ASH 2022: From Our Partners

Examining Safety, Efficacy of Pirtobrutinib in CLL/SLL, MCL, and WM; Results Seen for Patients With Intolerance to Covalent BTK Inhibitors

Pirtobrutinib, an investigational, highly selective Bruton tyrosine kinase (BTK) inhibitor, demonstrated promising efficacy and safety across multiple types of B-cell lymphoma in abstracts presented during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition.^1-4

The reversible, noncovalent BTK inhibitor is being studied in patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), and other conditions including Richter syndrome.⁵ Starting with ibrutinib in 2014, covalent BTK inhibitors have transformed treatment of CLL and other B-cell hematologic malignancies, but resistance and intolerance cause problems for many patients. Although off-target effects have been reduced with second-generation BTK inhibitors, some patients still experience adverse events (AEs) that lead to discontinuation. For these patients, pirtobrutinib may offer a treatment option.

“One striking property of this drug is there is really low toxicity,” said M. Lia Palomba, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, who presented data on WM in an oral session. When asked what the ultimate role of pirtobrutinib would be relative to existing BTK inhibitors, she said this was not yet clear but noted that a study for use in first-line CLL is already approved.

The phase 1/2 BRUIN study (NCT03740529), a wide-ranging study that has tested pirtobrutinib in 773 patients,⁵ featured coauthors from Strategic Alliance Partners of The American Journal of Managed Care®. Manish R. Patel, MD, director of drug development at Florida Cancer Specialists and Research Institute; and Ian W. Flinn, MD, PhD, a medical oncologist with the Center for Blood Cancers, Tennessee Oncology, and director of lymphoma research, Sarah Cannon Research Institute, both in Nashville, were coauthors on abstracts detailing extended follow-up in CLL/SLL and results for patients previously intolerant of BTK inhibitors^1-2; in addition, Patel was the second author on an abstract detailing results on a cohort with WM,³ and Flinn was a coauthor on an abstract focusing on MCL.⁴

Extended Follow-up in CLL/SLL
BRUIN was a phase 1 dose escalation study followed by a phase 2 expansion cohort study, which tested a recommended phase 2 oral dose of 200 mg/d. At the data cutoff of January 31, 2022, the expansion cohort consisted of 276 patients with CLL/SLL who had enrolled in phase 1 or 2 who had prior covalent BTK inhibitor treatment and had been assessed following treatment or discontinuation.¹ Key end points were overall response rate (ORR), progression-free survival (PFS), and safety. Patients had received several other therapies, including anti-CD20 therapy (89%) and chimeric antigen receptor T-cell therapy (6%). Many patients had high-risk features, including 85% with unmutated immunoglobulin heavy chain variable region gene (IGHV); 75% of the group discontinued prior BTK inhibitor therapy due to disease progression.

Results. In this group with relapsed/refractory CLL/SLL, the ORR by investigator assessment was 74% (95% CI, 69-79), with 3 complete responses (CR, 1%), 174 partial responses (PR, 64%), 23 PRs with lymphocytosis (8%), and 1 nodular PR (< 1%). After a median follow-up of 13.9 months, estimated PFS was 68% (95% CI, 62-74) for 12 months and 54% (95% CI, 46-61) for 18 months. The most common treatment-emergent AEs (TEAEs) were fatigue (26%), diarrhea (22%), and contusion (18%); grade 3 or higher neutropenia was seen in 20% of patients. Investigators found low rates of grade 3 or higher cardiac related TEAEs, including hypertension (3%), hemorrhage (2%), and atrial fibrillation/flutter (1%); 2% of patients stopped taking the drug due to TEAEs.

Results for Those Previously Intolerant to Covalent BTK Inhibitor
Nirav N. Shah, MD, an associate professor at Medical College of Wisconsin, presented data for an abstract that evaluated responses to pirtobrutinib among patients across multiple disease types who had stopped taking covalent BTK inhibitors.2 Shah explained that although second-generation BTK inhibitors are more selective than ibrutinib, “the frequency of cytopenias, infections, and diarrhea have not technically decreased.” Any interruption of treatment can adversely affect outcomes, he said.

Shah explained the mechanism of action for pirtobrutinib, which he noted had been previously shown to be well tolerated with “promising efficacy in poor-prognosis B-cell malignancies,” in patients who had received prior treatments.

“It’s highly selective for BTK; it inhibits both wild-type and C41 mutant BTK,” he said, adding that the “favorable oral pharmacology allows continuous BTK inhibitor inhibition regardless of the intrinsic rate of BTK turnover.”
He presented results for 127 patients who had been BTK intolerant coming into BRUIN. The median time on treatment was 10 months for the overall study population (773 patients) compared with 15 months for the 127 patients who were BTK intolerant. The ORR was 76.9% in CLL/SLL (95% CI, 66.9-85.7) and 81.0 (58.1-94.6) with a 42.9% CR rate in MCL.

Discontinuations due to treatment-related AEs occurred in 2.6% of the overall study population (20 patients) compared with 6% of the BTK-intolerant population (7 patients).

AEs of any grade were similar between the overall study population and the BTK-intolerant population except for neutropenia; 14.7% of the overall population had neutropenia compared with 21.3% of the BTK-intolerant population. For grade 3 or higher events, BTK-intolerant patients were more likely to have neutropenia (17.3% for the BTK-intolerant group vs 11.5% for the overall group) and fatigue (1.6% vs 0.8%).

The other AE of grade 3 or higher reported was anemia, 2.4% in the BTK-intolerant group vs 2.1% in the overall population. AEs of special interest in grade 1-2 were bruising (15.1% overall vs 26.8% BTK intolerant), rash (6.0% overall vs 8.7% BTK intolerant), arthralgia (3.5% overall vs 4.7% BTK intolerant), hypertension (3.4% overall vs 3.1% BTK intolerant), and atrial fibrillation 0.8% both overall and BTK intolerant). No AEs or higher were reported in more than 0.1% of the study population.

First “Sizable Cohort” in WM
Palomba reported on a cohort of 80 patients treated prior to the data cutoff on July 29, 2022; 63 had previously been treated with a covalent BTK inhibitor; the median number of overall prior therapies was 3. Investigators described this as the first time results for pirtobrutinib had been reported in a “sizable cohort” of patients with WM.

The major response rate (MRR) was 67% (95% CI, 53.7-78.0); of the group, 15 (23.8%) had a very good PR and 27 (42.9%) had a PR. For patients previously treated with both covalent BTK inhibitor and chemoimmunotherapy, MRR was 68% (95% CI, 53.3-80.5). Among patients previously treated with a covalent BTK inhibitor, median PFS was 19.4 months (95% CI, 15.1- 22.1); median overall survival was not reached. WM safety profiles were consistent with the overall treatment population.

Results in Mantle Cell Lymphoma
Results reported at ASH evaluated 90 patients with MCL before the January 31, 2022, cutoff date; all had been treated with a BTK inhibitor. Patients had received a median of 3 prior treatments. Pirtobrutinib produced ORR of 58% (95% CI, 46.0-68.`) and a median duration of response of 21.6 months (95% CI, 7.5-not evaluable), as well as a median PFS of 7.4 months (95% CI, 5.3-12.5). Response rates were not affected by the number of prior lines of therapy or classes of therapy used previously. 

References
1. Mato AR, Woyach JA, Brown JR, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed / refractory CLL/SLL: additional patients and extended follow-up from the phase 1/2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA: December 10-13, 2022; Abstract 961. https://ash.confex.com/ash/2022/webprogram/Paper159497.html
2. Shah NN, Wang ML, Brown JR, et al. Safety and tolerability of pirtobrutinib monotherapy in patients with B-cell malignancies who were previously intolerant to a covalent BTK inhibitor: results from the phase 1/2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA: December 10-13, 2022; Abstract 1797. https://ash.confex.com/ash/2022/webprogram/Paper159035.html
3. Palomba ML, Patel MR, Eyre TA, et al. Efficacy of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor in relapsed/refractory Waldenström macroglobulinemia: results from the phase 1/2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA: December 10-13, 2022; Abstract 229. https://ash.confex.com/ash/2022/webprogram/Paper159123.html
4. Wang ML, Shah NN, Jurczak W, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pretreated relapsed/refractory mantle cell lymphoma; additional patients and extended follow-up from the phase 1/2 BRUIN study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; New Orleans, LA: December 10-13, 2022; Abstract 4218. https://ash.confex.com/ash/2022/webprogram/Paper159425.html
5. Loxo@Lilly presents updated pirtobrutinib data from the phase 1/2 BRUIN clinical trial at the 2022 American Society of Hematology Annual Meeting. News release. Eli Lilly. December 12, 2022. https://investor.lilly.com/news-releases/news-release-details/loxolilly-presents-updated-pirtobrutinib-data-phase-12-bruin

In Community-Based Study, Switching to Ixazomib in Newly Diagnosed MM Brought Improved Responses Across Age Groups

Patients younger and older than 75 years with newly diagnosed multiple myeloma had improved responses after transitioning from bortezomib-based therapy to an all-oral regimen of ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone without harming quality of life (QOL), according to results from a community-based study.

A subgroup analysis from US MM-6 (NCT03173092), presented in December 2022 during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, Louisiana, showed that regardless of age, patients with MM were able to experience improved responses to the proteasome inhibitor ixazomib after switching from bortezomib (Velcade) after 3 cycles.¹

“Achieving prolonged therapy with parenteral proteasome inhibitors (PI) in MM can be challenging in routine practice due to issues relating to poor tolerability and the burden of repeated, clinic-based treatment administration, particularly for older patients and those with comorbidities,” the investigators wrote.

According to the abstract, previously reported results showed that patients who received the regimen of ixazomib, lenalidomide, and dexamethasone (iRd) after bortezomib had improved clinical outcomes and maintained QOL. The new analysis presented at ASH examined the data by age group: those younger than 75 years and those 75 years and older.

The community-based setting for the study was key because moving patients out of a hospital clinic was seen as step toward improving QOL. Both the first author of the abstract, Ruemu E. Birhiray, MD, partner with Hematology-Oncology of Indiana in Indianapolis, and several coauthors practice with leading community oncology networks that are Strategic Alliance Partners of The American Journal of Managed Care®. Hematology Oncology of Indiana is part of the American Oncology Network; coauthors Robert M. Rifkin, MD, FACP, of Rocky Mountain Cancer Centers in Denver, Colorado; Christopher A. Yasenchak, MD, of Willamette Valley Cancer Institute and Research Center in Eugene, Oregon; and Roger M. Lyons, MD, FACP, of Texas Oncology in San Antonio, are all part of The US Oncology Network.

Patients were enrolled at community sites to receive iRd for up to 39 cycles or until disease progression or toxicity. Key secondary end points included rates of partial, very good partial, and complete response; and duration of therapy (DOT).

Characteristics. Of the 140 patients receiving iRd as of February 28, 2022, 81 were younger than 75 years (58%) and 59 were 75 years or older (42%). For the younger group, the median age was 69 years (range 49-74); for the older group, the median age was 77 years (range 75-90). In the younger group, 60% were men, compared with 54% for the older group; 19% of the younger group were Black, compared with 17% for the older group; 11% of the younger group were Hispanic, compared with 5% for the older group; and 30% of the younger group had stage III disease, compared with 34% of the older group.

Among the patients enrolled, 47% of the younger group had lytic bone disease, compared with 44% of the older group; 91% of the younger group and 97% of the older group had at least 1 comorbidity at the start of iRd.

Results. Overall response rate increased from 60% at the end of bortezomib induction to 79% after transition to iRd in patients younger than 75 years; it increased from 64% to 76% in those 75 years and older.

Treatment was stopped due to progressive disease in 20% of the younger group vs 19% of the older group; due to adverse events (AEs) in 29% of the younger group vs 17% of the older group; and due to other reasons in 35% of the younger group vs 38% of the older group.

With a median follow-up of 20 months, 22% of those in the younger group and 17% in the older group were still on study treatment. Median DOT was 11.8 months and 8.5 months for iRd, respectively, and 14.8 months and 11.1 months for total PI-based therapy.

Adverse events. Treatment-emergent AEs were seen in 98% of the younger patients and 95% of the older patients, of which 81% and 75% were considered treatment-related, respectively. Serious treatment-emergent AEs were seen in 41% and 47% of the respective groups, with 14% of the serious events in each group considered treatment-related. Each age group had 2 on-study deaths. The most common treatment-emergent AEs were diarrhea (47% and 49% in the younger and older groups), peripheral neuropathy not otherwise classified (43% and 34%, respectively), and fatigue (36% and 31%). The most common AEs grade 3 or higher in younger patients were diarrhea (7%), neutropenia (6%), anemia (6%), and decreased platelets (6%).

Among older patients the most common grade 3 or higher AEs were diarrhea (10%), pneumonia (8%), and hypokalemia (7%). AEs led to modification/discontinuation of any of the 3 drugs in 60%/16% in the younger patients and 58%/14% of the older patients.

Quality of life. “Patient-reported quality of life was assessed via questionnaires that patients completed electronically, and activity and sleep levels were measured using wearable digital devices,” Birhiray explained in the presentation. Overall, EORTC-QLQ-C30 Global Health QOL Score was maintained in both groups, with daily activity and hours of sleep generally maintained. 

Reference
Birhiray RE, Rifkin RM, Yasenchak CA, et al. In-class transition (iCT) from parenteral bortezomib to oral ixazomib therapy in newly diagnosed multiple myeloma (NDMM) in patients from the community-based US MM-6 study: subgroup analyses of the fully accrued dataset in patients aged < 75 and ≥ 75 years. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 3255. https://ash.confex.com/ash/2022/webprogram/Paper163071.html

PolaR-ICE Effective as Second-line Treatment in DLBCL, Bridge to Autologous Stem Cell Transplant

Adding polatuzumab vedotin (polatuzumab, Polivy) to rituximab-based salvage therapy produced strong responses and allowed 61% of patients who had failed their first treatment for diffuse large B-cell lymphomas (DLBCL) to successfully bridge to autologous stem cell transplant (ASCT), according to a phase 2 study (NCT04665765).¹

Results from 41 patients, presented during the 64th American Society of Hematology Annual Meeting and Exposition, could offer an effective option for those with relapsed or refractory DLBCL, even as chimeric antigen receptor (CAR) T-cell therapy becomes standard of care for many patients.

Alex F. Herrera, MD, a hematologist/oncologist who is associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California, presented the findings for a combination called PolaR-ICE (polatuzumab, rituximab, ifosfamide, carboplatin, and etoposide). Polatuzumab, an antibody-drug conjugate that targets CD79b, has been studied with classic chemotherapy combinations in transplant-eligible DLBCL.² It is approved for use after 2 prior therapies in the United States and as a first-line therapy in Europe.

As Herrera and some commenters noted, the data being presented were gathered before results for the ZUMA-7 (NCT03391466) and TRANSFORM (NCT03575351) studies led to approval of CAR T-cell therapy in second-line treatment for DLBCL. And yet, Herrera said, many patients who receive CAR T-cell therapy in the second line still relapse.

CAR T-cell therapy “is not necessarily the standard if they’re transplant eligible,” he said. “So, I think there’s still a role to consider studying this regimen further.”

In concluding remarks, Herrera noted the 61% of patients who proceeded to ASCT after PolaR-ICE is larger than the 36% of patients who proceeded to ASCT in the standard-of-care arm in ZUMA-7 (studying axicabtagene ciloleucel)³ or the 47% who received ASCT in the TRANSFORM trial (studying lisocabtagene maraleucel).⁴

When asked whether PolaR-ICE could even be a bridging therapy for CAR T-cell therapy, Herrera said, “I think that’s a great question.”

Methods. Herrera outlined the study protocol, which called for eligible patients to receive 2 cycles of PolaR-ICE for 2 cycles every 3 weeks with granulocyte colony-stimulating factor, followed by PET-CT. Patients with complete response (CR) proceeded to ASCT or could receive a third cycle of PolaR-ICE at the investigator’s discretion. Patients with partial response (PR) also received a third cycle.

Following ASCT, patients who recovered from toxicities could receive 3 to 4 cycles of polatuzumab consolidation. According to the abstract, a 2-stage design was used with 20 patients enrolled (including lead-in); because 8 CRs were seen, a total of 40 patients were enrolled. Safety and CR were coprimary end points; overall response rate (ORR), progression-free survival (PFS), and overall survival were secondary end points.

Results. Of the 41 patients enrolled, 37 were evaluable for response; 1 died prior to assessment, and 1 was unevaluable and replaced. One patient had clinical progressive disease (PD) and was included in ORR as PD, and 1 patient is pending evaluation. Forty patients have toxicity data available.
Twenty-two patients have received 3 cycles of PolaR-ICE; 16 were treated with 2 cycles, and 2 were treated with 1 cycle. Among 37 evaluable patients plus 1 with PD, 35 had objective response after 2 cycles of PolaR-ICE for an ORR of 92%; 21 (55%) had a CR, 14 (37%) had a PR, 1 had stable disease, and 2 had PD. Overall, the ORR after salvage for PolaR-ICE was 89% with a CR rate of 61%, after 1 patient with PR converted to PD, and 2 with PR converted to CR following a third cycle of treatment.

Thus far, 22 patients have received ASCT and 13 patients reached consolidation polatuzumab. Median follow-up time in survivors is 6.6 months; although Herrera said early data show PFS favors patients whose DLBCL relapsed after first-line treatment, longer follow-up is needed. PFS curves are in the 70% range for the patients who received ASCT, but Herrera cautioned the audience “to pause before drawing too many conclusions.”

The most common treatment-related adverse events (TRAEs) were anemia (78%), nausea (70%), thrombocytopenia (70%), leukopenia (50%), fatigue (48%), and neutropenia (48%). Grade 3 or higher TRAEs were anemia (43%), thrombocytopenia (43%), and neutropenia (43%).

References
1. Herrera AF, Chen L, Crombie JL, et al. Polatuzumab vedotin combined with R-ICE (PolaR-ICE) as second-line therapy in relapsed/refractory diffuse large B-cell lymphoma. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 442. https://ash.confex.com/ash/2022/webprogram/Paper165699.html
2. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304
3. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
4. Kamdar M, Solomon SR, Arnason J, et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6

Additional Results From POLARIX Study Show Improved PFS With No Reduction in HRQOL

New data from the POLARIX study (NCT03274492) show that substituting polatuzumab vedotin (Polivy) for 1 part of a classic first-line chemotherapy combination to manage diffuse large B-cell lymphoma (DLBCL) improved progression-free survival (PFS) without compromising health-related quality-of-life (HRQOL).¹

“These data may represent a benchmark for patient-reported HRQOL in frontline DLBCL in the modern era,” the investigators reported.

The results, presented during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, Louisiana, showed that physical functioning and fatigue scores were similar at baseline and improved during and after treatment for patients in both arms of the POLARIX study. The main results, presented in 2021 at the 63rd ASH Meeting and Exposition in Atlanta, Georgia, showed that combining polatuzumab with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) improved PFS by 27% compared with the standard of care, R-CHOP, which consists of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.²

Jeff P. Sharman, MD, was an author on the original POLARIX study and is the senior author on the HRQOL analysis presented at ASH 2022. Sharman is director of research at the Willamette Valley Cancer Institute and Research Center in Eugene, Oregon, and the medical director of hematology research for The US Oncology Network. The US Oncology Network is a Strategic Alliance Partner of The American Journal of Managed Care®.

In the POLARIX study, 879 patients were randomly assigned 1:1 to receive either Pola-R-CHP (n = 440) or R-CHOP (n = 439). Lymphoma symptom scores were measured using the Functional Assessment Cancer Therapy-Lymphoma subscale. Physical functioning, fatigue, constipation, diarrhea, nausea, and vomiting were measured with the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Patients questionnaire.

Patients who had not experienced progression were given questionnaires during treatment on the first day of cycles 1, 2, 3, and 5 and at the end of treatment. Patients also received questionnaires biannually for 2 years after treatment ended and then once a year for 3 years. Data from patients who experienced clinically meaningful improvements or worsening or no change from baseline in functioning, fatigue, or lymphoma symptom scores were reported based on validated thresholds.

More than 80% of patients responded to questionnaires throughout the study. At baseline, scores for lymphoma symptoms, physical functioning, and fatigue were similar in both treatment arms, and reported levels of constipation, diarrhea, nausea, and vomiting were similarly low. According to the abstract, both Pola-R-CHP and R-CHOP brought rapid improvement in lymphoma symptoms in most respondents beginning with the first cycle; 82.3% and 81.3% of patients experienced clinically meaningful improvement, respectively. Investigators reported this was “sustained with improvement plateauing by the first assessment after [end of treatment].” Results showed improvements in physical functioning (42.4% of patients in the Pola-R-CHP group vs 39.6% of patients in the R-CHOP group) and fatigue (74.8% of patients vs 68.2% of patients, respectively).

Between cycle 2 and the end of treatment, diarrhea was more frequently reported in the Pola-R-CHP group (17%-34%) than the R-CHOP group (18%-24%), and constipation was more frequently reported with the R-CHOP group (21%-42%) than the Pola-R-CHP group (23%-35%). For both groups, diarrhea and constipation symptoms returned to baseline levels by the end of treatment.

Nausea and vomiting were reported less frequently in both arms and returned to baseline levels at end of treatment in both arms. For the Pola-R-CHP group, 12% to 33% of patients reported nausea vs 11% to 30% of patients in the R-CHOP group. Additionally, 3% to 11% of patients in the Pola-R-CHP group reported vomiting vs 4% to 10% of patients in the R-CHOP group.

Genentech, the manufacturer of polatuzumab, said in a statement that other data presented at the 64th ASH Annual Meeting & Exposition in New Orleans showed that the Pola-R-CHP combination had the potential to reduce the number of patients in second-line treatment by 27% compared with R-CHOP.^3,4 A biologics license application has been accepted by the FDA, with a decision expected by April 2, 2023.⁴

Long-term PFS data show that after a median follow-up of 3 years, Pola-R-CHP continues to offer a statistically significant reduction in the risk of worsening disease or death compared with R-CHOP (HR, 0.76; 95% CI, 0.60-97). Overall survival data remained immature and similar between the 2 arms after 39.7 months (HR, 0.94; 95% CI, 0.67-1.33; P = .73).³ 

References
1. Friedberg JW, Thompson CA, Trněný M, et al. Health-related quality of life (HRQoL) in patients with diffuse large B-cell lymphoma (DLBCL) treated with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in the phase III POLARIX study. Abstract presented at: 64th American Society of Hematology Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA. Abstract 2949. https://ash.confex.com/ash/2022/webprogram/Paper157761.html
2. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304
3. Genentech presents new and updated data for Polivy in previously untreated diffuse large B-cell lymphoma at ASH 2022. News release. Genentech. December 11, 2022. https://www.gene.com/media/press-releases/14976/2022-12-11/genentech-presents-new-and-updated-data-
4. Boissard F, Tilly H, Lenz G, et al. Epidemiological impact of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) use in previously untreated diffuse large B-cell lymphoma (DLBCL) in terms of second line (2L) treatment: an ad hoc analysis from the POLARIX study. Abstract presented at: 64th American Society of Hematology Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA. Abstract 2958. https://ash.confex.com/ash/2022/webprogram/Paper157904.html

SPOTLIGHT: Roger M. Lyons, MD, Discusses 10-Year Review of MDS Patient Data From the Community Oncology Setting

One decade ago, Roger M. Lyons, MD, FACP, a board-certified hematologist at Texas Oncology in San Antonio, literally wrote the book on treatment guidelines in myelodysplastic syndromes (MDSs). These syndromes disrupt blood cell production and can lead to leukemia.¹ At the 64th American Society of Hematology Annual Meeting and Exposition in New Orleans, Louisiana, he offered a new tool for specialists managing MDS: a study based on 10 years of real-world data from patients in The US Oncology Network. The study stratified 2736 patients at low risk (32.4%, n = 885), intermediate risk (30.3%, n = 828), high risk (24.8%, n = 679), or very high risk (12.6%, n = 344). Among the patients at higher risk, azacitidine was the most common first-line therapy, used by 85.5% of patients, followed by decitabine (9.7%). Most patients treated with azacitidine (84.7%) did not advance to second-line therapy; patients in lower-risk groups were treated twice as long compared with those in the higher-risk groups.²

Evidence-Based Oncology™ (EBO) spoke with Lyons about the creation of this real-world data set and the pros and cons of different treatments for MDS. This interview is edited lightly for clarity.

EBO: Can you discuss the mission of your study on real-world treatment patterns in MDS?

Lyons: This is a 10-year study of patients in The US Oncology Network. So this [is] real, live data. Most of the studies that you see are coming out of academic medical centers, and frankly, the patient distribution is somewhat different.² Not everybody can get into these academic centers, not everybody can afford to go to them, and the patient mix is different. So this is real-world data [from] where the majority of people with MDS are treated in the United States, probably most Western European countries, and perhaps Japan as well. We have this information; we wanted to see what it looked like and whether there was a correlation or similarity to what we knew about other published data and to keep a baseline of information for people to use when they’re looking at their own data—to say, “Does this correspond to what has been seen over a 10-year period in a community-based oncology practice?”

It’s not state of the art because it’s over a 10-year period; we are not looking at cohorts at different time frames trying to see [whether] things are different. There’s only a little difference at the end where venetoclax was added in, and there are not enough patients there to make a difference. There’s not anything else that’s changed dramatically over time. So, I don’t think we can talk about change over time. It’s primarily looking at a large group of patients treated by 1400 [physicians] over 10 years. We’re trying to put together what is going on in the world of patients with MDS.

EBO: Most of your patients at high risk were treated with azacitidine. Approximately 10% received decitabine. Was there any pattern to these treatment differences, or were these practice preferences?

Lyons: There are 3 hypomethylating agents available. There’s oral decitabine as well. So there’s azacitidine, which was the first on the market. Most people have a lot of experience with it. It’s easy to give; you can give it subcutaneously or [via] IV [intravenous] [administration]. The subcutaneous [method] is easy for the patient. They don’t need an IV started; if they don’t have a line, they’re in and out, and the cost is fairly reasonable for a chemotherapy drug; the toxicity levels are quite low. People are very comfortable with that agent. We helped develop the treatment schedules 10 or 15 years ago1….A downside compared with decitabine is that [azacitidine] is given over 7 days. You can skip the weekends [and] give for 5 days, and it’s probably as effective, but most [physicians] aren’t comfortable doing that for patients [at] higher risk.

Although the data didn’t show much difference, decitabine has a little more toxicity; the side blood count [levels] go down a little more in my experience. The price is much the same, but [decitabine] has to be given [via] IV [administration]. And that doesn’t have a distinct advantage other than the 5-day schedule, but it can’t be given subcutaneously.

The oral agent, which is decitabine in a mixture of something that allows it to be absorbed, is expensive. It’s a pill given 5 days in a row, but it’s much more expensive than the other drugs. There are a few patients [who] you want to give it [to] if they can’t get back to you—if they live at a distance or don’t have transportation. But insurance companies are not happy with that choice. 

References
1. Lyons RM. Myelodysplastic syndromes: therapy and outlook. Am J Med. 2012;125(suppl 7):S18-S23. doi:10.1016/j.amjmed.2012.04.018
2. Lyons RM, Cheng WH, Moore-Schiltz L, et al. Treatment patterns and overall survival (OS) among patients with myelodysplastic syndromes (MDS) treated in the US community oncology setting: a real-world retrospective observational study. Abstract presented at: 64th American Society of Hematology Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA. Abstract 3085. https://ash.confex.com/ash/2022/webprogram/Paper163098.html