Patients with chronic lymphocytic leukemia (CLL) experienced a lower incidence of cardiovascular-related toxicities and a lower overall toxicity burden following treatment with acalabrutinib (Calquence) compared with ibrutinib (Imbruvica), according to results of a post-hoc analysis of the phase 3 ELEVATE-RR study (NCT02477696) that were presented during the 2021 ASH Annual Meeting.

This analysis aimed to further evaluate Bruton tyrosine kinase (BTK) inhibitor–associated adverse events (AEs) and the toxicity profile of ibrutinib and acalabrutinib in the multicenter, open-label study. This trial demonstrated noninferiority and tolerable safety after randomizing previously treated patients with CLL 1:1 to acalabrutinib at 100 mg by mouth twice daily or ibrutinib at 420 mg by mouth once daily.

The primary end point of ELEVATE-RR was noninferiority by independent review committee–assessed progression-free survival, and secondary end points included incidence of any-grade atrial fibrillation (afib)/flutter, grade 3 or higher infection, Richter transformation, and overall survival.

“Event-based analyses demonstrated a higher BTK inhibitor­–related toxicity burden with ibrutinib in this head-to-head trial,” John F. Seymour, AM, from the Peter MacCallum Centre and the Royal Melbourne Hospital in Melbourne, Australia, said in his presentation. “Exposure-adjusted assessments of afib/flutter, hypertension, and bleeding events demonstrated a lower cardiovascular-related toxicity burden with acalabrutinib compared to ibrutinib. Cumulative incidences of hypertension and afib/flutter were also lower with acalabrutinib in patients without a prior history of these events.”

After a median follow-up of 41 months, investigators assessed events of clinical interest in 268 patients receiving acalabrutinib and 265 patients receiving ibrutinib. Of these events, any-grade afib/flutter, hypertension, and bleeding were statistically higher with ibrutinib. Exposure-adjusted incidence and exposure-adjusted time with these events were about 1.5 to 4.1 times higher with ibrutinib.

Other common BTK–related AEs noted for being significantly higher with ibrutinib in this analysis were any-grade diarrhea (46% vs 35%), arthralgia (23% vs 16%), back pain (13% vs 8%), muscle spasms (13% vs 6%), and dyspnea (12% vs 4%). Incidence of any-grade contusion and urinary tract infection (UTI) were also higher with ibrutinib. Besides UTI, exposure-adjusted incidence and exposure-adjusted time with events were about 1.4 to 13.1 times higher with ibrutinib.

The only AEs with statistically higher incidence with acalabrutinib were any-grade headache and cough, which occurred at rates of 35% and 29%, respectively, with acalabrutinib versus 20% and 21% with ibrutinib. Headache with acalabrutinib was associated with 1.6 times higher exposure-adjusted incidence and exposure-adjusted time with events, and cough was associated with 1.2 times higher exposure-adjusted incidence and exposure-adjusted time with events.

Investigators observed a longer median time to onset of any-grade afib/flutter with acalabrutinib versus ibrutinib, at 28.8 months and 16.0 months, respectively. Any-grade hypertension had a similar median time to onset for both therapies. Concomitant medication use for afib/flutter or hypertension for all patients was less common with acalabrutinib.

The cumulative incidence of any-grade afib/flutter and hypertension were consistently lower with acalabrutinib up to 36 months, according to Seymour. Additionally, incidence of these 2 AEs was lower in patient subgroups regardless of the number of prior therapies, age, and having no prior history of afib/flutter and hypertension. For patients with no prior history of afib/flutter or hypertension, there was a lower cumulative incidence in patients receiving acalabrutinib compared with ibrutinib (afib/flutter HR, 0.37; 95% CI, 0.20-0.67; hypertension HR, 0.23; 95% CI, 0.11-0.48).

With any-grade bleeding events, there was a similar time to onset for acalabrutinib and ibrutinib. Incidence was lower for the acalabrutinib arm regardless of age and in patients with 1 to 3 prior lines of therapy. Few patients in either treatment arm required dose modification due to bleeding events. Also, fewer patients given acalabrutinib used concomitant medication for bleeding events than patients given ibrutinib. The cumulative incidence of any-grade bleeding over 36 months was lower with acalabrutinib.

At the data cutoff, 43% of patients on the ELEVATE-RR trial were still receiving treatment. Patients on ELEVATE-RR had previously been treated for CLL with 1 or more prior lines of therapy, presence of del(17p) and/or 11q, and an ECOG performance status of 2 or less. Those enrolled were stratified by their del(17p) status, ECOG performance status, and number of prior therapies.

Seymour JF, Byrd JC, Hillmen P, et al. Characterization of Bruton tyrosine kinase inhibitor (BTKi)-related adverse events in a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia (CLL). Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3721.

Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. 

. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210

Articles

Acalabrutinib was linked to a lower incidence of cardiovascular-related toxicities and overall toxicity burden compared with ibrutinib in patients with chronic lymphocytic leukemia.

Acalabrutinib Decreases Toxicity Burden in Patients with CLL

Patients with relapsed/refractory large B-cell lymphoma (LBCL) experienced a clinically meaningful improvement in quality of life (QoL) after 100 days of treatment with axicabtagene ciloleucel (axi-cel; Yescarta). Complete findings on the use of the autologous anti-CD19 CAR T-cell therapy as a second-line treatment were recently presented in an analysis of the phase 3 ZUMA-7 trial (NCT03391466) during the 2021 ASH Annual Meeting and Exposition.

Using the patient-reported outcome (PRO) instruments EORTC QLQ-C30, EQ-5D-5L, and Work Productivity and Activity Impairment: General Health (WPAI), investigators reported patients treated with axi-cel (n = 165) in the QoL analysis set assessed at day 100 achieved a statistically significant difference in mean change of scores from baseline in favor of axi-cel vs SOC (n = 131). Patients had a change from baseline in favor of axi-cel at day 100 in the prespecified PRO end points for EORTC QLQ-C30 physical functioning (

 < .0001), EORTC QLQ-C30 global health status/QoL (

 < .0001), and EQ-5D-5L visual analog scale (VAS; 

“Sensitivity analyses controlling for covariates and patterns of missingness showed similar results with retained significance at day 100,” said Mahmoud Elsawy, MD, MSc, an assistant professor in the Division of Hematology at Dalhousie University in Halifax, Nova Scotia. “[Furthermore] the mean estimated scores for the axi-cel arm returned to or exceeded the scores at baseline by day 100 to day 150 vs month 9 or later in the SOC arm.”

EORTC QLQ-C30 is a cancer-specific 30-item questionnaire that includes global health status and functional and symptom scales. The questionnaire has functional scales for physical, role, emotional, cognitive, and social functioning. Symptom scales include fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.

EQ-5D-5L is a general questionnaire with 5 QoL domains plus a global assessment. The domains include mobility, self-care, usual activities, pain/discomfort, and anxiety and depression. The VAS provides a rating of global assessment of the patient’s state of health on the day of assessment.

WPAI measures work productivity and activity impairment. The instrument has scales for absenteeism, presenteeism, overall work impairment, and activity impairment.

Eligible adult patients underwent an initial disease assessment prior to treatment and were reassessed at day 50, 100, 150, and month 9, then every 3 months thereafter from randomization up to 24 months or at the time of an event-free survival (EFS) event, whichever occurred first. Prespecified hypotheses for 3 PRO domains (EORTC QLQ-C30 physical functioning, EORTC QLQ-C30 global health status/QoL, and EQ-5D-5L VAS) were tested using a mixed-effect model with repeated measures at day 100 and subsequent time points if previous time points were found to be statistically insignificant.

Investigators defined clinically meaningful change as 10 points for each EORTC QLQ-C30 score, 7 points for the EQ-5D-5L VAS score, and 0.06 for the EQ-5D-5L index. Exploratory analyses on other domains of EORTC QLQ-C30 and EQ-5D-5L were also performed.

Axi-cel showed a favorable statistically significant change from baseline (

 < .05) at day 100 in the EORTC QLQ-C30 scales for nausea and vomiting, diarrhea, insomnia, and appetite loss. Statistically significant changes from baseline were also seen in role functioning at days 100 and 150. Social functioning, fatigue, and dyspnea measures all moved favorably in a statistically significant manner for axi-cel at day 100, day 150, and month 9.

Regarding the WPAI PRO instrument, investigators reported that patients treated with axi-cel had statistically significant (

 < .05) lower mean absenteeism, and lower mean activities impairment at day 100 compared with those receiving SOC treatment.

ZUMA-7 enrolled a total of 359 adult across 77 sites in the United States, Canada, Europe, and Israel. Patients were randomized 1:1 to receive either conditioning chemotherapy plus axi-cel or SOC investigator-selected platinum-based chemotherapy for at least 2 cycles. Responding patients in the SOC arm proceeded to high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) and nonresponding patients were given additional treatment off of study protocol.

Patients with relapsed/refractory LBCL who a maximum of 1 year removed from their first-line therapy were eligible for the trial. Eligible patients also needed to intend to proceed to HDT-ASCT. Optional steroid-bridging therapy was permitted.

The primary end point of the trial was EFS by blinded central review. The key secondary end points were objective response rate and overall survival. Additional secondary end points included progression-free survival, safety, and PROs.

Baseline patient demographics for patients included in the QoL analysis set were comparable. Among the 165-patient axi-cel group, 28% were at least 65 years old vs 32% in the SOC group (n = 131). Most patients in both arms were primary refractory (72% vs 68%, respectively) and were negative for double/triple hit status per investigator (62% vs 58%, respectively). Investigators noted a second-line age-adjusted International Prognostic Index score of 2 or 3 in 42% of the axi-cel arm and 43% of the SOC arm.

“Score comparisons at later timepoints warrant cautious interpretation because attrition due to disease progression, new lymphoma therapy, or death was disproportionately higher on the SOC arm and may select patients with the best outcomes,” Elsawy said. “[Nonetheless] the superior clinical outcomes and patient experience with axi-cel over SOC should help inform treatment choices in second-line relapsed/refractory LBCL.”

Elsawy M, Chavez JC, Avivi I, et al. Patient-reported outcomes in a phase 3, randomized, open-label study evaluating the efficacy of axicabtagene ciloleucel (axi-cel) versus standard of care therapy in patients with relapsed/refractory large b-cell lymphoma (ZUMA-7). Paper presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 430.

Axicabtagene ciloleucel improved the quality of life in patients with relapsed/refractory large B-cell lymphoma receiving the agent as a second-line therapy.

Patients with LBCL Experience Improved Quality of Life Following Axi-Cel Treatment 

Despite the majority of patients in a recent study stating that their oncologist told them that their multiple myeloma was incurable, a substantial amount believed that they could still be cured. Further, prognostic awareness was associated with higher rates of psychosocial distress and symptom burden and lower quality of life (QOL) in patients with myeloma.

These findings were recently presented at the 2021 ASH Annual Meeting and Exposition.

“Multiple myeloma is an incurable hematologic malignancy requiring long-term continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life, psychosocial distress and prognostic awareness by line of therapy are lacking,” study author Betsy O’Donnell, MD, director of Lifestyle Medicine and medical oncologist in the Multiple Myeloma Disease Center at Massachusetts General Hospital said while presenting the findings.

In an attempt to fill this research need, O’Donnell and her team conducted a cross-sectional, multi-site study of 180 patients with multiple myeloma. Sixty patients were newly diagnosed, 60 underwent 2-3 lines of therapy, and 60 underwent 4 or more lines of therapy. Individuals on maintenance therapy were excluded. A validated questionnaire was used to analyze patient’s feelings of QOL, symptom burden, fatigue, psychological distress, and perceptions of prognosis.

The average age of study participants was 68, 52% were female, and 89% were white.

Findings revealed that there was no significant difference in QOL, symptom burden, fatigue, depression, anxiety, or PTSD symptoms by line of therapy. Overall, 24% of patients were experiencing clinical depression, 24% anxiety and 24% PTSD.

The majority (84%) of patients reported that it was “extremely” or “very” important to know about their prognosis, with 66% stating that they received adequate information on their prognosis.

“Patients reported that prognostic information was extremely or very helpful in making decisions about treatment, coping with disease and preparing for the future,” O’Donnell explained.

Interestingly, 85% of patients reported that their oncologist told them that their cancer was curable, but only 31% acknowledged that they were terminally ill, and 42% reported that they believed their cancer was curable.

Patients who were receiving 2-3 lines of therapy were more likely than those getting their first line of therapy to acknowledge their terminal illness (36.7% versus 19.6%; 

=0.045) and that their disease was not curable (90% versus 75.9%; 

“With regard of treatment goals, nearly 23% of all patients report that their primary goal of therapy was cure, and 18% reported that their oncologists’ primary goal was cure,” O’Donnell said. “Although the majority reported that their oncologist had told them their cancer was incurable, a substantial proportion still report that they believe that they were curable.”

The patients who acknowledged their terminal illness reported higher rates of depression, anxiety, and symptom burden, as well as lower QOL.

O’Donnell concluded, “Multiple myeloma patients undergoing treatment experience impaired quality of life and elevated psychological distress across the disease and continued irrespective of their line of therapy … Interventions are needed to improve patient QOL, reduce their psychological distress and cultivate adaptive coping strategies that may help improve the patient experience over the multiple myeloma disease course.”

O’Donnell E, Shapiro Y, Nadeem O, et al. Quality of life, psylogical distress, and prognostic awareness in patients with multiple myeloma. Presented at: Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 4082

Patients with myeloma who reported that their disease was incurable had lower quality of life. However, many patients may also have misconceptions about the curability of their disease. 

Prognostic Awareness Impacts QOL in Patients With Myeloma 

The FDA has approved the drug abatacept (Orencia) in combination with certain immunosuppressants to prevent moderate to severe acute-graft-vs-host disease (aGVHD) for patients at least 6 years of age who have received unrelated donor hematopoietic stem cell transplant. Abatacept is designed to inhibit specific protein targets and prevent donor T-cells from attacking healthy tissues posttransplant.

Abatacept is the first agent to receive regulatory approval for prevention of this condition, and the decision was supported by real-world evidence as a component detailing its clinical efficacy.

“Acute graft versus host disease can affect different parts of the body and become a serious post-transplant complication,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “By potentially preventing the disease, more patients may successfully undergo bone marrow or stem cell transplantation with fewer complications.”

The double-blind, placebo-controlled GGVHD-1 trial compared the use of abatacept with placebo in a total of 186 patients who underwent stem cell transplantation from a matched unrelated donor. All patients also received immunosuppressive drugs. The research measured severe, defined as grade III to IV, aGVHD-free survival, overall survival (OS), and moderate-severe, defined as grade II to IV, aGVHD-free survival 6 months following transplantation.

Results showed that although abatacept did not significantly improve GVHD-survival vs placebo, at 87% vs 75%, respectively, it did improve OS rate, at 97% and 84%, respectively. With regard to moderate-severe aGVHD-free survival, patients in the investigative arm experienced a 50% rate vs 32% for those in the control arm.

Additional efficacy evidence came from the registry-based, GVHD-2 study, which leveraged real-world findings from the Center for International Blood and Marrow Transplant Research in patients who underwent stem cell transplantation from a mismatched unrelated donor.

In this effort, investigators evaluated outcomes from a total of 54 patients who recieved abatacept to prevent aGVHD, in combination with standard immunosuppressive drugs, compared with 162 patients who received standard immunosuppressive drugs alone. The study measured OS at 6 months post transplantation. OS rates in the investigative and control arms were 98% and 75%, respectively.

Regarding safety, the toxicities that were most frequently reported with abatacept included anemia, hypertension, cytomegalovirus (CMV) reactivation/CMV infection, fever, pneumonia, nosebleed, decreased levels of CD4 lymphocytes, increased levels of magnesium in the blood, and acute kidney injury.

The FDA also noted that those who receive the agent should be monitored for Epstein-Barr virus reactivation per institutional practices and they should receive preventative medication for Epstein-Barr virus infection prior to treatment initiation and for 6 months following transplantation. Patients should also be monitored for CMV infection/reactivation for 6 months after transplant.

FDA approves first drug to prevent graft versus host disease. News release. FDA. December 15, 2021. Accessed December 15, 2021. https://bit.ly/33zfoxR

Abatacept is now available for use in combination with certain immunosuppressants to prevent moderate to severe acute-graft-versus-host disease for select patients who have received unrelated donor hematopoietic stem cell transplant.

FDA Approves Abatacept to Proactively Treat Acute Graft-Versus-Host-Disease

Patients with polycythemia vera (PV) who have controlled hematocrit (HCT) levels, but elevated white blood counts (WBC) are at an increased risk of thrombotic events (TEs), according to a presentation of the REVEAL study (NCT02252159) at the 2021 ASH Annual Meeting. The findings suggest that by controlling WBC in patients with PV, the risk of TEs may also be controlled.

Specifically, findings from the REVEAL study demonstrated that an elevated WBC count of >11 109/L at HCT levels greater than 45% increased risk of TE (HR, 1.81; 95% CI, 0.993-3.301; 

 = .0526). An elevated WBC count of greater than 12 109/L also increased risk of TE (HR, 1.95; 95% CI, 1.066-3.554;

=.0300). Other covariates observed in the analysis were consistent with previously demonstrated trends.

“PV in particular is associated with thrombotic risk,” explained Aaron Gerds, MD, MS, of Cleveland Clinic Taussig Cancer Institute, in a presentation of the findings. “[In] this particular analysis we look[ed] to evaluate the association between elevated blood counts and occurrence of thrombotic events in patients with polycythemia vera using this REVEAL database.”

The REVEAL study is a multicenter, noninterventional, prospective observational study, which enrolled patients with PV from US community practice and academic centers. Key inclusion for this trial included a clinical diagnosis of PV per physician judgement. Patients also needed to be under physician supervision for management of PV and older than 18 years of age.

Exclusion criteria included a life expectancy of under 6 months, a history of allogeneic hematopoietic cell transplantation or a plan to receive this treatment, or history of splenectomy. Enrolled patients need to have at least 3 laboratory blood count values post enrollment. In addition, patients who developed TE following enrollment but did not have laboratory values within 6 months of TE enrollment were not included.

Researchers collected data at diagnosis, at a 6-month period, and during follow-up 3 years from last patient enrollment. The data collection period was between July 2014 and August 2019.

The main study threshold was to determine the association between blood counts and TEs.

For patients with elevated HCT and TEs, main observed associations included age (HR, 1.03; 95% CI, 1.010-1.046; 

 = .0026), male sex (HR, 0.54; 95% CI, 0.362-0.799; 

 = .0021), history of TE (HR, 2.49; 95% CI, 1.667-3.717; 

 < .0001), and HCT greater than 45% vs <45% (HR, 1.84; 95% CI, 1.234-2.749; 

Similar associations were linked with elevated WBC and PLT counts (>400 x 109/L). In regard to WBC, there was an increased risk for age (HR, 1.02; 95% CI, 1.007-1.042; 

 = .0068), male sex (HR, 0.58; 95% CI, 0.393-0.858, 

 = .0063), history of TE (HR, 2.42; 95% CI, 1.623-3.619; 

 < .0001), and HCT >45% vs <45% (HR, 2.35; 95% CI, 1.598-3.465; 

Regarding increased PLT counts, there was an increased risk for age (HR, 1.03; 95% CI, 1.010-1.046; 

 = .0022), male sex (HR, 0.62; 95% CI, 0.416-0.914; 

 = .0162), history of TE (HR, 2.45; 95% CI, 1.640-3.654; 

 <.0001), and HCT >45% vs <45% was (HR, 1.60; 95% CI, 1.088-2.359; 

A total of 104 (4.7%) of 2271 enrolled patients experienced a post-enrollment thrombotic event. Thirty of these patients experienced an arterial TE event, and 76 experienced a venous TE event. The most common arterial TE event was transient ischemic attack (n = 5) and the most common venous TE event was deep vein thrombosis (n = 37).

Laboratory parameters were modeled with consideration for sex, age, disease duration, and TE status at time of enrollment as a baseline covariates and treatment history (either hydroxyurea or other PV treatments). At the end of follow-up laboratory test, blood counts were included a binary time-dependent covariates using the following thresholds: HCT greater than 45%, WBC greater than 11 x 109/L, and PLT greater than 400 x 109/L.

Researchers determined laboratory values including linear interpolation. Furthermore, researchers evaluated alternative thresholds with the following values: WBC (<7 x 109/L 

Researchers used the Cox proportional hazards model to calculate hazard ratios (HRs) and 

values of <.05 were considered statistically significant. Except for WBC, PLT, and HCT, all covariates were measured at baseline.

“This analysis of the REVEAL study, which is the largest real-world cohort of patients with PV prospectively studied, demonstrated that there was an association between elevated blood counts and thrombotic events, particularly a white blood cell count over 11 in all patients,” Gerds concluded.

He added that “We should be moving beyond the conventional risk models, and start to include additional factors—whether we're talking about blood counts, allele burdens, even lymphocyte counts, perhaps—to make better models to predict thrombosis. Because thrombosis is associated with inferior outcomes overall in these populations, if we can make better models, we can intervene in higher-risk populations to improve their overall outcomes.”

Gerds A, Mesa R, Burke J, et al. A real-world evaluation of the association between elevated blood counts and thrombotic events in polycythemia vera (analysis of data from the REVEAL study). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 239.

A presentation at the 2021 ASH Annual Meeting revealed a significant association between elevated white blood counts and thrombotic events among patients with polycythemia vera and controlled hematocrit levels. 

 White Blood Count May Be Key to Controlling Thrombotic Events in Polycythemia Vera 

Patients with chronic lymphocytic leukemia (CLL) who received frontline ibrutinib (Imbruvica)-rituximab (Rituxan; IR) compared with fludarabine, cyclophosphamide, and rituximab (FCR) experienced improved quality of life (QOL), which was sustained throughout continuous ibrutinib therapy.

“The results of this quality-of-life analysis support the use of frontline Ibrutinib in previously untreated younger CLL patients,” said lead investigator Priyanka Pophali, MD, assistant professor at the University of Washington Carbone Cancer Center, during a presentation of the findings at the 2021 ASH Annual Meeting.

The randomized, phase 3 ECOG-ACRIN clinical trial E1912 established IR as the standard of care for patients with CLL age 70 or younger in the frontline setting, and quality of life was a secondary endpoint. Investigators compared continuous IR with time-limited FCR therapy, “due to the differing profile of treatment-related toxicities over the short and long-term,” Pophali explained.

Patients who were enrolled in the trial completed the Functional Assessment of Cancer Therapy-General (FACT-G) and Leukemia subscale at randomization (baseline), 3, 6, and 12 months post-randomization, and every 6 months for 2 years regardless of disease status.

Investigators measured the primary outcome with the FACT-Leukemia Trial Outcome Index (TOI), which is a 31-item questionnaire with scores ranging from 0 to 124.

“The FACT-Leukemia trial outcome index is a summation of the factsheet physical well-being, functional well-being, and leukemia subscales,” Pophali said.

The primary endpoint was the difference in FACT-Leukemia TOI change scores from randomization to 12 months between patients treated with continuous therapy (arm A) and patients treated with time-limited therapy (arm B). Comparisons between the treatment arms were performed using two-sample t tests; linear mixed effects models were used to estimate the trajectories of patient-reported outcome (PRO) scores.

The PRO data was provided at baseline and 12 months for 65.8% of patients in arm A and 67.4% in arm B.

At enrollment, there were no significant differences in the baseline FACT-Leukemia TOI scores (mean ± SE) between the 2 arms: A (93.27 ± 1.03); B (92.68 ± 1.38; 

= 0.73). The FACT-Leukemia TOI score improved from baseline to 12 months in both arms.

The change scores from baseline to 12 months were not significantly different between arm A (7.59 ± 1.09) and arm B (8.22 ± 1.44; 

= 0.73). Change in FACT-Leukemia TOI from baseline to 3 months was 5.77 ± 0.77 and 4.06 ± 1.18 (

= .22); and from baseline to 6 months was 6.87 ± 0.87 and 8.01 ± 1.44 (

The improvement in FACT-Leukemia TOI scores was maintained in both treatment arms after 6 months, with no major difference in total FACT-Leukemia TOI scores between the 2 arms over the first 36 months.

An analysis of the FACT subscales showed physical well-being improved in arm A (0.37 ± 0.22) and declined in arm B (-0.92 ± 0.39) from baseline to 3 months (

 = .004 for difference in physical well-being change between arms). There were, however, no significant differences in functional well-being and FACT-Leukemia subscales from baseline to 3, 6, and 12 months.

Overall, the results showed that quality of life improvement is maintained during IR continuous therapy, and since the regimen was previously shown to improve PFS and OS over FCR, these findings further support the use of IR in previously untreated patients with CLL, concluded Pophali.

Pophali P, Wang X, Zhao F, et al. Quality of life in patients <= 70 years of age with chronic lymphocytic leukemia treated frontline with ibrutinib-rituximab versus fludarabine cyclophosphamide rituximab: analysis from ECOG-ACRIN E1912. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021. Atlanta, GA. Abstract 1562.

Ibrutinib, both in the frontline setting and in the form of continuous treatment, was associated with improved quality of life over chemoimmunotherapy for patients with chronic lymphocytic leukemia. 

Patients With CLL Experience Better Quality of Life With Ibrutinib Plus Rituximab 

When patients with cancer experience depression and anxiety, they are less likely to enroll in oncology clinical trials, according to findings presented at the 2021 American Society of Hematology Annual Meeting and Exposition.

“Although thousands of cancer clinical trials are available today, engagement remains low, with only 2% to 7% of cancer patients in the United States participating in cancer clinical trials,” study author Victoria Morris, PhD, research director at the Cancer Support Community, said while presenting the findings. “There are many systemic and person-level factors that can contribute to this lack of engagement…However, another contributing factor that can impact participation is attitudinal barriers such as fear-based perceptions about what it means to participate in a cancer clinical trial.”

The observational, cross-sectional study involved 625 patients with blood cancer (46.4% myeloma; 19.5% chronic lymphocytic leukemia; 11.4% non-Hodgkin lymphoma; 4.0% acute myeloid leukemia; 3.5% Hodgkin lymphoma; 3.2% chronic myeloid leukemia; 1.6% acute myeloid leukemia; 1.3% myeloproliferative neoplasm; 7.4% other lymphoma; and 1.8% other leukemia).

Participants filled out Cancer Support Community’s Cancer Experience Registry, which includes sociodemographic and clinical data as well as ranking on a scale of 0 (strongly disagree) to 4 (strongly agree) on 8 statements about clinical trials. Participants also completed the Anxiety and Depression subscales from the Patient-Reported Outcomes Measurement Information System (PROMIS-29v2.0).

PROMIS responses were averaged to determine the level of depression and anxiety on a 5-point scale, while 8 hierarchical regression models were examined—one for each of the clinical trial perception variables—to determine the impact that depression and anxiety had on how patients think of clinical trials. Clinical history and sociodemographic variables were controlled for.

“Regression models indicated that psychosocial distress comprised of both depression and anxiety accounted for a significant amount of variance in 7 of the 8 clinical trial perceptions, above and beyond the controls,” Morris said. “Depression and anxiety—2 psychosocial factors that are highly prevalent in the cancer space—can bias attention in was that alter perceptions, thus potentially playing a role in trial perceptions.”

The average anxiety and depression score was 1.91 (SD = .93). These psychosocial effects were predictors for the following perceptions:

“I would be unable to fulfill trial requirements due to logistical barriers.” (15% of participants responded “agree” or “strongly agree”; 

“I don’t trust the medical establishment and fear I will be used as a ‘Guinea pig.’” (13%; 

“I am uncomfortable being randomly assigned.” (53%; 

“I fear receiving a placebo (for example, a sugar pill) in a clinical trial.” (49%; 

“I don’t understand what clinical trials are.” (8%; 

“There are no clinical trials available in my community.” (30%; 

“I fear side effects that might come with treatment on a clinical trial.” (46%; 

The only perception that anxiety and depression did not impact, however, was the belief that insurance would not cover the clinical trial.

These findings show that clinicians should consider psychosocial barriers when discussing the options of clinical trial participation to patients.

“While attempts to alter perceived barriers to participation in cancer clinical trials often focus on information dissemination to address misconceptions about cancer clinical trials, the present study indicates that underlying person-level psychological factors may shape perceptions about cancer clinical trials and need to be considered,” Morris said.

This study should just be the first of more research that should analyze the magnitude and directionality of these findings, according to Morris.

“But one thing is clear: the decision about whether to engage in a cancer clinical trial is complex and multi-faceted, and any and all barriers to participation need to be considered so that we can better empower patients in their treatment decision making.”

Rogers K, Morris V, Miller M, LeBlanc T. The relationship between depression, anxiety, and clinical trial perceptions among patients with hematologic cancer. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 1901.

If patients with cancer experience depression or anxiety, it can result in low clinical trial enrollment. 


Patient Mental Health Key Factor in Cancer Clinical Trial Perception

Children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia experienced similar efficacy outcomes and a more favorable safety profile after receiving tisagenlecleucel (Kymriah) in a real-world registry data, compared with data from the ELIANA trial (NCT02435849).

Findings from this registry, which were presented at the 2021 ASH Annual Meeting and Exposition, also demonstrated that safety and efficacy outcomes were consistent in patients both younger than and older than 18 years.

In particular, tisagenlecleucel “is an autologous T cell product directed against CD-19,” Samuel John, MD, division chief of hematology/oncology and Distinguished Chair in Pediatric Oncology Research at UT Southwestern Medical Center, said during the presentation. “The T cells identify and kill the patient's leukemia cells.”

In this noninterventional, prospective study, researchers analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry of 561 patients up to age 25 years with relapsed/refractory B-cell acute lymphoblastic leukemia.

“Acute lymphoblastic leukemia is the most common form of childhood cancer,” John said during the presentation. “This specific subtype, B-ALL, accounts for greater than 80% of cases. Although the majority of pediatric patients with B-ALL have excellent outcomes, approximately 15% to 20% of patients will relapse. Outcomes for these patients are poor, with the five-year survival estimate of approximately 50%. Treatment options in the relapsed setting include intensified chemotherapy regimens, stem cell transplant and use of novel immunotherapy including chimeric antigen receptor T cells.”

All patients in this registry were treated with tisagenlecleucel after August 30, 2017, either in the United States or Canada.

“Tisagenlecleucel was approved in 2017 for the treatment of pediatric and young adult patients up to the age of 25 with relapsed refractory B-ALL,” John explained in the presentation. “The CIBMTR collects data on these patients who received commercial tisagenlecleucel. Early real-world data for tisagenlecleucel from the CIBMTR registry reported similar efficacy to that in the ELIANA clinical trial with no new safety signals.”

Researchers performed age-specific analyses in patients younger than (n = 389) and older than 18 years (n = 172) at the time tisagenlecleucel was administered. Efficacy was evaluated in patients with at least 12 months of follow-up and included duration of response, best overall response of complete remission, relapse-free survival, event-free survival and overall survival. Patients who completed the first assessment at 100 days were part of the safety evaluation in this study. There were several adverse events of interest including neurotoxicity and cytokine release syndrome, both of which were graded using the ASTCT criteria.

Although most patient characteristics were comparable at baseline, there were some factors that differed by age group. Patients 18 years and older had greater disease burden than those younger than 18, as shown by lower rates of morphologic complete remission and minimal residual disease negativity before infusion. In addition, older patients were more likely to be heavily pretreated before infusion versus the younger patients.

Efficacy in this study was assessed in 410 patients for a median of 25.9 months (range, 12-43.6). Overall response rates in this registry were 86.8% compared with 82.3% from the ELIANA trial. Minimal residual disease status information was available for 195 patients, of whom 97.9% were considered minimal residual disease negative.

Event-free survival at 12 months in patients with available efficacy information was 52.6% compared with 57.2% from the ELIANA trial. In addition, the duration of response at 12 months was comparable in both studies (61.4% vs. 67.4%, respectively).

At 12 months, relapse-free survival was 62.5% compared with 66% from the ELIANA trial. Both age groups had similar rates of relapse-free survival and overall survival.

Researchers assessed safety in 493 patients for a median of 23.9 months (range, 2-43.6). Most adverse events of interest to the researchers were observed within the first 100 days of infusion. Safety outcomes in patients from the CIBMTR registry were more favorable than those from the ELIANA trial.

“This may be related to a lower disease burden prior to T-cell infusion for patients treated with commercial tisagenlecleucel,” John said during the presentation.

From the registry, 22.9% had prolonged neutropenia and 21.9% had prolonged thrombocytopenia.

Safety data were mostly similar across age groups, although more patients 18 years and older had any-grade cytokine release syndrome or neurotoxicity. These adverse events were subsequently treated.

“Ongoing accrual of patient data into the CIBMTR registry will provide further insights into the use of tisagenlecleucel in the real-world setting,” John concluded.

John S, Pulsipher MA, Moskop A, et al. Real-world outcomes for pediatric and young adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) treated with tisagenlecleucel: update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry. Presented at: 2021 ASH Annual Meeting & Exposition; December 9-14; Atlanta, GA. Abstract 428.

Tisagenlecleucel evoked similar efficacy and a preferrable safety profile in children and adults with B-ALL being treated in a real-world analysis, compared with the clinical trial ELIANA.



Real-World Data Supports Clinical Benefit of Tisagenlecleucel in Relapsed/Refractory B-Cell ALL 

Patients with triple-class relapsed/refractory multiple myeloma experienced superior overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR), following treatment with ciltacabtagene autoleucel (cilta-cel) compared with physician’s choice of treatment (PCT), according to data from a meta-analysis of the phase 1/2 CARTITUDE-1 trial (NCT03548207).

Results from the main analysis, which leveraged indirect treatment comparisons (ITCs), were presented during the 2021 ASH Annual Meeting. The overall effect estimate was found to be strongly in favor of cilta-cel, with a 76% reduction in the risk of death compared with PCT in both the modified intent-to-treat (mITT; HR, 0.24; 95% CI, 0.22-0.27) and ITT (HR, 0.24; 95% CI, 0.10-0.60) populations. The CAR T-cell therapy was also found to reduce the risk of a next line of treatment by 83% vs PCT.

Consistent results were reported across the additional analyses on the first index dates for OS. The CAR T-cell therapy reduced the risk of death by 78% vs PCT (HR, 0.22; 95% CI, 0.14-0.35) in the mITT population. In the ITT population, the CAR T-cell therapy reduced the risk of death by 72% vs standard of care (HR, 0.28; 95% CI, 0.17-0.47). An analysis using first index dates was also conducted for PFS, and the effect estimate indicated that cilta-cel reduced the risk of disease progression and death by 78% (HR, 0.22; 95% CI, 0.08-0.43) in the mITT population and 82% (HR, 0.28; 95% CI, 0.10-0.45) in the ITT population.

"These results are consistent across both populations and all available index dates," presenting study author Parameswaran Hari, MD, MRCP, MS, of the Medical College of Wisconsin, said in a poster presentation on the data. "In the absence of head-to-head randomized comparisons between cilta-cel and treatments used in real-world clinical practice, our meta-analysis of ITCs suggests that cilta-cel offers substantially more clinical benefit than PCT [in this population]."

The CAR T-cell therapy is currently under investigation in patients with triple-class exposed relapsed or refractory multiple myeloma as part of the CARTITUDE-1 trial. No clear standard of care currently exists for this population; as such, no randomized clinical trials could be designed to directly compare the efficacy of cilta-cel with other relevant options. To gain some insight, ITCs between cilta-cel and PCT have previously been conducted.

For the analysis presented at the 2021 ASH Annual Meeting, investigators pooled ITCs examining cilta-cel vs PCT in this patient population to derive single-summary effect estimates of comparative effectiveness. A total of 5 ITCs were included in the analysis.

Outcomes of interest included OS, PFS, TTNT, and ORR, and if data from at least ITCs were available for one of these outcomes, then a meta-analysis was conducted. These analyses utilized robust variance estimation to account for the use of CARTITUDE-1 in each pairwise ITC. Investigators calculated pooled summary effect estimates with the use of a random effects model; these were presented as hazard ratios with corresponding 95% confidence intervals.

Moreover, analyses comprised ITCs that used all index dates for both populations, and additional analyses were performed with ITCs using the first index date for these populations.

Data on PCT were extracted from the long-term follow-up results of 3 global, randomized clinical trials with daratumumab (Darzalex): the phase 3 POLLUX trial (NCT02076009), the phase 3 CASTOR trial (NCT02136134), and the phase 1 EQUULEUS trial (NCT01998971). PTC data were also leveraged from the Flatiron database, the US-based retrospective MAMMOTH study, a representative German patient registry maintained by Oncology Information Service (OIS), and the prospective LocoMMotion study.

Notably, each of the ITCs utilized a data cutoff of February 2021 for CARTITUDE-1 except for the MAMMOTH ITC, which used a data cutoff of September 2020. Patients in the PCT group of each ITC had to satisfy the key eligibility criteria for CARTITUDE-1 and who received at least 1 subsequent therapy after meeting these criteria; by using inverse probability of treatment weighing, investigators made this comparable to CARTITUDE-1.

The mITT population was comprised of those who had been infused with cilta-cel in CARTITUDE-1, and all eligible patients in the PCT arms who had not progressed or died within 47 days (52 days for OIs and LocoMMotion) after treatment initiation. The ITT population was comprised of all enrolled patients in CARTITUDE-1 and all eligible patients in the PCT arms.

The ITT population included 229 patients from the Flatiron Health Multiple Myeloma Registry, 329 patients from the post-daratumumab clinical trials cohort, 190 patients from the MAMMOTH trial, 222 from the OIS Registry, and 246 from the LocoMMotion study. The mITT population was comprised of 196 patients from the Flatiron registry, 267 patients from the post-daratumumab cohort, 122 patients from MAMMOTH, 174 patients from the OIS Registry, and 163 patients from LocoMMotion.

Data from the first index date analysis for ORR showed that the CAR T-cell therapy significantly increased the odds of achieving response by 86 and 14 times compared with PCT in the mITT and ITT populations, respectively.

“In the absence of head-to-head randomized comparisons between cilta-cel and treatments used in real-world clinical practice, this meta-analysis of indirect treatment comparisons suggests that cilta-cel offers substantially more clinical benefit than physician’s choice of treatment for patients with triple-class exposed relapsed or refractory multiple myeloma,” the study authors concluded.

Hari P, Berdeja J, De Stefano V, et al. Meta-analysis of ciltacabtagene autoleucel versus physician’s choice in the treatment of patients with relapsed or refractory multiple myeloma. Presented at: 2021 ASH Annual Meeting; December 11-14, 2021; Atlanta, GA. Abstract 1676.

In comparison to physicians’ choice of treatment, ciltacabtagene autoleucel demonstrated significant advantages in progression-free and overall survival, time to next treatment, and overall response rate.


Cilta-cel May Be Superior Therapy in Triple-Class Relapsed/Refractory Myeloma

The addition of ibrutinib (Imbruvica) to rituximab (Rituxan) plus mini-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone [R-mini-CHOP]) to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) resulted in improved progression-free survival (PFS), quality of life (QOL), and function, according to a primary analysis of the Australasian Leukaemia & Lymphoma Group NHL29 Study.

The results were presented during the 2021 ASH Annual Meeting and Exposition.

“The 2-year overall survival [OS] rate in the [standard-of-care group] is 59%, and the 2-year progression-free survival was 47%. We also know that the addition of ibrutinib to full dose R-CHOP in younger patients has efficacy…however, significant toxicity limits the ability to complete therapy in patients 60 years and above,” Emma Verner, MBBS, of the Department of Haematology, Concord Repatriation General Hospital in Australia, said during a presentation of the findings.

“We therefore hypothesized that the addition of ibrutinib to mini-CHOP in elderly patients with diffuse large B-cell lymphoma would be both tolerable and efficacious, improving the 2-year overall survival.”

Following data cutoff of June 6, 2021, median follow-up in 79 patients aged 75 or older was 34.3 months (range, 0.2-66.3). In total, 80% completed 6 cycles of R-mini-CHOP and 71% completed 8 cycles.

The overall response rate was 76%, including 56 complete responses (70%), 5 partial responses (6%), a single patient had stable disease (1%), and 9 with progressive disease (11%). Seven patients (9%) were not evaluable and 2 (2.5%) were missing end of trial response assessments. Response rates did not differ by cell of origin (COO; non-Germinal Centre B [GCB], 82% vs GCB, 71%; 

Although there was a trend toward improved OS, a target of a 15% increase from 59% with the current standard of care was not seen. The 2-year OS with the combination was 68% (95% CI, 57%-78%; 

 = .11). Median OS was not reached (NR; 95% CI, 35-NR); however, this was longer in those with a lower International Prognostic Index (IPI) of 1 to 3 (not reached [NR]) compared with an IPI of 4 (35 months) or 5 (19 months).

Of note, the 2-year PFS with the addition of ibrutinib was 60% (95% CI, 49%-72%; 

 < .03), a significant difference from 47% with the standard of care. Median PFS was 53 months (95% CI, 20-NR).

The COO had no impact on 2-year OS, with the median in GCB (95% CI, 29-NR) and the non-GCB (95% CI, 24-NR) groups not reached (

 = .99). The same was seen with 2-year PFS, with a median in GCB of 30 months (95% CI, 17-NR) and not reached in non-GCB (95% CI, 19-NR; 

Lastly, according to the primary analysis, 2-year disease-free survival (DFS) was 85% (95% CI, 60%-95%), with the median NR (95% CI, 32-NR).

Twenty-eight deaths occurred (35%): 16 due to progressive lymphoma, 5 from infection, 2 from respiratory failure, 2 from other malignancy, 1 from cardiac arrest, 1 from intra-abdominal hemorrhage, and 1 due to gastric hemorrhage.

Almost all patients (99%) experienced at least 1 adverse event (AE), with 24 (30%) reporting with grade 1 to 2, 49 (64%) with grade 3 to 4, and 5 (6%) with grade 5 AEs. The most common grade 3 or greater AEs were lung infection (13%), other infections (11%), anemia (11%), febrile neutropenia (9%), thrombocytopenia (9%), and atrial fibrillation (8%). Serious AEs occurred in 67%, the most common being lung infection (11%), atrial fibrillation (9%), fever (9%), and other infection (9%).

Investigators temporarily stopped treatment with ibrutinib in 62% of patients and permanently stopped treatment in 25%. Treatment discontinuation occurred due to toxicity (11%), progressive disease (6%), patient choice (4%), death (4%), or consent withdrawal (3%).

The study also found that EORTC-QLQ-C30 global health status among patients significantly improved between screening (n = 78; mean [standard deviation], 58 [25]), end of treatment (n = 57; 63 [23]), and 18-month post-treatment (n = 29; 74 [19]) (

 = .007). Patients reported significant reductions in fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation, and diarrhea. However, the investigators noted that there was no impact of Cumulative Illness Rating Scale-Geriatric score on disease response rate or risk of death.

In the prospective, multicenter, single-arm, phase 2 study, investigators administered six 21-day cycles of ibrutinib at 560 mg plus R-mini-CHOP, comprised of 375mg/m2 rituximab, 400 mg/m2 cyclophosphamide, 25 mg/m2 doxorubicin, 1 mg vincristine on day 1, and prednisone at either 40mg/m2 or 100mg/day for 5 days. Treatment was followed by 2 additional 21-day cycles of rituximab plus ibrutinib.

To be eligible for the trial, patients had to be 75 years or older, have newly diagnosed de novo DLBCL, have an ECOG performance status of 2 or less, and have stage I to IV disease. Patients were excluded if they had central nervous system involvement, required coagulation with warfarin, required dual antiplatelet therapy with aspirin and a P2Y12 antagonist, or a malignancy within 3 years.

Two-year OS served as the primary end point. Secondary end points included response rates, PFS, DFS, and toxicity.

Median age was 81.5 years (range, 75-95). More than half of patients were female (51%), had stage III or IV (81%) disease, and had an IPI risk score of 3 to 5 (63%). On centralized immunohistochemistry (IHC), 57% were non-GCB cell-like subtype and 43% were GCB.

“To conclude, the addition of ibrutinib to mini-CHOP was deliverable, with a respectable 2-year overall survival [rate] of 68%. However, our ambitious target of the 15% increase was not reached in a small sample size,” Verner said. “We are encouraged by our significantly improved progression-free survival of 60%. And despite the considerable, but not unexpected, toxicity in this elderly cohort, the quality of life and functioning improvements in survivors are also promising. This data supports further study of adding Bruton tyrosine kinase inhibitors to mini-CHOP in elderly patients with diffuse large B-cell lymphoma.”

Combining ibrutinib with rituximab resulted in improved 2-year progression-free survival among elderly patients with previously untreated diffuse large B-cell lymphoma. 

Hematology