The discovery of new biomarkers and development of monoclonal antibodies have contributed to the advancement of therapy which could give patients with certain hematologic malignancies a longer survival, shifting the treatment paradigms towards a chemotherapy-free era.1 At the 60th American Society of Hematology (ASH) Annual Meeting which was held in San Diego, United States, three research groups published the latest findings from their clinical trials that could potentially be the standard therapy for untreated chronic lymphocytic leukemia (CLL), old patients with CLL, and transplant-ineligible multiple myeloma (MM).2-4
Ibrutinib in combination with rituximab for untreated CLL
Fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy (CIT) have long been acknowledged as the gold standard for treating physically fit patients who have never received treatment for CLL before.2 Despite being the gold standard treatment, FCR is also known to be very toxic with 34% to 85% of the patients treated with FCR reported to have grade ≤3 neutropenia, and infections occurred in 16% to 36% of patients.5
Ibrutinib is an irreversible Bruton’s Tyrosine Kinase (BTK) inhibitor, a novel agent that was designed to be the targeted therapy in various B-cell neoplastic disorders including CLL.6 Initially, ibrutinib was found to have robust and durable efficacy in patients with relapsed/refractory CLL.2 However, comparing with the current gold standard (FCR), ibrutinib as a first-line treatment for younger (aged ≤70 years old) CLL patients has yet to be examined.
With such knowledge gap existing, Dr. Tait Shanafelt of the Standford University, United States, led a research team to conduct a phase 3, randomized, active-controlled trial to confirm the efficacy of ibrutinib-rituximab (IR) combination compared with FCR.2
The study recruited 529 patients aged ≤70 years with CLL and treatment-naïve but required therapy.2 These patients were randomly assigned in a 2:1 ratio to receive ibrutinib (420mg/day until disease progression) plus rituximab (50mg/m2 on day 1 of cycle 2; 325mg/m2 on day 2 of cycle 2; 500mg/m2 on day 1 of cycle 3 till 7) or six courses of intravenous fludarabine (25mg/m2) plus cyclophosphamide (250mg/m2) and day 1 to 3 with rituximab (50mg/m2 on day 1 of cycle 1; 325mg/m2 on day 2 of cycle 1; 500mg/m2 on day 1 of cycles 2-6) every 28 days.2 The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS), which were analyzed using the stratified log-rank test in an intention to treat (ITT) fashion.2
The result presented during the meeting was the scheduled interim analysis with a median follow-up of 33.4 months.2 During the study period, there was 77 PFS events and 14 deaths.2 The IR arm had a 64.8% significant PFS reduction over FCR (HR=0.352; 95% CI: 0.223-0.558; p<0.0001, Figure 1).2 Risk of death was also significantly lower in the IR arm as compared with the FCR arm (HR=0.168; 95% CI: 0.053-0.538; p<0.0003; p for superiority=0.0005).2 “There is a remarkably lower risk of death in patients receiving the new therapy in comparison with standard chemotherapy,” commented by Dr. Shanafelt on the study results.7
A significantly lower rate of grade 3 and 4 treatment-related AEs was also observed in the IR arm (58% vs. FCR arm 72%, p=0.0042).2 Of which, grade 3 and 4 neutropenia and infectious complications were both significantly lower in the IR arm (23% vs. FCR arm 44%, p<0.0001; 7.1% vs. FCR arm 17.7%, p<0.0001, respectively).2
Subgroup analysis showed that the PFS improvement with IR was superior to FCR independent of age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, disease stage, or del11q23 gene status.2 However, patients with immunoglobulin heavy-chain variable region gene (IGHV) mutation showed an insignificant benefit (HR=0.435; p<0.07) while superiority of IR was established in the IGHV unmutated patients (HR=0.262; p<0.0001).2
Ibrutinib as a monotherapy for older CLL patients
Meanwhile, Dr. Jennifer Woyach of the Ohio State University Comprehensive Cancer Center, United States, presented encouraging results to support the use of ibrutinib as monotherapy for older patients with CLL.3
The phase 3, randomized crossover design trial recruited 547 patients aged ≥65 years with untreated, symptomatic CLL. Other inclusion criteria were creatinine clearance (CrCl) ≥40mL/min, bilirubin ≤1.5 times of upper limit of normal, without significant life-limiting intercurrent illnesses, and warfarin treatment not being needed.3
Patients were randomly assigned in a 1:1:1 ratio to receive either bendamustine-rituximab combination therapy (BR), ibrutinib, or IR.3 Any patients with disease progression on the BR arm were allowed to cross over to the ibrutinib arm.3 The goal of this study was to determine 1) whether ibrutinib-containing regimens prolong PFS better than CIT; 2) whether IR can prolong PFS better than ibrutinib alone.3
The sample size of more than 166 patients in each arm allowed the trial to detect an improvement in 2-year PFS from 61% in BR arm to 75% in the ibrutinib and IR arms using two one-sided log-rank tests with a type I error rate of 2.5% and 90% power.3 AEs occurred in each arm during the study period were compared using Fisher-exact tests.3 The results presented in the meeting were analyzed as a per-protocol analysis.3
At the time of analysis, 525 (96%) of the recruited patients were eligible and included in the primary PFS analysis.3 The median follow-up time was 32 months, and median PFS was 41 months for the BR arm but has not been reached in the other two arms (Figure 2).3 The comparisons of median PFS in each treatment arm were presented in Table 1.3 The 2-year PFS estimate were 74%, 87%, and 88% in the BR arm, ibrutinib arm, and IR arm, respectively (Figure 3).3 “Ibrutinib [was] superior to bendamustine plus rituximab throughout,” commented Dr. Woyach on the study results.8
Percentage of treatment-emergent AEs and death occurred during the study period were presented in Table 2.3 “BTK inhibition with ibrutinib is not without significant toxicity in older patients, so close monitoring is still warranted. Strategies to limit toxicity through either the use of more selective BTK inhibitors or potentially limiting the duration of therapy are of great interest,” said Dr. Woyach in reaction to the observed safety profile in this study.8
Nevertheless, the study results demonstrated that ibrutinib was superior to CIT in prolonging PFS older patients with CLL, providing evidence to support its use as a standard of care treatment for this population of CLL patients.3 As a remark, Dr. Woyach noted there are two ongoing studies in this patient population comparing ibrutinib plus obinutuzumab with or without venetoclax, which should provide more evidence for the use of ibrutinib-based therapy.8
Daratumumab plus lenalidomide-dexamethasone (D-Rd) combination therapy for transplant-ineligible MM
Another area with research interest is the treatment for newly diagnosed MM (NDMM) that are ineligible for transplantation. Currently, the standard of care for this patient population is with the use of lenalidomide-based therapies.4 That is until the recent ASH meeting where Dr. Thierry Facon of Claude Huriez Hospital in Lille, France, and his team presented the results from a trial that showed the risk reduction on disease progression and death by adding daratumumab to Rd, which may reshape the treatment landscape for these patients.4
Daratumumab is a CD38-targeted, immunoglobulin G1k monoclonal antibody with single-agent activity in heavily pretreated MM patients.4 It has been tested in combination with Rd and bortezomib-dexamethasone combination in relapsed/refractory settings, and bortezomib-melphalan-prednisolone in transplant-ineligible settings and showed positive results in terms of reduced risk of disease progression or death.9-11 To explore further about the capability of adding daratumumab to the current standard of care, Dr. Facon and his team conducted a phase 3 study to evaluate D-Rd vs. Rd in transplant-ineligible MM and presented the interim analysis at the ASH meeting.4
This phase 3, multinational, randomized trial recruited 737 patients from 14 countries who were ineligible for high-dose chemotherapy with autologous stem cells transplantation due to age ≥65 years old or because of comorbidities.4 Patients were randomly assigned in a 1:1 ratio to receive 28-day cycles of Rd±D (25mg of R was given orally per day on day 1-21; 40mg of d was given orally on day 1, 8, 15, and 22; 16mg/kg of D was given intravenously per week for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter) treatment until disease progression or intolerable toxicity occurs.4 The primary endpoint was PFS, with other secondary endpoints including overall response rate (ORR), minimal residual disease (MRD)-negative rate (with a sensitivity of 10-5), and safety.4
The pre-specified interim analysis occurred on September 24, 2018, that is when 239 of PFS events have occurred.4 At that time, the median follow-up time was 28 months.4 Risk of disease progression or death was reduced by 45% in the D-Rd arm (HR=0.55; 95% CI: 0.43-0.72; p<0.0001, Figure 3).4 The addition of daratumumab brought a deeper response with complete response (CR) or better rate of 47.6% in the D-Rd arm compared with 24.7% show in the Rd arm (OR=2.75; 95% CI: 2.01-3.76; p<0.0001).4 Very good partial response (VGPR) or better rate was also higher in the D-Rd arm as compared with the Rd arm (79.3% vs. 53.1%; OR=3.4; 95% CI: 2.45-4.72; p<0.0001).4 “These results support D-Rd as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma,” said Dr. Facon.12
In terms of survival, 19% of patients died during the study period (HR=0.78; 95% CI: 0.56-1.1) with the follow-up still ongoing.4 Higher rates of grade ≤3 pneumonia, neutropenia, and leukopenia defined by a difference of ≤5% were observed in the D-Rd arm, which is consistent with previous studies with daratumumab.4
“In older patients who are not candidates for stem cell transplantation, these are very encouraging results,” said Dr. Facon who found strong clinically significant benefit in delaying disease progression with no major safety issues by adding daratumumab to the current standard of care.12
Keep on driving the field forward
The three clinical trials results shared from the 60th ASH meeting provided a glimpse of the entire event, which marked some significant results that may change the clinical practice for achieving better treatment outcomes in CLL and MM. With many other fascinating findings presented during the meeting, it was surely a fruitful week for healthcare professionals, researchers, patients, and those who have an interest in the field.
1. Klener P, Etrych T. Biological therapy of hematologic malignancies: toward a chemotherapy-free era. Curr Med Chem. 2017.
2. Shanafelt TD, Wang V, Kay NE, et al. A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912). ASH Annual Meeting and Exposition. December 1-4, 2018. San Diego, California. Abstract LBA-4.
3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression Free Survival (PFS) Compared with Bendamustine Plus Rituximab in Untreated Older Patients with Chronic Lymphocytic Leukemia (CLL): Results of Alliance North American Intergroup Study A041202. ASH Annual Meeting and Exposition. December 1-4, 2018. San Diego, California. Abstract 6.
4. Facon T, Kumar SK, Plesner T, et al. Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA). ASH Annual Meeting and Exposition. December 1-4, 2018. San Diego, California. Abstract LBA-2.
5. Burger JA, O’Brien S. Evolution of CLL treatment—from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018:1.
6. Akinleye A, Chen Y, Mukhi N, et al. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6(1):59.
7. Ibrutinib/Rituximab Improves OS, PFS Versus FCR for Untreated CLL. OncLive. 2018 (Accessed December 13, 2018, at https://www.onclive.com/conference-coverage/ash-2018/ibrutinibrituximab-improves-os-pfs-versus-fcr-for-untreated-cll)
8. Ibrutinib Established as Standard for Older CLL Patients. OncLive. 2018 (Accessed December 13, 2018, at https://www.onclive.com/conference-coverage/ash-2018/ibrutinib-established-as-standard-for-older-cll-patients)
9. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
10. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
11. Mateos M-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528.
12. Daratumumab Plus Rd New Frontline Standard in Transplant-Ineligible Myeloma. OncLive. 2018 (Accessed December 13, 2018, at https://www.onclive.com/conference-coverage/ash-2018/daratumumab-plus-rd-new-frontline-standard-in-transplant-ineligible-myeloma)