Siddiqi Spotlights Latest Data on Optimization of Therapy in Hematologic Malignancies

Tanya Siddiqi, MD

Data presented during the 2021 ASCO Annual Meeting offered insight into the optimization of BTK inhibitors, induction therapy, consolidative therapy, and radiation therapy for patients across the paradigm of hematologic malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), central nervous system (CNS) lymphoma, and classical Hodgkin lymphoma (cHL), said Tanya Siddiqi, MD.

In a virtual presentation during the 2021 ASCO Direct Highlights™ webcast in San Diego, a program developed by Physicians’ Education Resource® (PER®), LLC, Siddiqi, director of the CLL Program at the Toni Stephenson Lymphoma Center and an associate clinical professor in the Division of Lymphoma in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, discussed data from 4 clinical trials presented during the 2021 ASCO Annual Meeting in various hematologic malignancies.

Chronic Lymphocytic Leukemia

The randomized, phase 3 ELEVATE-RR trial (NCT02477696) was a noninferiority study directly comparing the BTK inhibitors acalabrutinib (Calquence) and ibrutinib (Imbruvica) in patients with previously treated CLL.¹

“Acalabrutinib is a novel, second-generation BTK inhibitor that is supposed to be much more specific in targeting BTK as opposed to ibrutinib. The thought was that [acalabrutinib] might have an improved safety profile [vs ibrutinib] because of that,” said Siddiqi.

The study randomized patients 1:1 to 100 mg of twice daily, oral acalabrutinib (n = 268) vs 420 mg of once daily, oral ibrutinib (n = 265). Patients were required to have previously treated CLL, the presence of a 17p or 11q deletion, and an ECOG Performance Status (PS) of 0 to 2. Patients with significant cardiovascular disease, those on concomitant treatment with warfarin or an equivalent vitamin K antagonist, or those who received prior treatment with ibrutinib, a BCR inhibitor, or a BCL-2 inhibitor were excluded.

Baseline patient characteristics were similar between arms. About half of patients had bulky-stage, advanced CLL without an IGHV mutation, which confers a poor prognosis, said Siddiqi.

The results demonstrated that noninferiority was met with acalabrutinib vs ibrutinib per independent review committee assessed progression-free survival (PFS). At a median follow-up of 40.9 months, the median PFS was 38.4 months in both arms (HR, 1.00; 95% CI, 0.79-1.27). Moreover, the similarity with acalabrutinib vs ibrutinib was comparable across all prespecified subgroups.

Regarding safety, any-grade atrial fibrillation or flutter was observed in 9.4% (n = 25) of patients with acalabrutinib compared with 16% (n = 42) of patients with ibrutinib. Notably, no patients who developed atrial fibrillation on acalabrutinib required treatment discontinuation compared with 7 patients who developed atrial fibrillation with ibrutinib. The median time to onset was 28.8 months with acalabrutinib vs 16 months with ibrutinib.

“Atrial fibrillation and flutter are major concerns of patients being treated with ibrutinib,” Siddiqi said. “[The safety data] were somewhat expected, knowing what we know about acalabrutinib, but it was reassuring to see a marked difference and a seemingly much lower cardiac toxicity in terms of atrial fibrillation and flutter [with acalabrutinib].

Acalabrutinib was associated with statistically significantly more any-grade headache and cough, and grade 3 headache and fatigue compared with ibrutinib. Conversely, ibrutinib led to more any-grade diarrhea, hypertension, arthralgia, and contusion, and grade 3 diarrhea and hypertension.

“I’ve had to dose-reduce for some of these symptoms on both arms,” said Siddiqi. “The headaches [associated with acalabrutinib], in our experience, have been self-limiting and they go away after a while. Caffeine helps. If patients can push through the initial headaches, they definitely get better.”

In addition to atrial fibrillation, other adverse effects (AEs) of special interest such as bleeding events, hypertension, and interstitial lung disease/pneumonitis were more prevalent with ibrutinib vs acalabrutinib.

Mantle Cell Lymphoma

The randomized, phase 2 ECOG-ACRIN E1411 trial (NCT01415752) is an ongoing 4-arm study evaluating whether induction therapy with bendamustine plus rituximab (Rituxan; BR) followed by consolidative rituximab can be improved upon for patients with MCL.²

Patients with MCL were randomized to BR followed by rituximab, BR plus bortezomib (Velcade; BVR) followed by rituximab, BR followed by rituximab and lenalidomide (Revlimid), or BVR followed by rituximab and lenalidomide. Eligible patients had untreated MCL with an ECOG PS of 0 to 2 and adequate organ function.

During the 2021 ASCO Annual Meeting, initial results of the study were presented on the comparison of BR followed by rituximab (n = 181) vs BVR followed by rituximab (n = 180). Patient characteristics were similar between arms; most patients were White males over the age of 60 with an ECOG PS of 0.

The objective response rate (ORR) was 89.8% with BR compared with 89.2% with BVR, encompassing complete response (CR) rates of 59.7% vs 66.3%, respectively.

The 2-year PFS rate was 74.8% with BR vs 79.7% with BVR (HR, 0.83; 95% CI, 0.60-1.15). The median PFS was 5.4 years vs 5.9 years, respectively.

Regarding safety, grade 3 or higher hematologic toxicities during induction were slightly higher with BVR. Grade 3 or higher non-hematologic toxicities were also higher with BVR. Notably, peripheral sensory neuropathy was higher with BVR (3%) vs BR (0%) and was attributed to the addition of bortezomib.

“The conclusions of this intergroup trial at this stage were that the addition of bortezomib to BR did not meet the primary end point of increasing 2-year PFS, or improved ORR, CR, or median PFS. [BVR] did not generate any unexpected toxicity, which was reassuring,” Siddiqi said.

“However, this trial helps [to solidify] BR as a very reasonable backbone for induction therapy [in MCL] ,” she added. “We need to see improvements in induction in MCL, but if we can continue to see early minimal residual disease detectability with deep and durable responses, that is what we are going to be trying to achieve in MCL.”

Central Nervous System Lymphoma

“Primary CNS lymphoma is a very rare disease, but we don’t have a lot of knowledge of how to treat and cure these patients,” Siddiqi said.

The phase 2 CALGB 51101 trial (Alliance; NCT01511562) randomized patients who underwent 5 cycles of induction therapy to myeloablative consolidation with autologous stem cell transplant (arm A; n = 54) vs non-myeloablative consolidation with cytarabine and etoposide (arm B; n = 54).³

Eligible patients had a pathologic diagnosis of diffuse large B-cell lymphoma without current or prior systemic lymphoma. Patients had to have a Karnofsky PS of at least 30, negative HIV serology, and no history of prior organ transplant.

Overall, most patients were male with a median age of 61 years, a median Karnofsky PS of 80, no deep-brain involvement, normal Slit Lamp results, and negative cerebrospinal fluid cytology.

At a median follow-up of 3.8 years, the 2-year PFS rate was 73% with the myeloablative approach compared with 51% with the non-myeloablative approach. The median PFS was 6 years vs 2.4 years, respectively. The 2-year estimated PFS in 70 patients who completed consolidation was 86% with myeloablative consolidation vs 70% with non-myeloablative consolidation.

The median overall survival (OS) was not reached in either arm, but the 2-year OS rates were 87% with myeloablative treatment vs 78% with non-myeloablative treatment.

At the end of induction treatment and despite receiving the same treatment, 56% of patients randomized to myeloablative treatment derived a confirmed or unconfirmed CR compared with 44% of patients randomized to the non-myeloablative treatment. At the end of consolidation, the confirmed or unconfirmed CR rates were 70% vs 50%, respectively.

Regarding safety, no treatment-related deaths occurred on study, but 2 grade 4 sepsis events occurred in patients who received myeloablative consolidation. Common grade 3 or higher AEs with both consolidative approaches included decrease platelet, neutrophil, lymphocyte, and white blood cell counts, febrile neutropenia, anemia, oral mucositis, and hyperglycemia.

“The induction led to 50% CRs in these patients. The consolidation added to the CRs, but the PFS was not different across both arms if we measure after consolidation was initiated,” Siddiqi said.

Classic Hodgkin Lymphoma

The phase 2 CALGB 50801 trial (Alliance; NCT01118026) was designed to evaluate the role of radiation therapy for patients with bulky stage I/II cHL.⁴

Patients were given 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by a PET/CT scan for restaging. If patients were PET2 negative, they went on to receive 4 additional cycles of ABVD. If they were PET2 positive, patients received 4 cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) plus involved-field radiation therapy.

Eligible patients had stage I/II cHL with a mass greater than 10 cm or a mediastinal mass greater than .33 maximal intrathoracic diameter on chest X-ray. Overall, patients were a median age of 30 and 50% were female.

The results of the study indicated that 78% of patients were PET2 negative, and therefore, did not require exposure to radiation therapy or escalated BEACOPP.

“Based on the results of this trial, the author recommended omitting radiotherapy in PET2-negative patients who receive 6 cycles of ABVD. Of course, there are more comparative trials going on to look at novel agents and to study efficacy, safety, and cost to improve results in these patients,” Siddiqi concluded.

References

1. Byrd JC, Hillmen P, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2021;39(suppl 15):7500. doi:10.1200/JCO.2021.39.15_suppl.7500
2. Smith MR, Jegede O, Martin P, et al. ECOG-ACRIN E1411 randomized phased 2 trial of bendamustine-rituximab (BR)-based induction followed by rituximab (R) ± lenalidomide (L) consolidation for mantle cell lymphoma: effect of adding bortezomib to front-line BR induction on PFS. J Clin Oncol. 2021;39(suppl 15):7503. doi:10.1200/JCO.2021.39.15_suppl.7503
3. Batchelor T, Giri S, Ruppert AS, et al. Myeloablative versus non-myeloablative consolidative chemotherapy for newly diagnosed primary central nervous system lymphoma: results of CALGB 51101 (Alliance). J Clin Oncol. 2021;39(suppl 15):7506. doi:10.1200/JCO.2021.39.15_suppl.7506
4. LaCasce AS, Dockter T, Ruppert AS, et al. CALGB 50801 (Alliance): PET adapted therapy in bulky stage I/II classic Hodgkin lymphoma (cHL). J Clin Oncol. 2021;39(suppl 15):7507. doi:10.1200/JCO.2021.39.15_suppl.7507