Ryan McDonald

In patients with t(11;14) relapsed/refractory multiple myeloma (RRMM), venetoclax (Venclexta) at either 400 mg or 800 mg plus daratumumab (Darzalex) and dexamethasone elicited deep durable responses and showed a tolerable safety profile, according to preliminary results of an expansion cohort from a phase 1/2 study (NCT03314181).

“Venetoclax, daratumumab and dexamethasone, as we previously published, continues to demonstrate safety consistent with a known safety profile with no treatment-emergent deaths,” lead study author Jonathan L. Kaufman, MD, medical director, and section chief of Winship Cancer Institute Ambulatory Infusion Centers, said during a presentation of the data at ASH Annual Meeting 2021. “Venetoclax, daratumumab, and dexamethasone leads to deep responses, including a greater number of patients achieving a (very good partial response) and MRD negativity at least 10 to the minus 5, and to date, the preliminary efficacy continues to be consistent.”

These data that were from part 3 of the phase 1/2 study, while earlier results from part 1 of the study demonstrated that treatment with venetoclax, daratumumab, and dexamethasone (VenDd) was associated with a tolerable safety profile and overall response rate (ORR) of 95.8%.2 Moreover, part 2 of the study showed that Venetoclax plus daratumumab, bortezomib (Velcade; V) and dexamethasone induced a similar safety profile and conferred an ORR of 91.7% in patients with RRMM, regardless of t(11;14) status.

In part 3, Kaufman and colleagues wanted to analyze the safety and efficacy of venetoclax at 2 different doses — 400 mg and 800 mg — plus daratumumab and dexamethasone. Part 3 also included a group of patients who received DVd to act as a control to help the researchers properly interpret safety and efficacy.

Patients were randomized in a 4:2:5 fashion.

“The initial studies had more patients at the 800-milligram (dose) and we wanted to learn more about the 400-milligram dose in this study, hence the (randomization) numbers,” Kaufman said.

He noted that venetoclax, regardless of the dosing, was given continuously throughout the study, and daratumumab was administered subcutaneously on its regular schedule. Patients also received 40 mg of dexamethasone on a weekly basis. Patients in the bortezomib-included arm received the triplet therapy in regimens previously noted.

Evaluating the safety and efficacy of VenDd at the 400 and 800 mg dosing levels was the primary endpoint of the study.

Enrolled patients had to be aged 18 years or older, have t(11;14) RRMM, an ECOG performance status 0, 1 or 2, be non-refractory to proteasome inhibitors, non-refractory to anti-CD38 antibodies and received at least 1 prior line of therapy including an IMiD. Moreover, enrolled patients had to have standard adequate hematologic, renal and hepatic function.

Patients, however, were excluded from enrollment if they had prior treatment with venetoclax or any other BCL-2 inhibitors, if they had significant peripheral neuropathy, recent autologous transplant, or any allogeneic transplant, prior anti-CD38 therapy within 6 months prior to the first dose of study drug, and depending on the drug, a washout period of other anti-myeloma treatments 2-6 weeks prior to study enrollment.

Although the study accrual is not yet complete, the results presented at ASH included 15 patients in the Ven400Dd arm, 7 in the Ven800Dd arm and 19 patients in the DVd arm. Patients in both the Ven400Dd arm (range, 1-6) and Ven800Dd arm (range, 1-4) had received a median of 1 prior line of therapy, compared with 2 in the DVd arm (range, 1-4).

Kaufman noted that he anticipates that number will be matched by the time study accrual has been completed.

Moreover, 46.7% of the patient’s in the Ven400Dd arm, 28.6% in the Ven800Dd arm and 42.1% in the DVd arm had received a prior stem cell transplantation. Fourteen patients (93.3%) in the Ven400Dd arm, all patients in the Ven800Dd arm and 17 patients (89.5%) in the DVd arm received a prior proteasome inhibitor. All patients in both the Ven800Dd and DVd arm, as well as 93.3% of patients in the Ven400Dd arm, received a prior IMiD.

There have been no treatment-emergent deaths in this portion of the study, and as of the presentation of the data, 14 of the 15 patients in the Ven400Dd arm and all patients in the Ven800Dd arm remain on the study drug. Seven patients in the DVd arm have discontinued treatment, 6 of which were because of disease progression.

Toxicities were similar between the 3 treatment groups, according to Kaufman. All patients in the DVd arm experienced any grade treatment-emergent adverse event (TEAE) compared with 87% in the Ven400Dd group and 86% in the Ven800Dd arm. Some of the most common AEs that occurred in 20% or more of patients included, but were not limited to, insomnia, fatigue and diarrhea.

Similar differences were also observed regarding infections between the three groups. Grade 3/4 infections occurred more often in the Ven400Dd (13%) and Ven800Dd (14%) group than in the DVd (6%) group.

As far as efficacy, the ORR in the venetoclax groups, as Kaufman expressed, were “very high.” Patients in the Ven400Dd group achieved an ORR of 87% compared with 86% in the Ven800Dd group and 63% in the DVd group. Of note, 72% of the responses in the Ven800Dd group were considered VGPRs.

At the time of presentation of the preliminary results, the median time on treatment in the Ven400Dd group was 6.0 months (range, 0.2-16.5), 8.5 months (range, 1.8-15.9) in the Ven800Dd and 3.9 months (range, 0.5-14.8) in the DVd group.

“We are currently in development of a randomized phase 3 study to confirm these preliminary results,” Kaufman concluded.

1. Kaufman JL, Quach H, Baz R, et al. Safety and Preliminary Efficacy from the Expansion Cohort of a Phase 1/2 Study of Venetoclax Plus Daratumumab and Dexamethasone Vs Daratumumab Plus Bortezomib and Dexamethasone in Patients with t(11;14) Relapsed/Refractory Multiple Myeloma. Presented at 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 817.

2. Bahlis NJ, Baz R, Harrison SJ, et al. Phase I study of venetoclax plus daratumumab and dexamethasone, with or without bortezomib, in patients with relapsed or refractory multiple myeloma with and without t(11;14). J Clin Oncol. Published online August 13, 2021. doi:10.1200/JCO.21.00443.

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Venetoclax dosed at either 400 mg or 800 mg in combination with daratumumab and dexamethasone showed promising preliminary results in a phase 1/2 study.

Venetoclax Triplet Sustains Tolerability, Deep Response in R/R Multiple Myeloma With t(11;14)

Results from a primary analysis of the randomized phase 2 VISION HO141 trial (NCT03226301), presented during the 2021 ASH Annual Meeting, demonstrated that MRD-guided ibrutinib (Imbruvica) plus venetoclax (Venclexta) is a reasonable approach to treat patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL).

Moreover, the data showed that restarting treatment was feasible in patients who initially had undetectable MRD after 15 cycles of treatment but then developed detectable MRD at later assessments.

“The rationale for this trial is based on wanting to come up with a time-limited treatment for relapsed/refractory CLL,” lead study author Carsten Utoft Niemann, MD, PhD, Department of Hematology, Rigshospitalet, Copenhagen University Hospital, said during a presentation of the data. “Furthermore, we wanted to test the potential for MRD-guided therapy in CLL.”

Niemann also said that the researchers took inspiration from prior trials in the chronic myeloid leukemia (CML) space where study authors stopped and reinitiated treatment. As a result, Niemann noted, patients who had stopped treatment but had to be reinitiated on therapy upon future positive MRD results would not be considered a progression event.

To start, 225 patients (median age, 68 years; range, 36-87) received 2, 28-day cycles of ibrutinib lead-in at 420 mg daily. Then, 216 patients received venetoclax ramp-up during the third cycle. The dose of venetoclax reached 400 mg per day at cycle 4 and patients continued receiving the combination from cycles 4-15.

Of note, Niemann explained that the baseline characteristics patient population in the VISION HO141 trial reflected what has been seen in most other R/R CLL populations, with only 14% being Binet stage A and 24% having del(17p) and/or TP53 mutations.

After the first 15 cycles of treatment, in which several patients were lost due to death or leaving the study, 72 patients reached an undetectable MRD and 125 did not.

Of those patients who did not achieve undetectable MRD, 116 were administered ibrutinib maintenance. Patients who achieved at least partial remission (PR) and undetectable MRD in both peripheral blood and bone marrow samples at cycle 15 were randomized 1:2 between continuing ibrutinib maintenance (arm A; n = 24)) or observation (arm B; n = 48). MRD-positive patients at cycle 15 remained on ibrutinib until progression.

Here, Niemann and colleagues presented progression-free survival (PFS) data from the observation arm at month 27.

The primary endpoint of this analysis was to assess PFS rates among patients in arm B 12 months after MRD-guided venetoclax and ibrutinib treatment had stopped. Those individuals received an MRD test every 3 months and started treatment again if they were MRD-positive.

At 27 months, 71% of the patients in the observation arm (arm B) had undetectable MRD in peripheral blood samples and 54% had undetectable MRD in their bone marrow, compared with 75% and 63% in the ibrutinib maintenance (arm A) group, respectively.

Moreover at 27 months, 29% of patients in the non-randomized, ibrutinib arm achieved undetectable MRD in peripheral blood and 13% in their bone marrow.

“If we follow up in the group of patients who did not achieve undetectable MRD level[s], you will realize that 9 patients actually were allocated here even though they had undetectable MRD levels in bone marrow,” Niemann said. “This includes 2 patients by mistake not randomized by the local investigators and 7 patients who were included prior to an amendment. Before this amendment, it was required that patients should also have undetectable MRD levels at cycle 12. What is important here is that the MRD levels seem to stay stable for this patient group, continuing Ibrutinib. So if you have a patient in the relapsed refractory CLL setting being MRD positive at cycle 12 to cycle 15, it seems that you can, by continuing ibrutinib, keep the MRD level with a low degree of progressions.”

The study results demonstrated that the primary endpoint was met and that PFS at 27 months, 12 months after stopping treatment was 98% in the observation arm (arm B). Of note, this was above the predefined limit of 60%, according to Niemann.

Only 7 patients in the observation arm (arm B) needed to restart ibrutinib and venetoclax because of a detectable MRD. Six of those patients achieved de novo CR within the first 3 cycles and the seventh patient awaits evaluation.

For patients who achieved undetectable MRD at cycle 15 and remained on ibrutinib maintenance, no disease progression was reported (OS at month 27, 100%). Although there were some progressions in the group that did not achieve undetectable MRD and continued ibrutinib, the OS rate at 27 months was 92%.

The adverse event profile during the first 15 cycles of treatment was representative of what has been seen with single agent ibrutinib or single agent venetoclax as well as what has been reported for the combination thus far, according to Niemann.

A quarter of patients (25%) experienced a grade 2 AE during the first 15 cycles; 40% experienced a grade 3 AE and 25% experienced a grade 4 AE.

After cycle 15, patients in the observation arm experienced less adverse events than either of the other ibrutinib maintenance arms.

“We can conclude that MRD-guided ibrutinib with venetoclax for relapsed refractory CLL is feasible, [and] that the primary endpoint of the trial was met with 98% progression-free survival of patients in the observation arm being followed by MRD assessment every three months,” Niemann concluded. “[And the fact] that MRD levels remained stable for the MRD-positive patients who continue[d] ibrutinib maintenance and that all patients that were evaluated after reinitiating therapy upon becoming MRD-positive, actually successfully reinitiated therapy and went into complete remission and thus MRD-guided stop/start treatment with ibrutinib and venetoclax in relapsed refractory CLL is feasible and can be recommended similar to what has been seen for CML.”

Niemann CU, Dubois J, Brieghel C, et al. Time-Limited Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Who Have Undetectable MRD – Primary Analysis from the Randomized Phase II Vision HO141 Trial. Paper presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 69.

Data from the phase 2 VISION trial showed that restarting treatment with the combination was feasible in a select group of patients who initially had undetectable MRD after 15 cycles of treatment.

MRD-Guided Ibrutinib and Venetoclax Combination Shows Promise in Relapsed/Refractory CLL 

Data from a prospective screening study show that Black women have a 3.5-fold increased incidence of lymphedema with breast cancer treated with axillary lymph node dissection (ALND) and radiotherapy, according to a presentation given during the 2021 San Antonio Breast Cancer Symposium.

The results also indicated that Hispanic women have a 3-fold increased incidence of breast cancer-related lymphedema compared with White women. However, Andrea V. Barrio, MD, FACS, an associate attending physician in the Breast Service, Department of Surgery, at Memorial Sloan Kettering Cancer Center, noted that more data is needed to confirm this observation.

“Notably, the number of Hispanic women in our study was small,” Barrio, the study’s lead author, explained while presenting the data during a press briefing.

At the beginning of her presentation, Barrio noted that results from epidemiological studies have shown that Black women with breast cancer have an increased susceptibility to developing lymphedema. However, as she discussed, there is very little prospective clinical trial data confirming those results.

“The aim of our study was to assess the incidence of lymphedema in a prospective cohort of patients treated with axillary lymph node dissection to identify risk factors associated with lymphedema development and to evaluate the impact of race and ethnicity on lymphedema incidence and severity,” she said.

To evaluate this incidence, Barrio and her colleagues enrolled 827 women aged 18 years and older with breast cancer. Enrolled patients also had to have received a unilateral ALND either in the primary setting or after a sentinel lymph node biopsy to be eligible to be included in the analysis.

The study authors collected bilateral arm measurements using a perometer. The patients had these measurements taken at baseline, post-op, and every 6 months for 2 years. A relative increase in a patient’s arm volume of 10% or greater from baseline indicated the presence of lymphedema.

After accounting for ineligible criteria, the final study enrollment comprised of 276 patients (median age, 48 years; range, 40-57 years) who had at least 1 longitudinal measurement after baseline.

More than half (60%) of the patient population was White. The remaining patient population makeup included 20% Black, 11% Asian, and 6% Hispanic. Additionally, 68% of the patient population presented to the study with HR+/HER2- disease. Nineteen percent of the patients were diagnosed with HER2+ disease and 13% of the population had HR-/HER2- disease. Seventy percent of the study population received neoadjuvant chemotherapy, while the rest underwent upfront surgery. Almost all (94%) of the patients who had upfront surgery and underwent systemic chemotherapy received a taxane-containing regimen, Barrio explained.

The treatment characteristics also indicated that 95% of patients received radiotherapy and 93% of patients received nodal RT.

When assessing clinical characteristics by race and ethnicity, White and Black women were older (median age, 49 years, respectively). Black (30.3 kg/m

) patients had a higher baseline BMI compared with the White (25.2 kg/m

At a median follow-up of 22.6 months, 56 patients developed lymphedema. The results demonstrated that the 12-month lymphedema rate was 8.8% (95% CI; 5.9-13), and that the 24-month lymphedema rate was 24.7% (95% CI; 19.2-31.5%).

Barrio noted that the highest incidence of lymphedema observed was among Black women with a 24-month lymphedema rate of 39.4%. That rate was compared with 27.7% in Hispanic women, 23.4% in Asian women, and 20.5% in White women.

The results also showed that receipt of neoadjuvant chemotherapy was associated with a higher 24-month lymphedema rate compared to upfront surgery at 30.9% vs. 11.1% (

The highest incidence of lymphedema observed among Black women with a 24-month lymphedema rate of 39% compared to 28% in Hispanic women, 23% in Asian women, and 21% in white women.

Of note, Barrio said, among women with lymphedema, lymphedema severity did not vary across racial and ethnic groups with similar relative volume changes observed.

“We observed a higher incidence of lymphedema in black women treated with axillary lymph node dissection and radiotherapy after adjustment for other variables. Similar findings were observed in Hispanic women but confirmation in a larger data set is needed,” she said.

Barrio also highlighted how neoadjuvant chemotherapy was associated with a significant increase in lymphedema compared with adjuvant therapy in women who received ALND and RT.

As a result, Barrio concluded, “We postulate that neoadjuvant chemotherapy may cause fibrosis of tumor-filled lymphatics, as well as lymphatic endothelial damage prior to surgery, resulting in the higher lymphedema incidents observed in our study.

“In patient subsets unlikely to achieve a nodal pathologic complete response with neoadjuvant chemotherapy, alternatives to NAC to avoid ALND are needed. The etiology for the higher observed incidence of lymphedema and black women is largely unknown, but maybe due to race-based differences and inflammatory reactions, tissue fibrosis, and lymphatic function. Future studies should address the biologic mechanisms behind racial disparities in lymphedema development.”

Barrio AV, et al. Impact of race and ethnicity on incidence and severity of breast cancer related lymphedema after axillary lymph node dissection: Results of a prospective screening study. Presented at: 2021 San Antonia Breast Cancer Symposium; December 7-10, 2021; Virtual. Abstract GS4-01

In an epidemiological study, a 24-month lymphedema rate of 39.4% was the highest incidence of lymphedema observed among Black women.

Black Women More Likely to Develop Breast Cancer-Related Lymphedema Than White Women

Clinically effective results in a group of patients with HRD-positive, chemotherapy-naïve metastatic castration resistant prostate cancer (mCRPC) was induced with nivolumab (Opdivo) plus rucaparib (Rubraca), according to data from a final cohort analysis of the CheckMate 9KD trial.

Moreover, the study results, which were presented at the 2021 ESMO Annual Congress1, demonstrated noteworthy activity in individuals whose disease harbored 

However, as study author Daniel P. Petrylak, MD, professor of medicine and urology at Yale School of Medicine and co-director of the Cancer Signaling Networks Research Program at Yale Cancer Center in New Haven, Connecticut, noted in his presentation of data, there was limited clinical activity with the combination therapy in patients with HRD-negative tumors.

Among all cohorts of the phase 2 CheckMate 9KD trial (NCT03338790), patients had to have mCRPC, documented disease progression, an ECOG performance status of 0-1, available tumor tissue for HRD testing and no prior treatment with drugs that targeted T-cell co-stimulation or immune checkpoint pathways.

Here, Petrylak presented data from the final analysis of cohort A2 — which comprised 71 patients (median age, 73 years; range, 51-87 years) who had received 1 to 2 prior new hormonal therapies in the pre-chemotherapy setting. Patients in this cohort also did not receive any prior treatments with PARP inhibitors. Additionally, patients who made up the study population were ineligible for (or refused) immediate chemotherapy.

Nivolumab was administered at a 480-mg dose every 4 weeks (Q4W) and rucaparib was given at a 600-mg dose twice per day (BID). Treatment was given until a patient’s disease progressed or unacceptable toxicity was reached. Of note, nivolumab dosing was limited to a maximum of 2 years.

The primary endpoints assessed in this cohort were overall response rate (ORR) and PSA response rate (PSA-RR). Additional secondary endpoints included overall survival (OS), time to and duration of objective response, time to PSA progression, safety and radiographic progression-free survival (rPFS).

More than half (57.7%) of the patient population in the cohort had an ECOG performance status of 1. All other patients had an ECOG status of 0. HRD status was almost evenly split in the cohort:

47.9% of patients had HRD-positive tumors;

50.7% of patients had HRD-negative tumors, and

1.4% of patients had an undetermined HRD status.

In terms of prior treatment with new hormonal therapies, 60.6% of patients had received abiraterone monotherapy, 23.9% received enzalutamide monotherapy and 14.1% received a combination of those two.

The median treatment duration of nivolumab was 4.6 months and 5.5 months for rucaparib.

After a median follow-up of 17.5 months, the ORR among all evaluable patients (n = 39) was 15.4% (95% CI, 5.9-30.5). Confirmed ORR among the 20 patients with HRD-positive tumors was 25% (95% CI, 8.7-49.1). Moreover, the 9 patients whose disease harbored 

-positive mutations achieved an ORR of 33.3% (95% CI, 7.5-70.1). However, ORR was unfavorable in the 19 patients who had HRD-negative or not evaluable tumors (5.3%; 95% CI, 0.1-26.0).

The trend of noteworthy clinical activity in patients with HRD-positive tumors and 

-positive mutations continued in confirmed PSA-RRs. Among 66 evaluable patients, confirmed PSA-RR reached 27.3% (95% CI, 17.0-39.6). The confirmed PSA-RR rate among patients with HRD-positive tumors (n = 31) was 41.9% (95% CI, 24.5-60.9). And the 13 patients with 

-positive mutations achieved a confirmed PSA-RR of 84.6% (95% CI, 54.6-98.1).

Petrylak also noted that the results showed survival outcomes favored patients with HRD-positive tumors. Among the overall population (n = 71), the median rPFS was 8.1 months (95% CI, 5.6-10.9). The median rPFS in those with HRD-negative tumors (n = 37) was 5.6 months (95% CI, 3.7-9.1) compared to 10.9 months (95% CI, 6.7-12.0) in those with HRD-positive tumors (n = 34).

Treatment with the combination was also associated with favorable OS results. The median OS among all patients was 20.2 months (95% CI, 14.1-22.8). The median OS in the 34 patients with HRD-positive tumors was 22.7 months (95% CI, 14.1 months-NE). Patients in the HRD-negative group (n = 37) had the least favorable median OS at 19.0 months (95% CI, 8.2-22.1).

Most of the study participants (n = 64) experienced a treatment-related adverse event (TRAE) of any grade. And, approximately half (n = 36) experienced a TRAE that was classified as grade 3 or 4.

Petrylak noted that the most common TRAEs included nausea, anemia, fatigue and increased liver enzymes. He also highlighted that there were no study deaths related to treatment.

Although the results showed favorable outcomes associated with the use of nivolumab and rucaparib in these patients, Petrylak expressed that more research is needed.

“Longer follow-up is needed to better characterize the clinical benefits of adding nivolumab to rucaparib for patients with HRD-positive, chemotherapy-naïve metastatic castration resistant prostate cancer,” he concluded.

Petrylak DP, et al. 579MO - CheckMate 9KD cohort A2 final analysis: Nivolumab (NIVO) + rucaparib for chemotherapy (CT)-naïve metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2021 ESMO Annual Congress. September 16-21, 2021.

Clinically effective results in a group of patients with HRD-positive, chemotherapy-naïve metastatic castration resistant prostate cancer was induced with nivolumab plus rucaparib. 

Clinically Effective Outcomes in Subgroup of Patients with mCRPC Induced With Nivolumab-Rucaparib Combo

Despite the several classes of drugs either approved, or in development, for the treatment of myeloproliferative neoplasms (MPN), a big question remains.

“The main problem right now is…in whom should we develop these medications for, in whom should these medications be tested, and what should be the end points,” Srdan Verstovsek, MD, PhD, of The University of Texas MD Anderson Cancer Center, said during a presentation during the 2021 Society of Hematologic Oncology (SOHO) Annual Meeting.

“We are moving…from looking at the spleen and symptoms and anemia to survival benefit,” he explained. “I would expect that this trend will continue; we will see perhaps more survival benefit designed studies or time-to-progression or prevention of symptoms and signs in the first place—not to treat only patients that need therapy but prevent symptoms or signs from becoming a problem.”

The issue, Verstovsek noted, is that strategies are needed to identify how to target the newer therapies that are being developed and whether to study them as single agents, or in combination with other standard-of-care therapies.

Overall, Verstovsek reviewed several topics and provided insight into the possible future of the field of myeloproliferative neoplasms.

First, Verstovsek discussed prognostication factors in individuals with myelofibrosis. He explained that there are several questions healthcare providers must ask themselves when doing a prognosis of a patient. The main question he asks is if a patient qualifies for hematopoietic transplant.

Another question, which Verstovsek said he does not weigh as high, is whether the patient needs therapy. Because, he said, providers should be looking at the phenotype of the patients and not what the risk of dying is. The goal is to see when the patient would need therapy, according to Verstovsek.

“We should clinically assess the need for therapy rather than looking at risk of dying when we decide on the new medication,” he said. “Therefore, the question is, do we really need to be so precise and develop, as I see it now, 10 different prognostic scoring systems?”

The answer, according to Verstovsek, is no. Instead, prognostics for identifying treatment options for patients should be more individualized and rely on genetic information.

“That's why [these] type[s] of algorithms are more likely to exist in the future; for us to use rather than arguing which 1 of the multiple different prognostic systems is better than the other,” he said.

He noted that the advent of certain vaccinations may aid in enhancing the immune system and control the disease in its early stages, so the disease remains a prefibrotic myelofibrosis.

However, disease evolution and progression often happens.

In those instances, to gain valuable information for the application of new therapies, Verstovsek noted that the field of MPNs is shifting to subgrouping patients by their genetic profile.

In fact, he highlighted how significant clinical responses with IDH1/2 inhibitors has previously been reported. This is in addition to ongoing or planned studies assessing IDH inhibitors with JAK inhibitors.

“Therefore, the new way of looking at the algorithms for treatment of accelerated/blastic phase has to do with the implementation of [next-generation sequencing] analysis to include 

 mutations [are a] bad prognostic factor for transplant; [hypomethylating agent]-based therapy should be implemented for that. So IDH inhibitors for 

 mutations; hypomethylation otherwise, many times combined with a JAK inhibitor for control of the symptoms and signs.”

Verstovsek S. Next Questions: Myeloproliferative Neoplasms. Presented at: Society of Hematologic Oncology 2021 Annual Meeting; September 8-10. Accessed September 11, 2021.

Despite the several classes of drugs either approved, or in development, for the treatment of myeloproliferative neoplasms, a big question remains.

Addressing ‘A Main Problem’ Becomes Center of MPN Treatment Research

In comparison with commonly used triplet regimens dexamethasone, rituximab, and cyclophosphamide (DRC) and bortezomib, dexamethasone, and rituximab (BDR), patients with treatment-naïve Waldenström macroglobulinemia had favorable outcomes following treatment with fixed-duration rituximab (Rituxan) plus the chemotherapy bendamustine (R-Benda).

The data—which were previously published earlier this year in the 

—were presented by lead study author Jithma Abeykoon, MD, during the 2021 Society of Hematologic OncologyAnnual Meeting.

“The treatment paradigm for treating Waldenström macroglobulinemia is that one can use BTK [Bruton’s tyrosine kinase] inhibitor-based therapy, which is a continuous treatment, and the other paradigm is to use fixed-duration treatment with chemoimmunotherapy,” said Abeykoon, a fellow in Hematology and Medical Oncology at Mayo Clinic in Rochester, Minnesota, during the presentation. “However, there are no prospective studies to compare the most commonly used fixed-duration treatments such as R-Benda, DRC, or BDR.”

Because of that lack of prospective studies, Abeykoon explained that he and his colleagues wanted to conduct a retrospective study to assess outcomes associated with the 3 most often used treatment regimens in this space: R-Benda, DRC and BDR.

Abeykoon and colleagues retrospectively analyzed the outcomes of 220 treatment-naïve patients who were seen at Mayo Clinic between November 2000 and October 2019. The study authors identified 83 patients who were treated with the R-Benda combination, 92 who received DRC and 45 who were given BDR.

Of note, Abeykoon highlighted the fact that treatment patterns evolved over the approximately 2-decade duration of the information contained in the retrospective analysis. For instance, DRC and BDR were more commonly administered to this patient population between 2007 and 2013. However that pattern shifted after 2014, Abeykoon explained, once R-Benda was introduced into the treatment armamentarium.

The baseline characteristics, he noted, were quite similar across the 3 treatment arms.

After a median follow-up of 4.5 years for the entire patient cohort, the data demonstrated that R-Benda was associated with several improved outcomes. Treatment with R-Benda conferred a superior overall response rate (98%) compared with both DRC (78%) and BDR (84%; 

= .003). Moreover, major response rate was significantly higher in the group who received the combination (96%) than either the DRC (53%) or BDR (68%) group (

The use of R-Benda was also linked with a greater progression-free survival (median 5.2 years vs 4.3 years (DRC) and 1.8 years (BDR; 

= .0003). Median event-free survival, time-to-next therapy, and duration of response were not yet reached in individuals who received R-Benda. Patients who were treated with R-Benda also achieved a faster median time to best response (4.5 months) than those who received DRC (5.9 months) and BDR (6.7 months; 

= .005). Of note, the overall survival rates were similar across the 3 treatment groups.

Regarding adverse events (AEs), Abeykoon noted that neutropenia was higher in the R-Benda cohort (13%) compared with 1% in the DRC group and 2.5% in the BDR group. Neuropathy occurred more often in the BDR (17.5%) and DRC (3%) treatment arm than it did in the R-Benda arm (0%).

Overall, Abeykoon discussed, the AEs among this retrospective patient population were consistent with what has been previously reported. He cautioned, however, that the AEs could have been underreported since it was not a prospective study.

A total of 23 patients (R-Benda: 7%, DRC: 13%, BDR: 11%) received maintenance therapy with rituximab. The authors excluded those patients who were treated with rituximab maintenance following initial induction therapy. The observed outcomes remained superior and still favored treatment with R-Benda than DRC or BDR.

At a median follow-up of 4.3 years, Abeykoon emphasized, no secondary myeloid neoplasms were detected in any of the patients who received R-Benda or DRC.

“We find that the use of R-Benda primary therapy, that means in the upfront setting, was associated with more durable disease control and superior outcomes…as compared to DRC and BDR,” he concluded.

1. Abeykoon JP, Zanwar S, Ansell SM, et al. Assessment of fixed-duration therapies for treatment-naïve Waldenström macroglobulinemia. 

. 2021;96:945–953. doi:10.1002/ajh.26210

2. Abeykoon JP. Assessment of fixed-duration therapies for treatment-naïve Waldenström macroglobulinemia. Presented at: the 2021 Society of Hematologic OncologyAnnual Meeting. Virtual. September 8-13, 2021.

Rituximab with bendamustine lead to superior outcomes compared with than 2 other popular triplet therapies in patients with treatment-naïve Waldenström macroglobulinemia.