ONCOLOGY & hematology
Ibrutinib plus Venetoclax for Chronic Lymphocytic Leukemia
Inhibitors of Bruton tyrosine kinase (BTK) or B-cell lymphoma 2 (BCL2) protein are highly active as single agents in the treatment of chronic lymphocytic leukemia (CLL). Now, investigators report a phase II industry-sponsored trial of ibrutinib plus venetoclax in previously untreated patients with poor-risk features: del(17p), TP53 mutation, del(11q), unmutated IGHV, or age >65.
Ibrutinib 420 mg/day was administered for 3 months, after which venetoclax was initiated with a 4-week dosing ramp-up (to mitigate risk for tumor lysis syndrome) to a target dose of 400 mg/day. Combination therapy was continued for 24 four-week cycles.
Of 80 patients enrolled, 88% achieved complete remission after 12 cycles; 61% were minimal residual disease (MRD)–negative by multicolor flow cytometry, increasing to 89% after 18 cycles. Almost all patients had one or more poor-risk biomarkers. There were no unexpected toxicities; three patients had laboratory but not clinical evidence of tumor lysis syndrome.
CommentComplete remission with single-agent ibrutinib or venetoclax is achieved in only a minority of patients despite continuous therapy. Combining these agents deepens response, with most showing MRD-negative complete remission. Longer follow-up will be necessary to assess the duration of response after the 2-year treatment period and patients’ response to subsequent therapy with these or other agents targeting BTK or BCL2. This combination is also highly active in relapsed or refractory mantle cell lymphoma (NEJM JW Oncol Hematol Jun 2018 and N Engl J Med 2018; 378:1211) and provides an improved, chemotherapy-free option for poor-risk CLL.
— Michael E. Williams, MD, ScM
reviewing Jain N et al. N Engl J Med 2019 May 30; 380:2095
Venetoclax plus Obinutuzumab for Chronic Lymphocytic Leukemia
Obinutuzumab (Obin) plus the oral alkylating agent chlorambucil (Chl) is a standard initial treatment option for chronic lymphocytic leukemia (CLL) patients who are elderly or have coexisting illnesses. To compare response rates and outcomes with standard Obin plus Chl versus Obin plus the Bcl2 inhibitor venetoclax (Ven), investigators conducted an industry-funded, international, randomized, phase III trial in 432 previously untreated patients with coexisting illness and Cumulative Illness Rating Scale scores >6. Twelve 28-day cycles were administered, with no crossover upon disease progression or therapy-related toxicity.
The rate of complete remission was improved with Ven/Obin versus Chl/Obin (49.5% vs. 23.1%; P<0.001). At a median follow-up of 28 months (median 17 months postcompletion of therapy), progression-free survival (PFS; the primary endpoint) was also improved with Ven/Obin versus Chl/Obin (88.2% vs. 64.1%), as was minimal residual disease-negativity results at 3 months after treatment completion in peripheral blood (75.5% vs. 35.2%) and bone marrow (56.9% vs. 17.1%). Half of patients in each group had grade 3/4 neutropenia; grade 3/4 infections occurred in 17.5% of Ven/Obin recipients and 15.0% of Chl/Obin recipients. All-cause mortality was 9.3% with Ven/Obin and 7.9% with Chl/Obin.
CommentFixed-duration combination therapy demonstrated improved PFS with Ven/Obin, consistent with other trials of Ven plus rituximab in CLL and mantle cell lymphoma. Patients with poorer-risk biomarkers including TP53 mutation or deletion or unmutated IGHV status also benefited from Ven/Obin. It is encouraging that high response rates and durable disease control can be achieved with fixed-duration rather than continuous single-agent Ven therapy. The durability of the responses and the outcomes upon subsequent therapy will be of great interest.
— Michael E. Williams, MD, ScM
reviewing Fischer K et al. N Engl J Med 2019 Jun 6; 380:2225
Front-Line Ibrutinib plus Rituximab for Chronic Lymphocytic Leukemia
The oral Bruton tyrosine kinase inhibitor (TKI) ibrutinib (IBR) has demonstrated high activity in previously untreated and relapsed patients with chronic lymphocytic leukemia (CLL; NEJM JW Oncol Hematol Feb 2016 and N Engl J Med 2015; 373:2425; NEJM JW Oncol Hematol Sep 2014 and N Engl J Med 2014; 371:213).
Now, investigators have conducted a planned interim analysis of an industry-funded, multicenter, open-label, randomized phase III trial, in which 529 previously untreated CLL patients (age, ≤70 years) were randomized 1:2 to standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) for 6 cycles versus TKI therapy with IBR (420 mg/d in 4-week cycles) plus rituximab (R) in cycles 2–6. Patients with del(17p) were excluded owing to known poor response to FCR.
Three-year progression-free survival (PFS; the primary endpoint) was improved with IBR-R versus FCR (89.4% vs. 72.0%; hazard ratio, 0.35; P<0.001), as was overall survival (OS; 98.8% vs. 91.5%; HR, 0.17; P<0.001); 3-year PFS was significantly improved with IBR-R versus FCR for patients with the unfavorable biomarkers del(11q22.3) and IGHV unmutated status but was similar for those with the prognostically favorable IGHV mutation. Conversely, the rate of complete remission was lower with IBR-R versus FCR (17.2% vs. 30.3%), as was the rate of minimal residual disease negativity at 12 months (8.3% vs. 59.2%). Toxicities included atrial fibrillation in 7.4% of IBR-R recipients and 3.2% of FCR recipients and grade 3 hemorrhage in 1% of IBR-R recipients. There were 10 deaths among FCR recipients, most due to CLL progression or treatment-related toxicity, and 4 deaths among IBR-R recipients.
CommentSignificant PFS and OS benefits were observed for targeted, noncytotoxic treatment with IBR-R; the FCR responses were improved versus previous clinical trials, suggesting that the IBR-R benefit was not related to poor outcomes with FCR in the current trial. A lower rate of atrial fibrillation was observed with IBR compared with results of earlier phase III trials, possibly due to exclusion of patients older than 70 in the current trial. As the authors note, the benefit of adding R to IBR is unclear, given that outcomes were not improved in a prior phase III trial for IBR-R versus IBR alone (NEJM JW Oncol Hematol Feb 2019 and N Engl J Med 2018; 379:2517).
— Michael E. Williams, MD, ScM
reviewing Shanafelt TD et al. N Engl J Med 2019 Aug 1; 381:432
Frontline Immunotherapy for Myeloma
The immunomodulatory drug lenalidomide (L) plus weekly dexamethasone (d) is a standard induction regimen (Ld) for patients with myeloma who are ineligible for autologous stem cell transplant (SCT) consolidation therapy. Now, investigators report an interim analysis of a phase III, multicenter, pharmaceutical company–sponsored trial in which newly diagnosed patients were randomized to ongoing 28-day cycles of Ld alone (the control group) or Ld plus the anti-CD38 monoclonal antibody daratumumab (LdD, the intervention group); treatment continued until toxicity or disease progression occurred.
A total of 737 patients were randomized equally to receive a median of 27 LdD cycles versus 22 Ld cycles. During a median follow-up period of 28 months, disease progression occurred at 31.9 months in the control group and had not yet occurred in the intervention group (hazard ratio, 0.56). Rates of complete response, patient survival at 30 months, and achievement of minimal residual disease negativity were all significantly higher with LdD. The intervention group also had more frequent grade 3 to 4 neutropenia (50% vs. 35.3%) and pneumonia (13.7% vs. 7.9%)
CommentThe FDA recently approved daratumumab in combination with lenalidomide and dexamethasone for treating newly diagnosed multiple myeloma in patients ineligible for SCT. The addition of "Dara" to Ld induction improved outcomes, an improvement analogous to that observed with anti-CD20 monoclonal antibody combinations for B-cell lymphomas. Further analysis of low-risk versus high-risk cytogenetic subgroup responses will be of interest, as will study of daratumumab added to current three-drug induction regimens.
— Michael E. Williams, MD, ScM
reviewing Facon T et al. N Engl J Med 2019 May 30; 380:2104
Frontline Daratumumab for Transplant-Eligible Myeloma Patients
High-dose melphalan and autologous stem-cell transplant (SCT) consolidation following induction treatment is a standard of care for newly diagnosed, SCT-eligible, multiple myeloma patients. To assess the benefit of combining the anti-CD38 monoclonal antibody daratumumab with induction therapy for these patients, European investigators conducted an industry-sponsored, multicenter, randomized, open-label, phase III trial (CASSIOPEIA) of bortezomib, thalidomide, and once-weekly dexamethasone (VTd) with or without daratumumab prior to stem-cell collection and SCT consolidation.
A total of 1085 patients were equally randomized. Patients in both arms who achieved partial remission or better 100 days post-SCT underwent a second randomization to maintenance daratumumab or observation.
The stringent complete response rate at day 100 following SCT (the primary endpoint) was significantly higher with daratumumab plus VTd than with VTd alone (29% vs. 20%; P=0.001). Median progression-free survival was not reached for either arm but was improved with daratumumab plus VTd, as were achievement of complete response or better and residual disease negativity. Grade 3/4 neutropenia was more common with daratumumab; the frequency of grade 3/4 infections was similar in both arms.
CommentOutcomes were improved by incorporating daratumumab with an SCT regimen, as was recently observed by adding daratumumab to induction therapy in non-SCT eligible myeloma patients (NEJM JW Oncol Hematol Sep 2019). As noted by editorialists, remaining issues include determining the optimal dose and duration of daratumumab, identifying approaches to improve safety, and further optimizing therapy for high-risk myeloma subsets.
— Michael E. Williams, MD, ScM
reviewing Moreau P et al. Lancet 2019 Jul 6; 394:29 and Hofmeister CC et al. Lancet 2019 Jul 6; 394:3
Recombinant Zoster Vaccine Effective After Autologous Stem Cell Transplant
The recombinant zoster vaccine, approved in the U.S. in 2017, contains a novel adjuvant and was previously shown to be highly effective (>90%) in immunocompetent persons 50 years of age and older (NEJM Infect Dis Jan 2018). A good immune response to the vaccine was also seen in a prior phase I/IIa study involving immunosuppressed autologous hematopoietic stem cell transplant (HSCT) recipients at increased risk for herpes zoster infection (Blood 2014; 124:2921).
Now, investigators have conducted an industry-funded, international, randomized, phase III study to examine the clinical efficacy of the recombinant vaccine versus placebo in 1846 immunosuppressed, autologous HSCT recipients. Approximately 53% had multiple myeloma, 42% had lymphoma, and 2% had leukemia. Patients received 2 doses of recombinant zoster vaccine or placebo (50 to 70 days and 1 to 2 months after that, respectively) following autologous HSCT.
At a median follow-up of 21 months beginning 1 month after dose 2, confirmed herpes zoster infections occurred in fewer vaccine recipients than placebo recipients (49 vs. 135; vaccine efficiency, 68.2%; P<0.001). Vaccine recipients had significantly fewer herpes zoster–related complications, including less post-herpetic neuralgia and fewer hospitalizations. Expected adverse reactions (e.g., injection site reactions and fever) occurred more often in vaccine recipients, but serious adverse events were similar in both groups.
CommentMany physicians have seen enough cases of disseminated zoster infection to recommend up to 1 year of prophylaxis after autologous HSCT. However, because cases continue to be observed after the period of prophylaxis, vaccination is an attractive option. Although the 68.2% efficacy observed in this study is lower than the >90% efficacy observed in immunocompetent populations, it is still significant. Major questions remain, including those about insurance coverage for recipients younger than age 50, the duration of protection, and possible need for booster doses. Nonetheless, I intend to recommend this vaccine for autologous HSCT recipients.
— Daniel Kaul, MD
reviewing Bastidas A et al. JAMA 2019 Jul 9; 322:123
A New Option for Treatment-Refractory Multiple Myeloma
Multiple myeloma patients who are refractory to the three major classes of targeted therapies — proteasome inhibitors, immunomodulatory agents, and the anti-CD38 monoclonal antibody daratumumab — have limited treatment options and poor survival.
Now, investigators have conducted an industry-sponsored, multicenter, open-label, phase IIb trial of the exportin 1 inhibitor selinexor in 123 multiple myeloma patients with prior exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent (median number of prior regimens, 7). Of these patients, 102 had undergone prior stem-cell transplantation, 2 had received prior CAR-T cell therapy, and 118 were refractory to carfilzomib, pomalidomide, and daratumumab. Patients received selinexor (80 mg) plus dexamethasone (20 mg) orally on days 1 and 3 each week in 4-week cycles; treatment continued until disease progression, discontinuation, or death.
The overall response rate (≥50% decrease in myeloma paraprotein level; the primary endpoint) was 26%, with 2 patients achieving complete remission; an additional 13% achieved minimal response. Median progression-free survival was 3.7 months. Overall survival was 15.6 months in patients achieving minimal response or better, 5.9 months in those with stable disease, and 1.7 months in those with progressive or non-evaluable disease. Grade 3 or 4 adverse events included thrombocytopenia, anemia, hyponatremia, and neutropenia.
CommentThis trial identifies selinexor as a novel agent with unique mechanisms of action that, when combined with dexamethasone, has relevant clinical activity in heavily pretreated myeloma patients, including those with poor-risk biomarkers. Based on these results, selinexor was recently approved by the FDA for multiagent-refractory myeloma.
— Michael E. Williams, MD, ScM
reviewing Chari A et al. N Engl J Med 2019 Aug 22; 381:727
Colorectal Cancer Risk and Baseline Polyp Findings
Surveillance colonoscopy for colorectal cancer (CRC) is recommended at intervals determined by the most advanced lesions at baseline examinations. Guidelines from international professional organizations are generally concordant with regards to surveillance for high-risk polyps, but they diverge for nonadvanced adenomas and serrated polyps, owing partly to sparse evidence.
To assess the risk for CRC according to polyp subtype, investigators conducted a retrospective cohort study of nearly 123,000 patients in the Nurses’ Health Study 1, the Nurses’ Health Study 2, or the Health Professionals Follow-Up Study who underwent flexible sigmoidoscopy or colonoscopy between 1989 and 2013.
At a median follow-up of 10 years, the CRC risks associated with various adenoma subtypes versus no polyps were as follows:
Any adenoma: adjusted hazard ratio, 2.61; P<0.001
Advanced adenomas (≥10 mm, high-grade dysplasia, or villous histology): aHR, 4.07; P<0.001
Nonadvanced adenomas: aHR, 1.21; P=0.52
Any serrated polyp: aHR, 1.52; P=0.05
Large serrated polyps (≥10 mm): aHR, 3.35; P=0.008
Small serrated polyps (<10 mm): aHR, 1.25; P=0.38
CommentThe need for more intensive surveillance for high-risk polyps is not controversial, and these results reaffirm current guideline recommendations. However, the most notable findings in this study pertain to the much more prevalent nonadvanced adenomas and small serrated polyps, for which metachronous CRC risks were not significantly different than having no polyps at baseline. Assuming high-quality baseline colonoscopies, these data support lengthening surveillance intervals for average-risk patients with low-risk adenomas or small serrated polyps to up to 10 years.
— Charles J. Kahi, MD, MS
reviewing He X et al. Gastroenterology 2019 Jul 11; [e-pub]
Tumor Seeding at Colonoscopy: A Cause of Metachronous Colorectal Cancer?
Seeding of colorectal cancer (CRC) cells due to manipulation of the primary tumor during colonoscopy may contribute to metachronous CRC after surgical resection, but this has not been well studied.
Researchers from the Netherlands identified 22 metachronous CRC cases that were diagnosed 6 to 42 months after surgical resection. In five cases, the likely cause was attributed to tumor seeding because biopsy or polypectomy occurred at the anatomic location of the subsequently detected metachronous CRC after endoscopic manipulation of the primary tumor. For three patients with available tissue, the molecular signatures of the primary and metachronous CRC were identical.
In a separate review of 2147 surgically resected CRC cases, the risk for tumor seeding during colonoscopy was estimated at 0.3%–0.6%.
In a separate analysis of 26 CRC patients, flushing the working channel of colonoscopes used for tumor biopsy showed persistent tumor cells in the effluent in 81%. This was not resolved with repeat flushing, and tumor cells were demonstrated on the tip of needles reinserted after flushing. In one case, investigators successfully demonstrated viability of the contaminant tumor cells, which had a molecular profile similar to the primary tumor.
CommentAs tumor seeding is a possible contributor to metachronous CRC, risk-mitigating measures should be considered, such as performing all polypectomies before a CRC is biopsied and not reusing the forceps with which the cancer was biopsied. These measures are being implemented at my institution. In addition, it is important that clinicians not misinterpret these findings as implying that no additional endoscopic interventions should occur when a CRC is detected and biopsied. Synchronous polyps must be resected and the colon cleared of other lesions at the time of the baseline procedure. Synchronous neoplasia is one of the factors most consistently associated with occurrence of metachronous CRC, and the risk of leaving polyps behind far outweighs that of potential tumor seeding.
— Charles J. Kahi, MD, MS
reviewing Backes Y et al. Gastroenterology 2019 Aug 13; [e-pub]
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