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Wednesday, June 3, 2020

By Sarah LaCorte

The results from the largest study to date analyzing chronic lymphocytic leukemia (CLL) treatment patterns among U.S. Veterans Health Administration (VHA) patients were presented at the ASCO 2020 Annual Meeting (Abstract e19339). The study described the pharmacoepidemiology of three novel agents—ibrutinib, idelalisib, and venetoclax—and traditional chemotherapies/chemoimmunotherapies (CT/CIT) in the VHA.

The first novel agent for use in CLL was approved in 2014; however, the extent of novel agent uptake in the VHA is largely unknown. There is a documented connection between CLL and U.S. veterans: The Health and Medicine Division (HMD) concluded in its report "Veterans and Agent Orange: Update 2008" released July 24, 2009, that there is sufficient evidence of an association between exposure to Agent Orange, herbicides, and CLL, including hairy cell leukemia and other chronic B-cell leukemias. As a result, VA expanded CLL to include all chronic B-cell leukemias as related to exposure to Agent Orange or other herbicides during military service. VA's final regulation recognizing this association took effect on October 30, 2010.

To investigate novel agent uptake in the VHA, the researchers conducted a retrospective study of 26,879 adults with CLL in the VHA from October 1, 2013, to May 31, 2018. Patients came from all 18 Veterans Integrated Service Networks, spanning all 50 states and U.S. territories. All were followed for at least 6 months.

The analyzed data was extracted from the VHA electronic health record. Descriptive statistics were used to summarize baseline characteristics, CLL treatments, next therapies, and secondary complications.

A total of 3,670 patients out of the 26,879 patients received at least one of 12 CLL therapies of interest. All of the patients had a median age of 69 years (47% were 65+ and 26% were 75+), with a median age-adjusted Charlson comorbidity score of 6. Also, 6 percent had a history of exposure to Agent Orange.

Ibrutinib accounted for 89 percent of the novel agent use. Ibrutinib use across all lines of therapy (LOTs) increased sevenfold over the study period. For the next LOT after Ibrutinib, venetoclax (42%) and idelalisib (30%) were the most common therapies.

Across all LOTs, traditional CT/CIT use declined steadily over the study period. However, in 2018, there were still 17 percent of patients receiving CT/CIT. Ibrutinib was the most common therapy for the next LOT in these patients (43-74%). Incidence of diffuse large B-cell lymphoma post-index was 2-6 times higher in patients on CT/CIT than those on ibrutinib. Other secondary complications were similar between ibrutinib and CT/CIT.

The authors concluded that based on this data, "there has been a major shift in the treatment of CLL, with fast adoption of novel agents in the VHA from 2013 to 2018. The impact of this shift on health care resource use and cost burden in the VHA will need to be examined."

Sarah LaCorte is a contributing writer.

Tuesday, June 2, 2020

By Veronica Hackethal

Anti-CD19 CAR T-cell therapy is associated with highly durable remissions in relapsed B-cell lymphoma and chronic lymphocytic leukemia (CLL), according to research presented at the 2020 ASCO Annual Meeting (Abstract 3012). The study has the longest follow-up to date on this topic, and reports long-term remissions lasting over 9 years in B-cell lymphoma.

"These long-term remissions raise the possibility, but do not prove that CAR T cells could be curative for some B-cell lymphomas, including diffuse large B-cell lymphoma, low-grade lymphomas, and CLL," first author Kathryn Cappell, MD, PhD, told Oncology Times. She is associated with the National Cancer Institute.

Notably, the study showed that long-term adverse effects with anti-CD19 CAR T cells were rare, manageable, and usually mild. B-cell depletion and low immunoglobulin levels represented the most common long-term adverse effects. Nine percent of participants developed infections requiring hospitalization 6 months or longer after receiving CAR T cells. Sixteen percent of patients developed second malignancies on long-term follow-up, according to Cappell.

"This rate of second malignancies is not higher than expected given that the patients in the study had extensive previous chemotherapy treatments before enrolling in this study," she said.

The study included 43 patients who received Anti-CD 19 CAR-T therapy between 2009 and 2015. Anti-CD19 CAR T cells is a genetically engineered treatment that uses the patient's own T cells to express synthetic chimeric antigen receptors (CARs) targeted against the CD19 antigen found on malignant and normal B lymphocytes.

Overall, 63 percent of participants had chemotherapy-refractory lymphoma. Before entering the study, they had undergone a median of four previous lines of therapy. Most had aggressive lymphoma (89%, 28 patients), while 20 percent had low-grade lymphoma (8 patients), and 25 percent had chronic lymphocytic leukemia (CLL, 7 patients).

The study treatment consisted of conditioning with cyclophosphamide plus fludarabine chemotherapy, followed by anti-CD19 CAR T-cell therapy. Researchers divided the cohort into three treatment groups which differed by the CAR T-cell production process and conditioning chemotherapy dose. The median CAR T-cell dose per kilogram was 2 x 106, which varied by cancer type (aggressive lymphoma: 2 x 106 ; low-grade lymphoma: 3 x 106 ; CLL: 3.5 x 106).

Three patients required re-treatment, and the analysis included 46 CAR T-cell treatments in total.

Results showed an overall remission rate (ORR) of 76 percent, of whom 54 percent had complete remission and 22 percent had partial remission. Participants who were able to achieve complete remission had significantly higher median peak blood levels of CAR T cells compared to those who did not reach complete remission (86 CAR+ cells/µL vs 16 CAR+ cells/µL, respectively, P= 0.0041).

Analyses excluding three patients who could not be evaluated for response showed an overall response rate of 81 percent, of whom 58 percent showed complete remission and 23 percent showed partial remission.

Veronica Hackethal is a contributing writer.

Tuesday, June 2, 2020

​By Sarah LaCorte

A retrospective study evaluated health care resource utilization (HRU)/costs associated with venetoclax treatment in various sequencing scenarios, including prior use of ibrutinib for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The results were presented at the ASCO 2020 Annual Meeting (Abstract e19354).

Since it was approved by the FDA in March 2016, ibrutinib has become an established standard of care for CLL/SLL patients across all lines irrespective of patient age, comorbidities, and risk status. When the FDA approved venetoclax in May 2019, researchers found a need to understand the real-world treatment sequencing of targeted oral agents, and the implication of sequencing on HRU/costs.

In the study presented at ASCO 2020, Kerry Anne Rogers, MD, a hematologist-oncologist at the Ohio state Comprehensive Cancer Center, and co-authors identified adults with CLL/SLL with venetoclax with Optum Clinformatics Extended Data Mart De-Identified Databases between April 11, 2015, through June 30, 2019. They excluded investigational combination therapies.

The index date was the start of the first venetoclax-based line of therapy (index LOT) and the baseline period was the 12-month period pre-index. Mean all-cause HRU/costs per patient per month (PPPM) were calculated during the index LOT and the venetoclax ramp-up period, defined as the first 30 days post-index.

The study included 11,861 CLL/SLL patients who received ≥1 LOT: 121 patients (1.0%) were treated with venetoclax, including 25 patients (64.0% single agent) using venetoclax in first line (1L cohort), 30 (90.0% single agent) in second line (2L cohort), and 66 (83.3% single agent) in third line or later (3L+ cohort). The mean age was 71.6 years and 33.1 percent of patients were female. The mean baseline Quan-Charlson Comorbidity Index score was 4.7 and median follow-up from the start of 1L was 25.3 months. Median duration of index LOT was 4.2 months.

The majority of 2L+ venetoclax patients were previously treated with ibrutinib (2L: 56.7%, 3L+: 74.2%). Patients in all 3 cohorts had frequent outpatient (OP) visits PPPM during their index LOT (1L: 4.58; 2L: 4.75; 3L+: 5.71). Total costs PPPM during the index LOT were highest in the 1L cohort (1L: $21,762; 2L: $17,697; 3L+: $20,900), driven by higher OP costs (1L $9,402; 2L: $5,633; 3L+: $7,701). Increased total costs PPPM were observed during venetoclax ramp-up (1L: $31,707; 2L: $21,036; 3L+: $25,362). Compared to the overall 2L cohort, those treated with ibrutinib in 1L had lower total costs PPPM (index LOT: $15,350; V ramp-up: $15,882).

"The study provides valuable insights as we further explore the combination and sequencing of novel agents with complementary mechanisms of actions in CLL, such as ibrutinib and venetoclax. While this is a descriptive study, we found that the results reinforce our hypothesis and suggest that previous treatment with ibrutinib may help to reduce costs in subsequent treatment with venetoclax," said Qing Huang, PhD, MHS, second author on the study and Director, Real-World Value & Evidence, Oncology, Janssen Oncology. 

The authors concluded that the highest costs PPPM were observed for venetoclax treatment in the 1L. Prior treatment with ibrutinib was common among 2L and 3L+ CLL/SLL patients treated with venetoclax. Importantly, the study revealed that among 2L venetoclax patients, those previously treated with ibrutinib in 1L had $2,347 and $5,154 lower costs PPPM during 2L and venetoclax ramp-up, respectively, suggesting that previous ibrutinib treatment may help reduce costs in subsequent treatment.

Sarah LaCorte is associate editor.

Tuesday, June 2, 2020

By Sarah LaCorte

A study presented at the ASCO 2020 Annual Meeting used a simple global adverse event score to compare toxicity burden of ibrutinib (IB) versus the combination of bendamustine with rituximab (BR) in older patients with chronic lymphocytic leukemia (CLL) (Abstract e20004).

Ibrutinib, a Bruton's tyrosine kinase inhibitor, was FDA-approved for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) in 2016. Since then, it has shown superior progression-free survival compared with bendamustine and rituximab in CLL patients 65 years or older in a randomized phase III trial (N Engl J Med 2018; DOI: 10.1056/NEJMoa1812836).

In the phase III trial, patients receiving IB had higher rates of atrial fibrillation (AFIB) and hypertension (HTN); BR patients had higher rates of hematologic toxicity. The study showed that differences in treatment duration for BR (6 cycles) and IB (until progression) complicated adverse event (AE) comparisons.

Amy S. Ruppert, MAS, PhD, from The Ohio State University Comprehensive Cancer Center, and her research team wanted to investigate these adverse event comparisons further. To do so, they used an exploratory approach to compare toxicity burden between arms and provide assessment of atrial fibrillation, hypertension and infections (INF) in a clinical trial funded by the NIH (NCT01886872).

The researchers studied 537 patients as they began therapy, with 176 taking BR and 361 on IB. The 68 percent of patients on BR completed all 6 cycles. Adverse events (AE) were reported for each of cycles 1-6 and then every 3 cycles until progression or nonprotocol CLL therapy. Only grade (gr) 3-4 AEs were reported thereafter until death. Ruppert and her team then calculated a simple global AE score for each patient by summing grades of all grade 1-4 AEs and dividing by the number of cycles over which AEs were submitted.

At a median follow-up of 38 months, 64 percent of patients remained on IB. Treatment discontinuation for AE occurred in 10 percent and 14 percent of BR and IB patients. Overall, median AE score was 1.8 (interquartile range (IQR) 0.9-3.3) and 3.8 (IQR 2.3-5.9) in BR and IB arms (p < 0.01). For cycles 1-6, median AE score was 6.2 (IQR 3.8-9.0) and 4.8 (IQR 3.0-7.2) in BR and IB arms (p < 0.01).

In the IB arm, researchers found the median AE score post 6 cycles decreased significantly to 3.4 (IQR 1.9-5.6) (p < 0.01). Grade 3 or higher cumulative rates of AFIB, HTN, and INF over time appear in the table. A total of 100 patients (26/176 BR, 74/361 IB) had 137 severe INF (39% respiratory: 16 BR, 37 IB; 25% skin: 3 BR, 31 IB; 12% GU: 3 BR, 13 IB; 25% other: 12 BR, 22 IB). There were 7 grade 5 INF (3 BR, 4 IB), however none confirmed fungal.

The researchers concluded from the results that there was no difference in treatment discontinuation rates for AE. The overall toxicity burden was significantly higher for IB, although IB toxicity burden decreased after 6 cycles. Toxicity burden was significantly higher in cycles 1-6 for patients receiving BR. Ruppert and authors stated that the risk of severe AFIB, HTN, and INF is highest in the first year of IB. Overall, the main takeaway from the study was that a simple AE score provides valuable information, especially when evaluating regimens of varying length.

Sarah LaCorte is associate editor.

Sunday, May 31, 2020

By Sarah LaCorte

Research presented at the ASCO 2020 Annual Meeting found that causes of death in newly diagnosed chronic lymphocytic leukemia (CLL) patients differ according to their CLL-IPI risk group (Abstract 8026).

For most patients with newly diagnosed CLL, the ultimate cause of death for most patients and its relationship to co‐morbid health conditions is poorly defined. A previous study published in the British Journal of Haemetology found that CLL progression and CLL-related complications (infections and second malignancies) were the leading cause of death (COD) in a prospective cohort of CLL patients (2017;

Yucai Wang, MD, PhD, a hematologist/oncologist at the Mayo Clinic, and authors followed-up on the findings of this study and examined if COD differs according to International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) risk group in patients with newly diagnosed CLL.

The CLL-IPI stratifies patients with CLL into four risk categories with distinct prognosis. The CLL-IPI was developed using patient data from before use of targeted agents such as ibrutinib and venetoclax, which are known to have greater efficacy in patients with TP53 alterations.

Wang's group reviewed data of 1,276 patients identified from the Mayo Clinic CLL database who were diagnosed with CLL between January 2000 and December 2019 and seen within 1 year of diagnosis. The researchers used Gray's test to analyze cumulative incidences of cause-specific death. Deaths from different causes were treated as competing events and the researchers excluded deaths from unknown causes.

The median age at diagnosis was 63 years (range 24-92), and 880 (69%) were male. Based on CLL-IPI score, 449 (35%) had low-risk disease, 443 (35%) had intermediate-risk disease, and 384 (30%) had high/very high risk disease. Median follow-up time for the study was 6 years; 286 deaths occurred. The COD was CLL progression in 99 (35%), infection in 16 (6%), second malignancy in 47 (16%), CLL-unrelated in 59 (21%), and unknown in 65 (23%) patients.

The rates of death due to CLL progression were higher (17.3% at 5 years; 30.3% at 10 years) than the rates due to CLL-related complications (5.7% at 5 years; 12.9% at 10 years) or due to CLL-unrelated causes (8.6% at 5 years; 16.9% at 10 years) in the CLL-IPI high/very high risk group, but not the CLL-IPI low- or intermediate-risk group (Table). A higher CLL-IPI risk group was associated with a higher rate of death due to CLL progression (P< 0.001), as well as a higher rate of death due to CLL-related complications (P = 0.013), and CLL-unrelated causes (P< 0.001).

Based on these results, Wang and colleagues concluded that causes of death in newly diagnosed CLL patients differ according to their CLL-IPI risk group. They stated that "in patients with high/very high risk CLL, improving CLL disease control with novel agents seems justified. In patients with low/intermediate risk CLL, there should be increased efforts to reverse immune dysfunction to reduce infections and second malignancies."

Sarah LaCorte is associate editor.