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My Thoughts on the Implications of Key New Data in B-Cell Malignancies From ASCO and EHA 2020

Lydia Scarfò, MD

Assistant Professor
Internal Medicine
Università Vita-Salute San Raffaele
Consultant Hematologist
Strategic Research Program on CLL
Milan, Italy

Lydia Scarfò, MD, has disclosed that she has received consulting fees from AbbVie, AstraZeneca, Gilead Sciences, and Janssen.

View ClinicalThoughts from this Author

Released: July 16, 2020

In this commentary, I share my key take-aways from the 2020 ASCO and EHA virtual annual meetings focused on clinically meaningful presentations of new data that have the potential to affect our management of patients with various B-cell malignancies. 

Waldenström Macroglobulinemia (WM)
The first study that I want to highlight is the phase III ASPEN trial in WM that compared the next-generation BTK inhibitor zanubrutinib with ibrutinib, which is approved in this setting. This study showed a response (VGPR plus CR) rate with zanubrutinib that was similar, if not more favorable, than ibrutinib and with a more favorable safety profile. Lower incidences of all-grade and grade ≥ 3 atrial fibrillation, diarrhea, and hemorrhage were observed with zanubrutinib compared with ibrutinib, whereas patients receiving zanubrutinib had a higher probability of neutropenia (any grade and grade ≥ 3) but without an increased risk of infection. The results of this study may support the approval of zanubrutinib for patients with WM, expanding the therapeutic armamentarium in this space while providing a safer and more tolerable drug in terms of BTK inhibitor–associated adverse events (AEs).

Chronic Lymphocytic Leukemia (CLL)
Final results of the ASCEND trial were also presented and demonstrated an estimated 18-month PFS of 82% in the acalabrutinib arm vs 48% in the investigator’s choice (idelalisib/rituximab or bendamustine/rituximab) arm in patients with relapsed/refractory CLL. Furthermore, a progression-free survival benefit was observed in patients with high-risk characteristics such as del(17p) and/or TP53 mutation and unmutated IGHV. Regarding the safety profile, the discontinuation rate due to AEs was higher in the idelalisib/rituximab arm compared with acalabrutinib (16%) and bendamustine/rituximab (56% vs 16% vs 17%, respectively). Although not yet available in Europe, these data support the use of acalabrutinib in patients with relapsed/refractory CLL because of the favorable tolerability profile and high efficacy even in patients with high-risk disease.

Results from the long-term follow-up of the phase II study of acalabrutinib in patients with treatment-naive CLL (presented at EHA by John Byrd and colleagues) supported the idea that acalabrutinib can achieve durable responses without  new long-term safety concerns. After a median follow-up of 53 months, 86% of patients remained on acalabrutinib treatment. The ORR was very high (97%), with a CR of 7%, and was consistent in the different high-risk groups (unmutated IGHV, del[17p], TP53 mutation, complex karyotype); the 48-month event-free survival rate was 90%.

Al-Sawaf and colleagues presented an update on the safety and efficacy of first-line treatment with venetoclax/obinutuzumab compared with chlorambucil/obinutuzumab in previously untreated patients with CLL from the multicenter, open-label, randomized phase III CLL14 trial. Overall, the 2-year PFS was improved with venetoclax/obinutuzumab (HR: 0.31), but this trend was not observed in patients with TP53 aberrations. Although the undetectable measurable residual disease (uMRD) rate at 18 months was 47.2% and 7.4% in the venetoclax/obinutuzumab and chlorambucil/obinutuzumab arms, respectively, patients with TP53 aberrations, complex karyotype, and high-risk CLL-International Prognostic Index were associated with higher risk of MRD relapse after having previously achieved uMRD. No new safety signals emerged except for an increase of other neoplasms, particularly solid organ tumors, in patients treated with venetoclax/obinutuzumab (6.4%) compared with 1.9% of those in the control arm, that deserves further studies. Although much remains to be clarified regarding MRD kinetics and ways to improve disease eradication in patients with residual disease after treatment completion, the results of this study hold promise to eliminate the use of chemoimmunotherapy as a first-line treatment option in patients 65 years of age or older and for those with mutated IGHV.

In another study reported by Zelenetz and colleagues, the addition of zanubrutinib to venetoclax and obinutuzumab was analyzed in patients with treatment-naive CLL in effort to achieve more frequent uMRD responses and to apply an MRD-driven treatment duration strategy to identify the optimal duration of this regimen. At a median follow-up of 11 months, 84% of patients achieved an uMRD response in the peripheral blood and 73% of patients achieved an uMRD response in the bone marrow. Sixty-two percent of patients have met the prespecified MRD endpoint and, therefore, discontinued therapy at a median of 8 months (6 months of triplet therapy). At the time of per protocol treatment discontinuation, 43% of patients were in a PR, with 57% of patients in a CR/CR with incomplete marrow recovery. No clinical or laboratory tumor lysis syndrome occurred with venetoclax, and the AE profile was as expected, with few grade ≥ 3 AEs reported. This study serves as a proof of principle that combining targeted agents with different mechanisms of action based on an MRD-guided approach is feasible and achieves high rates of uMRD. Although longer follow-up is needed to confirm this strategy and duration of response, the results will likely pave the way for additional trials following an MRD-guided design.

In relapsed/refractory CLL, the CLARITY trial, presented by Rawstron and colleagues, combined venetoclax and ibrutinib and used an MRD-driven approach with the duration of treatment defined based on the time required to achieve uMRD and with treatment potentially discontinued after 3 consecutive uMRD measurements in peripheral blood samples and confirmed with bone marrow sampling. The CR rate improved steadily over time, reaching 62% at Month 26 with 40% of patients achieving uMRD in bone marrow after 12 months. Patients who achieved uMRD at Month 26 had a median 2.9-log CLL depletion at Month 4, whereas patients with detectable MRD at Month 26 had a median 1.4-log CLL depletion at Month 4. Furthermore, 70% of patients with > 2-log depletion after 2 months of venetoclax/ibrutinib stopped treatment following confirmed uMRD. Of the 23 patients who stopped treatment due to confirmed uMRD, 8 experienced MRD relapse (6 patients: 0.01% to 1% in peripheral blood; 2 patients: > 1% MRD). These data suggest that rapid disease clearance may be a reliable predictor of uMRD achievement with venetoclax/ibrutinib and that the initial rate of disease depletion may be highly predictive of longer-term response to this combination regimen in relapsed/refractory CLL.

Mantle Cell Lymphoma (MCL)
Ibrutinib plus venetoclax in combination with obinutuzumab was evaluated in patients with newly diagnosed MCL by Le Gouill and colleagues in a phase I/II trial to potentially bypass mechanisms of resistance. Here, findings suggest synergistic mechanisms contribute to very high CR rates early in the treatment duration (CR by cycle 6 was 86%; PR was 7%) with an ORR of 93%. All 12 evaluable patients achieved uMRD by cycle 3. Treatment was well tolerated without any relevant clinical manifestations. The results of this study are overwhelmingly positive, with a 2-year OS rate of 100%, warranting the need for larger clinical trials and supporting the potential use of this regimen as a first-line treatment option in patients with newly diagnosed MCL.

Hodgkin Lymphoma (HL)
HL frequently affects young people and although treatment is associated with high cure rates, this success with risk of treatment-related AEs, including cardiovascular, pulmonary, endocrine AEs; fertility impairment; and/or second malignancies over the course of prolonged follow-up. As such, there remains great interest in safely reducing treatment intensity to avoid long-term toxicities, particularly those related to radiotherapy but without compromising the cure rate. Combined modality treatment methods including chemotherapy and involved-field radiotherapy have largely been the standard of care in patients with early-stage unfavorable HL. Borchmann and colleagues reported the final results from the GHSG randomized phase III HD17 trial evaluating PET-guided omission of radiotherapy in patients with early-stage unfavorable HL. No significant difference in 5-year PFS rate was observed with chemoradiation (chemotherapy ABVD x 2 and BEACOPP x 2 + 30 Gy consolidation radiotherapy) compared with chemotherapy alone in patients with PET-negative scans after 4 cycles (PET4). Thus, radiotherapy can be safely omitted in the vast majority of patients with early-stage unfavorable HL. However, patients with PET4-positive disease have a worse prognosis than PET4-negative patients even with combined modality therapy. Additional results from this study indicated that patients with PET4-positive disease and a Deauville score ≥ 4 had a relevant risk of treatment failure (PFS rate at 5 years of 81.6%) and need to be identified earlier to tailor treatment. Based on these results, an individualized approach for patients with early-stage unfavorable HL responding to systemic therapy as determined by PET4 is desirable in clinical practice. In addition, PET-guided 2 + 2 chemotherapy with ABVD and BEACOPP is becoming the new GHSG standard of care for these patients based on 5-year OS outcomes that are comparable to the normal German population.

To date, there is no standard of care for patients who are ineligible for autologous stem cell transplant (ASCT) due to chemotherapy-refractory HL, comorbidities, or advanced age. Currently, pembrolizumab is only approved for heavily pretreated patients with relapsed/refractory HL. Results from the randomized, open-label phase III KEYNOTE-024 trial demonstrated prolonged PFS with pembrolizumab vs brentuximab vedotin in patients with relapsed/refractory HL who relapsed after or were ineligible for ASCT. The reported median PFS with pembrolizumab was 13.2 months vs 8.3 months with brentuximab vedotin (HR: 0.65), with 1-year PFS rate estimates of 53.9% vs 35.6%, respectively. The ORR with pembrolizumab was 65.6% vs 54.2% with brentuximab vedotin, which did not reach the predefined statistical level of significance. Treatment-related AEs were similar, with grade 3/4 events occurring in 19.6% of patients treated with pembrolizumab vs 25% for patients treated with brentuximab vedotin. Serious treatment-related AEs were numerically more frequent in the pembrolizumab arm at 16.2% vs 10.5% in the brentuximab vedotin arm, along with an expected higher incidence of immune-related AEs with pembrolizumab. Based on these results, pembrolizumab should be considered the preferred standard-of-care treatment option for patients with relapsed/refractory classical HL who have relapsed following previous ASCT or who are ineligible for ASCT.

Diffuse Large B-Cell Lymphoma (DLBCL)
Finally, the phase I ALEXANDER trial evaluated the combination of the first bicistronic CAR T-cell therapy targeting CD19 and CD22 (AUTO3) and pembrolizumab in patients with relapsed/refractory DLBCL. Although currently available CD19 CAR T-cell therapies are highly active in relapsed lymphomas, durable CRs are seen in only approximately 1 of 3 patients. Moreover, patients with relapsed/refractory DLBCL who fail CAR T-cell therapy have limited treatment options. In ALEXANDER, Osborne and colleagues target the potential pathways responsible for relapse following CAR T-cell therapy, which include PD-L1 upregulation leading to T-cell exhaustion, as well as CD19 antigen loss. The trial included 23 patients with high-risk relapsed/refractory DLBCL to evaluate the ability of AUTO3 to simultaneous target CD19 and CD22 to reduce the probability of antigen escape as well as adding pembrolizumab to the preconditioning regimen to prevent CAR T-cell exhaustion. AUTO3 was successfully manufactured for all 23 patients with relapsed/refractory DLBCL. The authors reported an ORR at all AUTO3 dose levels of 65% with the CR rate of 48%. At the recommended phase II dose (150-450 million cells) the ORR was 69% with a CR rate of 56%. Among patients who received the recommended phase II dose and preconditioning with pembrolizumab the day before CAR T-cell infusion, the CR rate was 63%. Safety data reported that the majority of grade 3 AEs were hematologic in nature, with incidence of cytokine-release syndrome to be manageable to a grade 1 severity. One case of grade 3 neurotoxicity presented, which was resolved with a short course of corticosteroids. Of note, there were no reported dose-limiting toxicities or deaths related to treatment with AUTO3. Overall, the safety and efficacy of AUTO3 in combination with pembrolizumab preconditioning is very promising. Considering the improved safety profile, the study has now opened an outpatient expansion cohort. It will be interesting to see the results of this cohort to understand if CAR T-cell therapy can be moved to the outpatient setting.

Your Thoughts?
How will these findings change your current practice for your patients with B-cell malignancies? Were there other trial results that you found interesting related to the care of your patients with B-cell malignancies? Please share your thoughts in the comment box below, and be sure to access the corresponding highlight slides and audio podcasts, coming soon!

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