ASH 2021 Recap: Leukemia & Lymphoma

POLARIX: Upgrading R-CHOP, Replacing Vincristine With Polatuzumab Vedotin, Improves Progression-Free Survival in DLBCL

The classic chemotherapy regimen known as R-CHOP may get an upgrade for patients who are newly diagnosed with diffuse large B-cell lymphoma (DLBCL), based on study results that showed replacing an old therapy, vincristine, with polatuzumab vedotin (Polivy) improved progression-free survival (PFS) by 27%.

The findings, from the phase 3 POLARIX trial,¹ were presented in the late-breaking session of the 2021 American Society of Hematology (ASH) Meeting & Exposition in Atlanta, with sessions also available online. Results were simultaneously published in the New England Journal of Medicine.²

In POLARIX, an international team of investigators set out to find a better first-line treatment for DLBCL than the combination of rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin hydrochloride), vincristine (Oncovin), and prednisone (R-CHOP) that has long been the default option. Although this combination cures 60% of patients, 40% see their cancer progress and may require salvage therapy and autologous stem cell transplant.

Polatuzumab vedotin is an antibody-drug conjugate that targets CD79b, which is expressed on the surface of malignant B cells; it received accelerated approval in 2019³ in combination with bendamustine and rituximab to treat relapsed or refractory DLBCL. It is made by Genentech, which previously announced the topline results of POLARIX.⁴

Vincristine is a widely used chemotherapy that blocks cell division. However, an important challenge with this drug is that it has been in short supply: Some longtime manufacturers have stopped producing it.⁴

In a press briefing before the late-breaking session, study coauthor Gilles Salles, MD, PhD, said there have been many attempts over the 20 years that R-CHOP has been used to modify the combination to boost its success rate, but none have panned out until now.

Although POLARIX found no significant difference in complete response rates or overall survival (OS) at the 2-year mark, patients who took the new combination were less likely to need additional treatment compared with those taking the usual regimen.

“This is the first randomized phase 3 study that has shown a benefit in patients with first-line DLBCL. It shows that it is possible to significantly reduce disease progression, including in patients with difficult-to-treat subtypes,” Salles said. “I think this could be a practice-changing result.”

Study Design and Results

Investigators randomized 879 patients aged 18 to 80 years, with 440 assigned to the polatuzumab regimen (called pola-R-CHP) and 439 to R-CHOP. Both groups received 6 cycles of their respective regimen plus 2 cycles of rituximab alone.

The primary end point was investigator-assessed progression-free survival. Secondary end points included OS and safety.

After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group:

• PFS for pola-R-CHP was 76.7% (95% CI, 72.7%-80.8%) vs 70.2% for R-CHOP (95% CI, 65.8%-74.6%) at 2 years; stratified HR for progression, relapse, or death was 0.73 by Cox regression (95% CI, 0.57-0.95; P = .02).
• The complete response rate was similar with pola-R-CHP vs R-CHOP (78.0% vs 74.0%; P = .16); however, disease-free survival responses point to a more durable response with pola-R-CHP than with R-CHOP (HR, 0.70; 95% CI, 0.50-0.98), according to the ASH abstract.
• OS at 2 years did not differ significantly between the groups: 88.7% (95% CI, 85.7%-91.6%) in the pola-R-CHP group vs 88.6% (95% CI, 85.6%-91.6%) in the R-CHOP group; HR for death, 0.94 (95% CI, 0.65-1.37; P = .75).
• The 2 groups had similar safety profiles.

Salles said the POLARIX investigators will keep following participants to learn more about long-term responses and outcomes. They also want to learn more about patient subgroups, to understand whether tumor biology contributes to the different responses to initial treatment. Better first-line treatment for DLBCL may give patients hope and time, as much as ASH 2021 focused on moving chimeric antigen receptor T-cell therapy into earlier lines of treatment in LBCL.

“It is quite satisfying that we were able to improve outcomes without significantly impairing patients’ quality of life,” said Salles. 

References

1. Tilly H, Morschhauser F, Sehn LH, et al. The POLARIX study: polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy in patients with previously untreated diffuse large B-cell lymphoma. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract LBA-1. https://ash.confex.com/ash/2021/webprogram/Paper154729.html
2. Tilly H, Morschhauser F, Sein LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. Published online December 14, 2021. doi:10.1056/NEJMoa2115304
3. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA. June 10, 2019. Accessed December 14, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-diffuse-large-b-cell-lymphoma
4. Al-Quteimat OM.Vincristine shortage: what other options we have? Am J Clin Oncol. 2020;43(2):146-147. doi:10.1097/COC.0000000000000648

SEQUOIA: At 26 Months, Zanubrutinib Prolongs PFS 58% Over Bendamustine + Rituximab in Patients With Treatment-Naïve CLL/SLL

Zanubrutinib, a next-generation Bruton tyrosine kinase (BTK) inhibitor, produced prolonged progression-free survival (PFS) compared with a combination of bendamustine and rituximab (BR) among treatment-naïve patients with chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), according to new trial results presented during the 2021 American Society of Hematology Meeting & Exposition, held in Atlanta and online.¹

Constantine Tam, MBBS, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, outlined interim phase 3 findings from 2 arms of the SEQUOIA trial. He presented remotely, but beyond the masks, the ASH session on CLL looked like a scene from before the pandemic, with attendees filling most of the chairs or standing in the small space at the rear of the meeting room. The results from SEQUOIA came last, and Tam began with background on the transformation of CLL treatment with the rise of B-cell receptor signaling inhibitors, notably the BTK inhibitors zanubrutinib and acalabrutinib.

Tam said that 2 large head-to-head randomized trials have shown that zanubrutinib has a reduced risk of adverse events (AEs) compared with the first-generation BTK inhibitor ibrutinib, which is approved to treat CLL.BTK inhibitors generally are associated with atrial fibrillation (AF), but this has been reduced with zanubrutinib compared with ibrutinib. In SEQUOIA, 3.3% of patients in the zanubrutinib arm had an AF of any grade, vs 2.6% in the comparator arm.

Four Arms of SEQUOIA

Tam explained that the SEQUOIA trial has 4 arms, and that he was presenting interim results from arm A and arm B, both of which are from cohort 1, in which patients are without deletion (17p) [del(17p)]. Cohort 2, with arm C and arm D, has patients with del(17p). All patients had untreated CLL/SLL, and Tam said 80% are older than 65 years, with an mean age of 70 years.

In arm A, patients received zanubrutinib 160 mg until disease progression, intolerable toxicity, or the end of the study. In arm B, patients received bendamustine 90 mg/m² on days 1 and 2, then rituximab 375 mg/m² for the first cycle, followed by 500 mg/m² for cycles 2 to 6.

From October 31, 2017, to July 22, 2019, 479 patients who met criteria for arms A and B were randomized for zanubrutinib (241 patients) or the combination of bendamustine and rituximab (238 patients). Unmutated immunoglobulin heavy chain variable (IGHV) was present in 53.4% vs 52.4% of patients, respectively, and del(11q) was present in 17.8% vs 19.3%.

Males made up the majority of both arm A (63.9%) and arm B (60.5%). In both arms, most patients were from Europe, with 72.2% in Arm A and 72.3% in Arm B; 14.1% and 11.8%, respectively, were from North America, and 13.7% and 16.0% were from Asia/Pacific.

At median follow-up of 26.2 months, PFS as determined by an independent review committee (IRC), which was the primary end point, significantly favored zanubrutinib (HR, 0.42; 95% CI, 0.28-0.63; P < .0001).

Secondary end points included safety assessments. The most common AEs besides AF included bleeding of any grade and of grade 3 or higher: These results were 45.0% and 3.8%, respectively, for zanubrutinib, vs 11.0% and 1.8% for BR. Other AEs included hypertension of any grade, 14.2% for zanubrutinib vs 10.6% for BR; infection of any grade and grade 3 or higher, 62.1% and 16.3%, respectively, for zanubrutinib, vs 55.9% and 18.9% for BR; and neutropenia of any grade and grade 3 or higher, 15.8% and 11.7% for zanubrutinib vs 56.8% and 51.1% for BR. Other secondary end points included:

• Estimated 24-month PFS: by IRC, 85.5% with zanubrutinib (95% CI, 80.1%-89.6%) vs 69.5% with BR (95% CI, 62.4%-75.5%)
• Objective response rate: by IRC, 94.6% (95% CI, 91.0%-97.1%) with zanubrutinib vs 85.3% with BR (95% CI, 80.1%-89.5%).Complete response rate: 6.6% with zanubrutinib vs 15.1% with BR
• Estimated 24-month overall survival (OS): 94.3% (95% CI, 90.4%-96.7%) with zanubrutinib vs 94.6% (95% CI, 90.6%-96.9%) with BR

Reporting OS is challenging, Tam explained, because patients in arm B who progressed were permitted to cross over to receive zanubrutinib; 15 patients did this and improved on the therapy. Thus, zanubrutinib’s advantage in OS might be impossible to know. In response to a question, he said, “We do know [zanubrutinib] is very reliable as a second-line agent…so there’s no reason to believe that those patients didn’t do well.”

He said the benefits of zanubrutinib occurred “across every important prognostic subgroup,” except for a small group of patients with mutated IGHV (HR, 0.67; 1-sided P = .0929).

Adverse Events

When looking at a table of common AEs such as rash, nausea, constipation, anemia, pyrexia, and thrombocytopenias, Tam noted that all were seen far less in the zanubrutinib arm.

“Looking at the more common AEs, including nausea, as well as an increased risk of cytopenias, even looking at the adverse events of special interest—once again, no surprises here,” Tam said.

More patients in the BR group stopped treatment due to AEs (31 patients; 13.7%) than in the zanubrutinib group (20 patients; 8.3%). AEs leading to death occurred in 11 patients in the zanubrutinib group (4.6%) vs 12 patients in the BR group (5.3%). No sudden deaths were reported.

In response to a question about infections, Tam revealed a remarkable point about the difference between the 2 arms: The most common infection was grade 2 upper respiratory tract infections. “We know the clinical significance of COVID is very important,” he said. As it turns out, the patients in the BR arm had completed treatment when the pandemic hit, but not so for the zanubrutinib arm. Five patients [in the zanubrutinib arm] had severe infections due to COVID-19, and 4 died. “So, there was actually a major difference in the severe infection[s],” Tam said. 

Reference

Tam CS, Giannopoulous K, Jurczak W, et al. SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab (BR) in patients with treatment-naïve (TN) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021, Atlanta, GA. Abstract 396. https://ash.confex.com/ash/2021/webprogram/Paper148457.html

Booster mRNA COVID-19 Vaccine Helps Some Patients With Blood Cancer Produce Antibodies for First Time

A year after the FDA allowed distribution of the first COVID-19 vaccines and a month after booster shots were authorized for Americans over age 18, a registry study has found that a third shot of mRNA vaccine could be crucial for some patients with blood cancers.¹

Data presented by the Leukemia & Lymphoma Society (LLS) at the 2021 American Society of Hematology Meeting & Exposition show that 43% of patients with blood cancers will produce antibodies after receiving a third dose of mRNA vaccine. For most patients, this booster shot comes 6 months after the initial 2 doses, which are given either 3 or 4 weeks apart, depending on the vaccine.

Some patients who received their third dose reached antibody levels on par with healthy adults, confirmed by measuring levels of detectable antibodies to the spike protein in SARS-CoV-2 before and after the third dose of the mRNA COVID-19 vaccines. As of December 13, 2021, two such vaccines were in use in the United States: The Pfizer-BioNTech vaccine was fully approved for adults for the first 2 doses for those 16 years and older and authorized for those aged 5 to 15, and the Moderna vaccine had an emergency use authorization for those 18 years and older.

Results from a study based on the LLS registry demonstrated that patients with blood cancers who had at least some antibodies after the first 2 doses are likely to produce large amounts after they receive their boosters.

“Our data [show] a clear benefit of giving blood cancer patients 3 primary vaccine doses, but there is still a large portion of patients who will remain at risk even with the additional dose,” Lee Greenberger, PhD, LLS chief scientific officer, said in a statement.²

In this study, about 20% (139 of 699) of patients with blood cancer still had no measurable COVID-19 antibodies after the third dose. The results, reported December 11, 2021, come from the largest pool of patients with blood cancer reported thus far.

As of July 2021, the LLS registry includes 24 patients who received a third dose of an mRNA vaccine. Twenty of these patients were seronegative more than 14 days after their second shot, as measured by the Roche Elecsys assay; 4 patients had low positive serology results. All patients were nucleocapsid antibody negative.

These patients ranged in age from 51 to 79 years; 11 had chronic lymphocytic leukemia; 7, non-Hodgkin lymphoma; 5, Waldenström macroglobulinemia; and 1, multiple myeloma. As for therapy, 6 patients were not currently receiving anti–B-cell therapy; 11 had received anti-CD20 therapy, including 8 within the prior 6 months; 6 had received Bruton tyrosine kinase inhibitors within the past 6 months; and 1 had received recent chemotherapy.

Third shots were received between April and June 2021, 21 to 114 days after patients their second shot; clinical guidelines called for patients with cancer to get boosters first and have shifted to give the third shot earlier to some patients, with a fourth added later.

The abstract offered details of each patient’s type of therapy and response to the vaccine. “In this limited set of patients, there was no evident pattern of antibody response amongst patients who received homologous versus heterologous vaccine nor between disease types,” the authors wrote. “While anti-CD20 therapy appeared to reduce antibody response to booster vaccination, there was substantial heterogeneity.”

The authors noted that although patients with B-cell malignancies did not mount a robust response to the first 2 mRNA vaccines, several patients demonstrated an antibody response to the booster. The authors called for clinical trials to understand which patients may benefit from a booster strategy, whether prior therapy affects response to vaccines, and how to offer these shots safely.

References

1. Greenberger LM, Saltzman LA, Senefield JW, Johnson PW, DeGennaro LJ, Nichols GL. SARS-CoV-2 antibody levels in blood cancer patients after a third SARS-CoV-2 “booster” vaccination—observational data from the LLS national registry. Presented at: 63rd American Society of Hematology Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 185. https://ash.confex.com/ash/2021/webprogram/Paper151419.html
2. Largest study to date demonstrates most blood cancer patients benefit from a third primary dose of mRNA COVID-19 vaccine. News release. Leukemia & Lymphoma Society. December 13, 2021. Accessed December 17, 2021. https://prn.to/3Fdml5t

Findings Show Need for Earlier Conversations About End-of-Life Care With Patients Who Have High-Risk AML

Results of a study of older adults with high-risk acute myeloid leukemia (AML) reveals missed opportunities for doctors to discuss end-of-life decisions when patients can still understand their options and express their wishes.¹

The findings, presented during the 2021 American Society of Hematology Meeting & Exposition, come 6 years after the Institute of Medicine report Dying in America found that most clinicians fail to initiate conversations with patients about end-of-life preferences, especially if patients are poor or young or have less education.² The need for better medical education in this area has received more attention over the past decade, but gaps remain.³

In the new study, investigators from Massachusetts General Hospital in Boston found that 60.5% of patients with AML took part in their final change of code status, the term used in hospitals and other health care settings to show whether lifesaving interventions will be given. The results suggest that 39.5% of the patients were too ill to take part in discussions about their own end-of-life care.

This leaves families and clinicians to make choices about resuscitation or other measures without the patient’s participation, study author Hannah R. Abrams, MD, clinical fellow in medicine at Massachusetts General Hospital, said during a press briefing held during the meeting.

“The code status often reflects a deeper conversation happening between patients and clinicians about what the patient’s goals are,” Abrams said. “We found that patients and physicians are having these conversations very late in the course of disease.”

For this study, investigators examined health records for 200 patients with high-risk AML who were treated in academic medical settings to identify the timing and nature of conversations leading to code status changes. Records were obtained from 2014 to 2021; high-risk AML was defined as either relapsed or refractory AML or newly diagnosed in patients 60 years or older. Investigators assessed transitions between full code, which calls for all lifesaving measures to be taken; restricted codes, including “do not resuscitate” and “do not intubate,” which bar certain measures only; and comfort measures only.

Among the patients, 86.0% were “full code,” and 8.5% had restrictions on life-sustaining therapies. Overall, 57% experienced a code status transition, with a total of 206 transitions across the group. The median time from diagnosis to the first code status transition was 212 days; most code changes took place in the final weeks of life, with a median of 2 days between the last code change and a patient’s death. More than half of the conversations leading to code status changes occurred when intensive life-sustaining measures were deemed futile and were transitions to comfort measures, whereas just 1 in 6 involved preemptive conversations held before a major health transition (15.6%). Two other processes that led to conversations were anticipatory conversations at the time of acute clinical deterioration (32.2%) and futility conversations after acute clinical conversations, focused on withdrawing life-sustaining therapies (51.0%).

Both older age and receipt of nonintensive chemotherapy were associated with a shorter period from the last code status transition to death compared with preemptive or anticipatory conversations. Investigators found that “a substantial minority” of the final code status transitions took place in the intensive care unit or emergency department (26.3%).

“It’s not built into our clinic visits to talk about this earlier in a patient’s course with AML,” Abrams said. Having these conversations preemptively during routine outpatient visits could help ensure that patients have an accurate understanding of their prognosis and help clinicians align treatment strategies with patients’ goals and preferences, she said. It is also important to have these discussions with patients more than once, because patients’ attitudes can shift as their disease progresses.

Investigators found that palliative care specialists were involved in just 42% of final code transitions, pointing to an area of need for people with high-risk AML.

Sharing these data could lead to both clinicians and patients starting these conversations much earlier, allowing patients to be more involved in their own end-of-life care, she said. 

References

1. Abrams HR, Nipp RD, Traeger L, et al. Code status transitions in patients with high-risk acute myeloid leukemia. Presented at: 63rd American Society of Hematology Meeting &Exposition; December 11-14, 2021; Atlanta, GA. Abstract 109. https://ash.confex.com/ash/2021/webprogram/Paper146451.html
2. Institute of Medicine. Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life. National Academies Press; 2015.
3. Sutherland R. Dying well-informed: the need for better clinical education surrounding facilitating end-of-life conversations. Yale J Biol Med. 2019;92(4):757-764.