Alessandra Tedeschi, MD:
One of the many open questions in CLL treatment is whether chemoimmunotherapy still has a role in the fit population. At EHA 2022, Eichhorst and colleagues¹ presented results from the randomized phase III GAIA/CLL13 study of 3 time-limited venetoclax-based regimens as frontline therapy vs chemoimmunotherapy in fit patients with CLL. In this trial, 920 treatment-naive patients with CLL and no del(17p)/TP53 mutation were randomized to receive 1 of the 3 venetoclax combinations—venetoclax plus obinutuzumab and ibrutinib, venetoclax plus obinutuzumab, or venetoclax plus rituximab—or to chemoimmunotherapy (CIT) with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR). FCR was used for patients aged 65 years or younger, whereas BR was for patients older than 65 years. Patients with del(17p) were excluded, as it is well known that chemoimmunotherapy is not effective in this setting. After the standard ramp-up, venetoclax was administered for 12 cycles, obinutuzumab or rituximab were administered for 6 cycles, and ibrutinib was administered for 12 cycles.

The coprimary endpoints are measurable residual disease (MRD) negativity for venetoclax plus obinutuzumab vs chemoimmunotherapy and PFS for ibrutinib plus venetoclax plus obinutuzumab vs chemoimmunotherapy.

Alessandra Tedeschi, MD:
Because GAIA/CLL13 was designed for fit, younger patients, the median age was rather low at 61 years.¹ In the chemoimmunotherapy arm, approximately two thirds of patients received BR, and one third received FCR. The arms were well balanced with regard to cumulative illness rating scale (CIRS) score and IGHV mutation status.

Alessandra Tedeschi, MD:
Results of the first coprimary endpoint at the 15-month follow-up showing a significantly higher rate of undetectable MRD for venetoclax plus obinutuzumab vs chemoimmunotherapy were presented at the American Society of Hematology 2021 annual meeting.² The rate of undetectable MRD was 92.2% with the triplet regimen vs 86.5% with venetoclax plus obinutuzumab vs 52.0% with chemoimmunotherapy (P <.0001).¹

This finding means that the addition of obinutuzumab to venetoclax, with or without ibrutinib, allows achievement of deeper responses than intensive treatment with chemoimmunotherapy. Of note, the combination of venetoclax plus rituximab—which has not been used as first-line therapy for fit patients with CLL—did not differ significantly in the rate of undetectable MRD vs chemoimmunotherapy.

Alessandra Tedeschi, MD:
The second coprimary endpoint of PFS with the triplet regimen vs chemoimmunotherapy was met.¹ The median PFS was not reached with the combination of venetoclax plus obinutuzumab and ibrutinib vs 52 months with chemoimmunotherapy (HR: 0.32; P <.000001). At 3 years, the PFS rate was 90.5% with the triplet regimen vs 75.5% with chemoimmunotherapy.

Of importance, PFS also was significantly superior with venetoclax plus obinutuzumab vs chemoimmunotherapy (P <.0001). By contrast, the median PFS with venetoclax plus rituximab (52.3 months) was very similar to the median PFS with chemoimmunotherapy (52.0 months), reminding us that this combination should not be used in fit patients with CLL.

Alessandra Tedeschi, MD:
PFS results according to IGHV mutational status may help guide clinicians in selecting the best treatment regimen for individual patients. Patients with unmutated IGHV had a greater benefit with the obinutuzumab-containing regimens vs chemoimmunotherapy.

At 3 years, the PFS rate was 86.6% with triplet combination, 82.9% with venetoclax plus obinutuzumab, and 65.5% with chemoimmunotherapy. However, patients with mutated IGHV exhibited similar PFS benefits with the venetoclax-based regimens or chemoimmunotherapy.¹ In fact, the PFS rates at 3 years were closer (96.0% with the triplet regimen vs 89.9% with chemoimmunotherapy). Similar results were seen with venetoclax plus obinutuzumab vs chemoimmunotherapy.

It is clear that patients with unmutated IGHV are those who benefit most from treatment with newer targeted regimens.

Alessandra Tedeschi, MD:
Looking specifically at the subgroup with mutated IGHV who were aged 65 years or younger, we see that chemoimmunotherapy provided a prolonged PFS that was similar to venetoclax plus obinutuzumab with or without ibrutinib.¹ At 3 years, there was only a 1.4% difference in the PFS rate with chemoimmunotherapy (95.0%) vs the triplet regimen (93.6%).

Alessandra Tedeschi, MD:
The PFS subgroup analysis for venetoclax plus obinutuzumab vs chemoimmunotherapy exhibited similar results to that of the triplet regimen vs chemoimmunotherapy.¹ Most subgroups benefited from this regimen, with the exception of those with Binet stage A at screening and those with no cytogenetic abnormalities, mutated IGHV, trisomy 12, and intermediate CLL-IPI risk.

Alessandra Tedeschi, MD:
This subgroup analysis of PFS showed that the triplet regimen of ibrutinib plus venetoclax and obinutuzumab was superior to chemoimmunotherapy across most subgroups.¹ The exceptions where the 95% Wald CI crossed 1.0 were the subgroups with no cytogenetic abnormalities, mutated IGHV, trisomy 12, and intermediate risk based on the International Prognostic Index for CLL (CLL-IPI).

Alessandra Tedeschi, MD:
The OS curves are nearly identical for all treatment arms, with 3-year OS rates of approximately 95%.¹ Longer follow-up is needed to determine whether there is an OS difference between regimens.

At 3 years, 98.3% of patients in the triplet arm did not need additional therapy vs 87.2% receiving chemoimmunotherapy.

Alessandra Tedeschi, MD:
Safety results showed no major differences between the 4 arms, including rates of grade ≥3 toxicities.¹ However, there were higher rates of infections and infestations, as well as febrile neutropenia, in patients treated with the triplet combination vs other arms. Off‑target events are a concern with ibrutinib used in combination regimens. In this study, grade ≥3 hypertension was seen in only 5.6% of the triplet arm vs ≤2% with the other regimens.

Secondary primary malignancies were more common with chemoimmunotherapy (49 events vs <30 in the other arms), mostly related to non-melanoma skin cancers. Richter transformation also was more common with chemoimmunotherapy and venetoclax plus obinutuzumab (6 events in each arm) vs the triplet regimen (0 events).

Alessandra Tedeschi, MD:
At EHA 2022, Sharman and colleagues³ presented a 5-year update from ELEVATE-TN, a phase III trial of acalabrutinib with or without obinutuzumab vs chlorambucil plus obinutuzumab in previously untreated, elderly or unfit patients with CLL. In 2019, positive results from ELEVATE-TN and the phase III ASCEND trial led to the FDA approval of acalabrutinib for treatment of adults with CLL/small lymphocytic lymphoma.⁴

ELEVATE-TN enrolled patients aged 65 years or older and patients younger than 65 years who are not candidates for intensive chemoimmunotherapy because of a high CIRS score or creatinine clearance <70 mL/min.³ In total, 535 patients were randomized 1:1:1 to 3 different arms: acalabrutinib plus obinutuzumab, acalabrutinib alone, and a chemoimmunotherapy arm of chlorambucil plus obinutuzumab, which has long been considered the standard of care for older, unfit patients with CLL. The primary endpoint of the study was PFS with acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab.

Alessandra Tedeschi, MD:
The baseline characteristics are shown in this table. The median age was approximately 70 years, which is typical in treatment-naive CLL.³ Of note, patients with del(17p) or mutated TP53 were included (~14% in each arm).

Alessandra Tedeschi, MD:
Early data analyses from ELEVATE-TN demonstrated a strong PFS benefit for both of the acalabrutinib arms vs obinutuzumab plus chlorambucil.⁵ The 5-year results presented at EHA 2022 confirm the superiority of the acalabrutinib‑containing regimens. The 60‑month PFS rate was 84% for acalabrutinib in combination with obinutuzumab and 72% for acalabrutinib monotherapy, and both are significantly superior (P <.0001) when compared with chemoimmunotherapy at 21%.³ The median PFS in the chemoimmunotherapy arm was 27.8 months vs not reached for the 2 acalabrutinib arms.

In studies of other BTK inhibitors, such as ibrutinib, we have seen that adding the anti-CD20 antibody rituximab does not translate to a better outcome. By contrast, in ELEVATE-TN, the addition of obinutuzumab to acalabrutinib prolonged PFS (P = .0259).

Alessandra Tedeschi, MD:
Of importance, the acalabrutinib‑based regimens demonstrated a significantly better PFS than chemoimmunotherapy in the subset of very high–risk patients (ie, patients with del17p or mutated TP53).³ At 5 years, 71% of patients who received acalabrutinib with or without obinutuzumab remained progression free vs only 18% of those who received obinutuzumab plus chlorambucil.

Alessandra Tedeschi, MD:
The update at 5 years demonstrated that the combination of acalabrutinib and obinutuzumab allows for the deepest responses, with a complete response (CR) rate of 32.4% vs 14.5% with single-agent acalabrutinib and 13.6% with chemoimmunotherapy (P <.0001 for acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil).³ The ORRs were 96.1% for acalabrutinib plus obinutuzumab, 89.9% for acalabrutinib monotherapy, and 83.1% for chemoimmunotherapy.

Alessandra Tedeschi, MD:
It is also clearly possible to achieve much better rates of undetectable MRD in patients using acalabrutinib plus obinutuzumab.³ Rates of undetectable MRD were 42% for the acalabrutinib combination vs 10% for acalabrutinib monotherapy and 9% for chemoimmunotherapy.

Alessandra Tedeschi, MD:
In this analysis, the 5-year OS rate was somewhat better with acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil at 90% vs 82%, respectively (HR: 0.55).³ There also was a trend toward better OS with acalabrutinib plus obinutuzumab when compared with acalabrutinib monotherapy (P = .0556).

A caveat when looking at these data is that 41% of patients in the obinutuzumab plus chlorambucil arm crossed over to receive acalabrutinib, which may have confounded the OS analysis.

Alessandra Tedeschi, MD:
With regard to safety, the most common AEs seen with acalabrutinib-based regimens were diarrhea (~43%), headache (~40%), and arthralgia (~30%), which were predominantly low grade.³ These AEs were more common with acalabrutinib-based regimens than with chemoimmunotherapy. In the obinutuzumab plus chlorambucil arm, diarrhea occurred in 21.3% of patients, headache 11.8%, and arthralgia 5.9%.

By contrast, neutropenia was most frequently seen with obinutuzumab plus chlorambucil (45.6% vs 34% with acalabrutinib plus obinutuzumab vs 12% with acalabrutinib monotherapy), and nausea also was more common with chemoimmunotherapy (31.4% vs ~25% with acalabrutinib-based regimens). Higher rates of infusion-related reactions occurred with obinutuzumab plus chlorambucil than with acalabrutinib plus obinutuzumab (40.8% vs 14.6%, respectively), thus confirming previously reported data on decreased rates of infusion‑related reactions induced by obinutuzumab in patients with CLL and FL treated with a BTK inhibitor.^6,7

Alessandra Tedeschi, MD:
Certain AEs are of particular concern with BTK inhibitors, as shown here. Given that this was an older population with a median age of 70 years and that many patients had comorbidities, this analysis found a rather low 5-year rate of any‑grade atrial fibrillation (6.2%-7.3% with acalabrutinib-based regimens vs 0.6% with chemoimmunotherapy).³ The rate of major bleeding also was low; 6.7% in the acalabrutinib plus obinutuzumab arm, 4.5% in the acalabrutinib monotherapy arm, and 1.2% in the chemoimmunotherapy arm. Likewise, considering the characteristics of the patient population, any‑grade hypertension was seen only in about 9% of patients receiving the BTK inhibitor.

Although the rate of infections was higher in patients receiving the BTK inhibitor (78.7% with acalabrutinib plus obinutuzumab and 75.4% with acalabrutinib monotherapy) compared with 44.4% with chemoimmunotherapy, it is important to remember that patients receiving acalabrutinib are on a continuous treatment with twice daily dosing.

Second primary malignancies were more common with the acalabrutinib-based regimens, occurring in 17.4% of those receiving acalabrutinib plus obinutuzumab, 15.1% with acalabrutinib monotherapy, and 4.1% with chemoimmunotherapy.

Alessandra Tedeschi, MD:
The ongoing, randomized, open-label phase II ROSEWOOD trial compared zanubrutinib plus obinutuzumab vs obinutuzumab monotherapy in 217 patients with grade 1-3a relapsed/refractory FL.⁸ In this trial, patients had received ≥2 prior lines of systemic treatment including anti‑CD20 antibodies, but not BTK inhibitors. The primary endpoint was ORR.

This is an important study considering that there is the need to identify an effective and well tolerated salvage therapy for these patients with FL.

Alessandra Tedeschi, MD:
This was a very heavily pretreated population with bulky disease in approximately 40% of patients and a median of 3 prior lines of therapy.⁸ Approximately one half of the patients were refractory to rituximab, and one third were refractory to the most recent line of therapy. Essentially, this is a population with disease that is very difficult to treat.

Alessandra Tedeschi, MD:
The IRC-assessed ORR was significantly higher in patients receiving zanubrutinib plus obinutuzumab vs obinutuzumab alone (68.3% vs 45.8%, respectively; P = .0017).⁸ Of importance, 37.2% of patients in the combination arm achieved a CR compared with 19.4% with obinutuzumab monotherapy (P = .0017). The combination improved responses across most patient subgroups except those with bulky disease.

Some patients who progressed on obinutuzumab monotherapy could be salvaged with the combination treatment. Objective responses were observed in 24% of patients who crossed over to zanubrutinib plus obinutuzumab. Of note, only 9% progressed with the combination vs 21% with monotherapy. Clearly, the combination of zanubrutinib plus obinutuzumab is active in FL.

Alessandra Tedeschi, MD:
To date, the median duration of response has not been reached in either arm.⁸ The 18-month response rates were 71% with the combination vs 55% with the monotherapy. Of note, there is a meaningful difference of >2 years for median PFS in favor of zanubrutinib plus obinutuzumab (27.4 vs 11.2 months with obinutuzumab monotherapy; HR: 0.51; P = .0040). In the obinutuzumab monotherapy arm, the median time to next treatment was 12 months vs not reached for the combination arm.

For now, median OS has not been reached, but the study was not powered to detect an OS difference.

Alessandra Tedeschi, MD:
Approximately one third of patients in the combination arm received treatment for ≥12 months, compared with one quarter in the monotherapy arm.⁸ In addition, the median number of treatment cycles was 9 for zanubrutinib and 7 for obinutuzumab in the combination arm and 6 for obinutuzumab in the monotherapy arm.

The median zanubrutinib dose intensity was nearly 100% (99.5%), indicating that zanubrutinib was well tolerated even in a heavily pretreated population.

Alessandra Tedeschi, MD:
In general, the combination of zanubrutinib plus obinutuzumab was very well tolerated.⁸ Hematologic treatment-emergent AEs (TEAEs) were common in the combination arm, including all-grade thrombocytopenia in 34.3% (grade 3/4 in 14.0%) and neutropenia in 27.3% (grade 3/4 in 22.4%). The rate of thrombocytopenia was lower in the obinutuzumab monotherapy arm (all grade: 23.9%; grade 3/4: 7.0%), and the rate of neutropenia was similar to the combination arm (all grade: 25.4%; grade 3/4: 19.7%). Outside of these hematologic events, few grade 3/4 TEAEs were reported.

Infusion-related reactions were more common with obinutuzumab monotherapy than with the combination (9.9% vs 2.8%, respectively).

Alessandra Tedeschi, MD:
Most other TEAEs of interest were low grade.⁸ Any-grade atrial fibrillation was seen in only 2% of patients, which is very similar to the rate reported with obinutuzumab monotherapy. Of note, the rate of major hemorrhage with zanubrutinib was 26.6%, but only 1.4% of these events were grade ≥3. Likewise, infections were seen in 47.6% of patients in the combination arm, but fewer than 20% were grade ≥3.

Alessandra Tedeschi, MD:
The phase III ASPEN study was the first trial to compare BTK inhibitor treatment in indolent lymphomas. Patients with Waldenström macroglobulinemia were randomized to receive either zanubrutinib or ibrutinib in this trial.⁹ In 2021, positive results from this study led to the FDA approval of zanubrutinib for treatment of adults with Waldenström macroglobulinemia.¹⁰

This study consisted of 2 cohorts according to MYD88 mutation status.⁹ Patient with MYD88 mutations enrolled in cohort 1 (n = 201) and were randomized 1:1 to receive zanubrutinib or ibrutinib. Those with wild-type MYD88 (cohort 2, n = 28) received zanubrutinib monotherapy, as these patients are historically less likely to benefit from ibrutinib.¹¹ The primary endpoint was CR or very good partial response (VGPR) in patients with MYD88 mutation (cohort 1).⁹

Alessandra Tedeschi, MD:
The baseline characteristics in cohort 1 were well balanced between treatment arms.⁹ The median age was approximately 70 years, and approximately three quarters of patients had received 1-3 prior lines of therapy. Wild-type CXCR4 was present in 64% of patients receiving zanubrutinib and 73% receiving ibrutinib.

In cohort 2, only 1 of 28 patients harbored a CXCR4 mutation, making this alteration much less frequent than was seen in cohort 1 (20%-30%).

Alessandra Tedeschi, MD:
As shown here, the study did not meet its primary endpoint (rate of CR or VGPR in cohort 1) after a median follow-up of 19 months.⁹ However, the rate of CR plus VGPR was numerically higher in all time points with zanubrutinib compared with ibrutinib. At 44 months of follow-up, the rate of CR plus VGPR by investigator assessment was 36% with zanubrutinib vs 25% with ibrutinib. The median time to VGPR or better was shorter with zanubrutinib at 6.7 months vs with ibrutinib at 16.6 months.

Patients with wild-type MYD88 (cohort 2) achieved very good responses with zanubrutinib—a major response rate of 65% and a VGPR in 27%. This is a favorable response considering that this population typically does not achieve major responses with ibrutinib.^11,12

Alessandra Tedeschi, MD:
There was no significant difference in the 42-month PFS rate between zanubrutinib (78%) and ibrutinib (70%) in the cohort 1 patients with mutated MYD88 (HR: 0.63).⁹

Alessandra Tedeschi, MD:
In cohort 1, OS also was nearly identical, with a 42-month OS rate of 88% for zanubrutinib vs 85% for ibrutinib (HR: 0.75).⁹

Alessandra Tedeschi, MD:
Although the 42-month PFS rate was very similar between arms in the overall population, those with a CXCR4 mutation who received zanubrutinib demonstrated a favorable PFS compared with ibrutinib (42-month PFS rate of 73% vs 49%, respectively).⁹ These PFS curves continue to diverge with a longer follow-up.

When patients were stratified according to CXCR4 mutational status, rates of VGPR or better were higher with zanubrutinib in patients with both mutated and wild-type CXCR4. Of note, the median time to a major response was shorter with zanubrutinib than ibrutinib in the CXCR4-mutated population (3.4 vs 6.6 months, respectively), but there was no difference in patients with wild-type CXCR4 (2.8 months for both arms).

Alessandra Tedeschi, MD:
More than 90% of patients experienced ≥1 AE across both cohorts.⁹ In cohort 1, treatment with zanubrutinib resulted in fewer AEs leading discontinuation (9% vs 20% with ibrutinib), dose reduction (16% vs 27% with ibrutinib), or death (3% vs 5% with ibrutinib). This is important for a drug that must be taken continuously because the long exposure without dose modifications or interruptions may translate to a better outcome in prolonged follow-up.

Alessandra Tedeschi, MD:
In cohort 1, the most common AEs occurred at a higher incidence with ibrutinib vs zanubrutinib.⁹ The ibrutinib arm had higher rates of any-grade diarrhea (35% vs 23% with zanubrutinib), muscle spasm (29% vs 12%), atrial fibrillation (21% vs 7%), and pneumonia (18% vs 5%). Of importance, grade ≥3 hypertension was more common with ibrutinib (19% vs 10% with zanubrutinib).

Alessandra Tedeschi, MD:
In cohort 1, ibrutinib was associated with all-grade atrial fibrillation/flutter in 24% of patients vs only 8% of those receiving zanubrutinib; grade 3/4 atrial fibrillation was seen in 8% vs 2%, respectively.⁹ Nearly all other AEs of interest also were more common with ibrutinib, with the notable exception of neutropenia (20% with ibrutinib vs 35% with zanubrutinib). However, this higher rate of neutropenia in the zanubrutinib arm did not translate into a higher rate of infection (27% with ibrutinib vs 22% with zanubrutinib). Other AEs of interest that were noticeably more common with ibrutinib vs zanubrutinib included diarrhea (35% vs 23%) and hypertension (26% vs 15%).

Rates of atrial fibrillation, bleeding, and hypertension were lower with zanubrutinib vs ibrutinib at all time points. In the first year, neutropenia was more common with zanubrutinib (25% vs 11% with ibrutinib), but by 36 months the rate was the same (8.3% vs 9.4% with ibrutinib).

Alessandra Tedeschi, MD:
With long-term follow-up of this phase III ASPEN study, zanubrutinib continues to show deep and durable responses in patients with Waldenström macroglobulinemia, with trends toward improved PFS and OS vs ibrutinib.⁹ The VGPR rates in the cohort with mutated MYD88 were 36.3% with zanubrutinib vs 25.3% with ibrutinib. In the cohort with wild-type MYD88, 31% of patients achieved VGPR or better, with CRs in 4%.

In the mutated MYD88 cohort, there were only nonsignificant trends toward improved PFS and OS with zanubrutinib at 42 months. By contrast, a more meaningful difference was seen in PFS at 42 months in patients with mutated CXCR4 (73% with zanubrutinib vs 49% with ibrutinib; HR: 0.50).

Zanubrutinib was associated with lower rates of key class effects vs ibrutinib, including atrial fibrillation, diarrhea, and hypertension, leading to fewer dose adjustments, discontinuations, and deaths. However, neutropenia rates are higher with zanubrutinib.

The ASPEN study facilitates personalized treatment in our patients with Waldenström macroglobulinemia because it demonstrates that zanubrutinib provides better quality of responses than ibrutinib and trends toward better PFS and OS in the CXCR4‑mutated and MYD88‑unmutated populations. This suggests that genotype may be able to guide choice of BTK inhibitor.