T1b to T3a (2002 AJCC) prostate cancer. All patients underwent brachytherapy more than 3 years before analysis. A total of 382 patients (40.7%) received ADT with a duration of 6 months or less in 277 and more than 6 months in 105. The median follow-up was 5.4 years. Multiple clinical, treatment, and dosimetric parameters were evaluated as predictors of cause-specific, biochemical progression-free, and overall survival. The 10-year cause-specific, biochemical progression-free, and overall survival rates for the entire cohort were 96.4%, 95.9%, and 78.1%, respectively. Except for biochemical progression-free survival in high-risk patients, ADT did not statistically impact any of the three survival categories. A Cox linear-regression analysis demonstrated that Gleason score was the best predictor of cause-specific survival, whereas percent-positive biopsies, prostate volume, and risk group predicted for biochemical progression-free survival. Patient age and tobacco use were the strongest predictors of overall survival. One hundred two patients have died, with 80 of the deaths a result of cardiovascular disease (54) and second malignancies (26). To date, only 12 patients have died of metastatic prostate cancer. After brachytherapy, androgen-deprivation therapy did not have an impact on cause-specific or overall survival for any risk group; however, ADT had a beneficial effect on biochemical progression-free survival in high-risk patients. Cardiovascular disease and second malignancies far outweighed prostate cancer as competing causes of death.

Low Progression-Free Survival for High-Risk Patients Treated with Reduced-Intensity Conditioning Regimen Allogeneic Stem Cell Transplantations with Volunteer Unrelated Donors.

Reduced-intensity conditioning regimens (RICR) are increasingly used before allogeneic stem cell transplantation (SCT) for patients not eligible for myeloablative conditioning. The relapse and survival rates after RICR allogeneic SCT were studied in 19 high-risk patients treated between February 2002 and December 2004. Ten males and 9 females with a median age of 47 years (15–55) received PBSC transplantation from a 10/10 (n=15) or 9/10 HLA antigen-matched donor (n=4). Acute leukemia was the main diagnoses (n=12; 6 AML and 6 ALL), the other diagnoses were 3 multiple myeloma, 2 CML, 1 NHL, 1 CLL. All patients had high-risk disease: 12 had second or > 2 complete remission, 5 second partial remission and 2 refractory disease. The preparative regimen consisted of cumulative dose of Busulfan 8mg/kg, Fludarabine 150 mg/m2 and ATG 7.5 mg/kg (Thymoglobulin, Genzyme, Lyon, France). Graft-versus-host disease (GVHD) prophylaxis regimen consisted of cyclosporine A and short-course methotrexate. Median follow-up was 14 months (5–39 months). Engraftment was complete in all but 2 patients with refractory disease and 14 patients achieved 100% donor CD3 (median 56 days, range 18–123). Grade 2 to 3 acute GVHD was seen in 3 (16%) patients, no grade 4 acute GVHD was observed. Grade 1 chronic GVHD was seen in 1 patient. Nine pts relapsed at a median time of 9.5 months, 3 pts had never reached a full CD3 donor chimerism. Twelve pts are alive, seven pts in complete remission, 2 pts with relapsed disease. Three pts relapsed and achieved a subsequent complete remission by chemotherapy, one of them received a second SCT, one a DLI and one other developed hepatic cGVHD and didn't receive DLI. Five pts died from recurrent disease, One pt died from cerebral toxoplasmosis and one other from cerebral hemorrhage due to a secondary poor graft function. Survival rate was 73% (95% CI 0.52–0.93) at 6 months and 60% (95% CI 0.38–0.83) at 1 year. PFS rate was 73% (95% CI 0.52–0.93) at 6 months and 33% (95% CI 0.09–0.57) at 1 year. In conclusion, in this cohort of pts, the progression-free survival is unsatisfactory. This can be explained by the advanced stage diseases and the low incidence of cGVHD, probably due to high immunosuppressive treatment. A less intensive immunosuppressive protocol can be tested to improve the results in this particular group of patients. [Display omitted] [Display omitted]

Impact of supplemental external beam radiotherapy and/or androgen deprivation therapy on biochemical outcome after permanent prostate brachytherapy

To evaluate the impact of supplemental external beam radiotherapy (EBRT) and/or androgen deprivation therapy (ADT) on 8-year biochemical outcome after permanent prostate brachytherapy. Between April 1995 and January 2001, 668 consecutive patients underwent brachytherapy using either (103)Pd or (125)I for clinical Stage T1b-T3aNxM0 (2002 American Joint Committee on Cancer) adenocarcinoma of the prostate gland. No patient underwent seminal vesicle biopsy or pathologic lymph node staging. The median follow-up was 58.6 months. Biochemical progression-free survival was defined by the American Society for Therapeutic Radiology and Oncology consensus definition. The clinical, treatment, and dosimetric parameters evaluated for biochemical progression-free survival included supplemental EBRT, ADT, patient age, clinical stage, Gleason score, preimplant prostate specific antigen (PSA), risk group, percentage of positive biopsies, isotope used, prostate volume, planning volume, percentage of target volume receiving 100%, 150%, and 200% of prescribed dose, minimal percentage of dose covering 90% of target volume, tobacco status, hypertension, and diabetes. For the entire group, the actuarial 8-year biochemical progression-free survival rate was 98.2%, 98.4%, and 88.2% for low-, intermediate-, and high-risk patients, respectively, with a median PSA level of <0.1 ng/mL for all risk groups and ADT and EBRT subgroups. At last follow-up, only 5 patients (0.8%) had died of metastatic prostate cancer. In multivariate analysis, Gleason score, percentage of positive biopsies, and ADT predicted for biochemical outcome in high-risk patients. In low- and intermediate-risk patients, none of the evaluated variables predicted for biochemical outcome. For the entire population, pretreatment PSA level, Gleason score, ADT, and clinical stage predicted for 8-year biochemical progression-free survival, with the percentage of positive biopsies approaching statistical significance. Prostate brachytherapy results in a high probability of 8-year biochemical progression-free survival for low-, intermediate-, and high-risk patients. Although the role of supplemental EBRT could not be adequately evaluated in high-risk patients, it did not improve biochemical outcome in low- and intermediate-risk patients. However, ADT resulted in a statistically significant improvement in progression-free survival for high-risk patients.