Dylann Cohn-Emery

Myelodysplastic syndrome (MDS) is often treated with the hypomethylating agents (HMAs) azacitidine (Vidaza) and decitabine (Dacogen) in the higher-risk setting. However, these agents can also be used in patients with lower-risk disease in certain situations, and newer ways of using these HMAs are under investigation.

“They are the backbone for management of higher-risk MDS. The trials with azacitidine showed survival advantage,” Rami Komrokji, MD, vice chair of the Department of Malignant Hematology and head of the Leukemia and MDS Section at Moffitt Cancer Center in Tampa, Florida, said in an interview with the 

Azacitidine was the first drug the FDA approved for treating MDS in 2004; it can be used intravenously or subcutaneously. Decitabine also showed a survival advantage in patients with MDS and the agency approved it in this setting in 2006.

 Decitabine is typically used as an intravenous (IV) therapy, according to Komrokji.

Although these 2 therapies are the main treatments for high-risk MDS, “there are slight differences between azacitidine and decitabine and how they get incorporated in the cells,” Komrokji said. Azacitidine infiltrates the patient’s DNA and RNA, whereas decitabine only interacts with the DNA. Additionally, azacitidine is metabolized by the kidneys whereas decitabine is metabolized by the liver.

Komrokji said that compared with conventional therapies such as low-dose cytarabine, best supportive care, and chemotherapy, both agents demonstrated an approximate 50% overall response rate, 20% complete response rate, and an average duration of response of a year to a year and a half. The agents also showed a median survival of around 24 months in patients with high risk.

“But in real life, nobody has been able to duplicate that, so what we tell our patients is somewhere around a year and a half expected survival with those agents,” he explained.

For patients with intermediate- or high-risk MDS and chronic myelomonocytic leukemia (CMML), decitabine plus cedazuridine (Inqovi) is the first oral HMA approved as of 2020.

 “That will inhibit an enzyme called CDA; so it stabilizes decitabine so it’s not metabolized in the gut and can be absorbed,” Komrokji said.

In the trial (NCT02103478), patients either received 20 mg/m

 of IV decitabine or 35 mg of oral decitabine plus 100 mg of oral cedazuridine for the first cycle, then crossed over for the second cycle.

 For the third cycle, all patients received oral decitabine/cedazuridine. This trial showed similar efficacy and safety with the oral regimen compared with the IV decitabine. Komrokji thinks that this year more overall survival data will be available for the oral decitabine.

“It’s a nice option for the patients; it allows oral therapy [and avoids] a daily office visit, particularly in the COVID-19 era where patients were worried about coming to the office all the time,” Komrokji said.

The monitoring for the oral regimen is the same as the IV regimen, including weekly monitoring at the start of treatment because the patient’s blood counts tend to drop. The main difference is that the oral regimen can be taken at home. Oral decitabine/cedazuridine is used as a 3-day or 5-day regimen.

The oral decitabine regimen is included in the National Comprehensive Cancer Network guidelines, but Komrokji is worried that one challenge is that physicians are not comfortable adopting the regimen into their practice completely because they may need to get the patient to achieve response and then switch them to a different therapy.6 Moreover, copayments for oral regimens can be too expensive for patients if their insurance does not pay for it. “I think if patient insurance approves the drug and the patient is reasonable with follow-ups, oral decitabine is really equivalent to IV decitabine,” Komrokji said.

Other oral HMAs are also in development for MDS, such as oral azacitidine (Onureg; CC-486), which is approved in AML. Unlike oral decitabine, this oral regimen was not bioequivalent to the IV and subcutaneous regimens and so it is not interchangeable.

Oral azacitidine was tested in patients with lower-risk MDS, “but the dosing probably was not the ideal for lower-risk MDS,” Komrokji explained. AML maintenance therapy with oral azacitidine is 300 mg for 2 weeks and the dose tested in the lower-risk MDS trial (NCT01566695) was 300 mg for 3 weeks. Although there were some responses, there was also excessive toxicity of myelosuppression and febrile neutropenia.

 Until investigators find the appropriate dose, Komrokji said he discourages people from using the oral regimen in MDS.

For patients with high-risk MDS, Komrokji mainly uses the 7-day azacitidine regimen even though he feels that both azacitidine and decitabine are close to being equivalent. However, in patients with end-stage renal disease, he prefers decitabine because of how it is metabolized.

“There have been some data suggesting that decitabine may be more active in patients who have a 

mutation, a subtype of MDS that has poor prognosis. Also, outside of clinical trials, sometimes I will use decitabine,” he said. Beyond those 3 instances, he uses azacitidine in high-risk MDS because of the survival data in the AZA 001 trial (NCT00071799).

In lower-risk MDS, azacitidine and decitabine are approved in the United States but not in Europe or Canada. For this patient population, HMAs reduce cytopenias, and are thus used in patients with low blood counts, and especially those with concomitant thrombocytopenia, neutropenia, and/ or anemia. Usually for low-risk disease, patients are given the 5-day regimen of azacitidine instead of the 7-day regimen after data showed that there was similar efficacy with less toxicity.

“I typically restrict the use in the lower-risk setting for patients who have gone through other lines of therapy,” Komrokji said. “It’s not my first line after ESA failure, unless patients have concomitant thrombocytopenia and neutropenia that will limit my other choices of treatment.”

Usually, if a low-risk patient is eligible for lenalidomide, he will use that before either HMA unless there is thrombocytopenia or neutropenia. Both azacitidine and decitabine are reasonable options if the patient does not respond to lenalidomide. “Hopefully we’ll be able to confirm that maybe a shorter course of HMAs are OK in lower-risk MDS,” Komrokji said.

Recently, trials have looked at combination therapies using these HMAs as the backbone. This is especially important for patients who have progressed on HMAs previously. Doublet and triplet therapies using HMAs plus immune checkpoint inhibitors, BCL-2 inhibitors, targeted therapy, or immunotherapy are being investigated.

 Azacitidine has been combined with venetoclax (Venclexta), pevonedistat, nivolumab (Opdivo) or ipilimumab (Yervoy), magrolimab, and APR-246 (Eprenetapopt), among others, and shown varying degrees of efficacy.

1. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. 

2005;10(3):176-182. doi:10.1634/theoncologist.10-3-176

2. Kantarjian H, Issa JPJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. 

2006;106(8):1794-1803. doi:10.1002/ cncr.21792

3. Saba HI. Decitabine in the treatment of myelodysplastic syndromes. 

. 2007;3(5):807-817. Accessed August 16, 2021. https://bit.ly/3yShnrT

4. FDA approves new therapy for myelodysplastic syndromes (MDS) that can be taken at home. News release. FDA. July 7, 2020. Accessed August 16, 2021. https://bit.ly/3xM4yxS

5. Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. 

2020;136(6):674- 683. doi:10.1182/blood.2019004143

6. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes, version 3.2021. Accessed August 16, 2021. https://bit. ly/3g4EeJi

7. Garcia-Manero G, Santini V, Almeida A, et al. Phase III, randomized, placebo-controlled trial of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. 

2021;39(13):1426-1436. doi:10.1200/JCO.20.02619

8. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. 

. 2009;10(3):223-232. doi:10.1016/ S1470-2045(09)70003-8

9. Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. 

. 2009;27(11):1850-1856. doi:10.1200/JCO.2008.17.1058

10. Bewersdorf JP, Carraway H, Prebet T. Emerging treatment options for patients with high-risk myelodysplastic syndrome. 

. 2020;11:2040620720955006. doi:10.1177/2040620720955006

Articles

Investigators are looking into newer ways of using hypomethylating agents to treat patients with low-risk and high-risk myelodysplastic syndrome.

Komrokji Discusses Using Hypomethylating Agents for Low- and High-Risk MDS

Considering there are no standard treatment approaches for accelerated phase myeloproliferative neoplasm (MPN AP), treating patients with this disease is an ongoing therapeutic challenge, according to an expert.

In her presentation at the Society of Hematology Oncology 2021 Annual Conference, Olatoyosi Sobulo Odenike, MD, explored the risk factors for evolution to MPN AP/blast phase (BP), outcomes for current treatment methods, and potential targeted therapies.

MPN AP is defined as patients with 10% or more blasts in the peripheral and/or bone marrow, and MPN BP is 20% or more. After the chronic phase of the Philadelphia chromosome (Ph)-negative MPNs, such as essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), evolves into MPN AP, the median survival is much shorter.

For ET and PV, overall survival (OS) is generally more than 10 years, and PMF, which also has the highest risk of evolution to MPN AP, has a median OS of 5 to 6 years. The median survival in MPN AP is 16 to 17 months for PMF. For patients who evolve to MPN BP, survival is even worse.

“Of note, even in the chronic phase of the disease, in patients who have 5% to 9% blasts…[have] outcomes that are very similar to those who have 10% or more blasts, arguing that patients who have blasts in this range are also on a continuum towards BP,” Odenike, a professor of medicine at the University of Chicago Medicine, said. “When the disease progresses to the BP, the OS is in the 3- to 5-month range.”

For patients in this setting, risk factors for transformation include receiving cytoreductive agents; increase in blasts, thrombocytopenia, anemia, or other lab parameters; and having PMF, as opposed to ET or PV. According to the Risk Scoring Systems used for MPNs, high-risk features are considered predictive for MPN AP/BP. These include baseline driver mutations, deleterious mutations, and germline susceptibility.

Identifying patients who are at high risk of progression is crucial, Odenike noted, because the survival rates after transplant are much higher in chronic phase compared with MPN AP/BP. When approaching treatment in patients with MPN AP/BP, Odenike posed questions to consider:

whether the patient is fit for intensive induction;

the degree of cytoreduction necessary prior to transplant, if any.

Retrospective data have shown a complete response (CR) rate plus CR with incomplete hematologic recovery (CRi) rate in the 30% to 40% range with intensive chemotherapy and CR rates in the 25% range with hypomethylating agents (HMAs) in patients with MPN AP. There was no OS advantage to one treatment over the other in the retrospective findings. However, without being able to receive an allogeneic stem cell transplant, there was not as much benefit to intensive chemotherapy. For patients who are transplant ineligible, fewer intensive regimens are preferred.

For patients with Ph-negative MPNs in the chronic phase, JAK inhibition has been a meaningful step forward in treatment. This is especially true for those who are symptomatic or have significant splenomegaly. Now the question has become whether it would be as useful in MPN AP/BP.

According to Odenike, there is no real benefit to JAK inhibition alone but there is some when it is combined with an HMA. The combination of ruxolitinib (Jakafi) and decitabine in 25 patients demonstrated a median survival of 9.5 months and an overall response rate (ORR) of 44%, 8% of which was CRi and 36% partial response. A similar trial showed a median OS of 8.4 months with the recommended phase 2 dose and an ORR of 45%. Although, it has still not been determined if the JAK inhibitor/HMA combination produces more efficacy than HMA alone for these patients.

The combination of an HMA plus venetoclax (Venclexta) received approval in acute myeloid leukemia, but the trial did not include patients with preexisting MPNs. Therefore, only retrospective data is available for this combination in MPN AP/BP. A small retrospective series have shown CR/CRi rates of around 43% in the frontline for MPN BP and a median OS of 7 months with venetoclax and an HMA.

Recently, IDH1/2 inhibitors have been approved in patients with acute myeloid leukemia and 

 mutations, and so these are also being looked at for MPN AP/BP in retrospective data. There is a potential benefit with IDH inhibitors, which have demonstrated a median survival of 9 months or more in this setting. Of note, some patients have stayed on single-agent therapy for several years after initiating treatment.

To treat patients with MPN AP/BP, using next-generation sequencing at the beginning of management allows for the detection of 

. Patients with TP53 mutations can have higher chemotherapy-resistance, so Odenike prefers to use HMA-based therapy. “For other mutations, a majority we don’t have any targeted therapies for, I have a relative equipoise between an intensive approach versus HMA-based therapy,” Odenike said. “But I will only use intensive chemotherapy if the patient is also able to then undergo an allogeneic stem cell transplant.”

For this population, participating in clinical trials is also extremely important. In fact, some novel agents that are being investigated in myeloid malignancies include epigenomic modulators, post translational modulators, immune checkpoint inhibitors, and targeted agents.

“The hope is that we will have many more trials that will allow patients with MPN AP/BP disease to participate in an effort to improve overall outcomes,” Odenike concluded.

Odenike OS. Accelerated Phase of MPN: What Is It and What to Do About It. Presented at the Society of Hematology Oncology 2021 Annual Meeting; September 8-10. Accessed September 9, 2021.

Olatoyosi Sobulo Odenike, MD, explored the risk factors for evolution to MPN AP/blast phase, outcomes for current treatment methods, and potential targeted therapies during a presentation.

Understanding and Treating Accelerated Phase Myeloproliferative Neoplasms 

The future of treatment in patients with polycythemia vera (PV), according to an expert, centers around adapting therapy to patients using the available criteria and eventually finding new targets, as well as using interferons or ruxolitinib (Jakafi) in their respective lines because of the efficacy shown with these agents.

“Treatment of patients with PV should be, in my opinion, tailored based on the risk,” Francesco Passamonti, MD, said in his presentation at the Society of Hematology Oncology 2021 Annual Conference. “This is quite important. In the future, we will probably have to work more on additional mutations and the role of additional mutations in the prediction of events in PV.”

Until these mutations are found, criteria such as being above 60 years old and history of thrombosis have to be considered according to Passamonti, a professor at Universita dell'Insubria in Varese, Italy.

When managing PV, it’s important to take into account the natural history of the disease. There is a median of 3.3% of people a year who experience thrombosis. The risk of myelofibrosis is 0.9% at 1 year, 5% at 5 years, and 34% at 10 years. Lastly, the risk of blast phase is 0.4% and the incidence stays at this rate over time.

According to the National Comprehensive Cancer Network (NCCN) guidelines, the initial indication for low-risk disease is to monitor for and manage cardiovascular risk factors, give 81 to 100 mg of aspirin per day, and use phlebotomy to maintain a hematocrit level of less than 45%. Passamonti said “the first question is if there is evidence for an alternative to this approach.”

One option comes from phase 2 trial data published in 2021 of ropeginterferon alfa-2b (Besremi; ropegIFN) in low-risk PV (NCT03003325). The study enrolled 127 patients randomized 1:1 to phlebotomy plus aspirin (n = 63) versus phlebotomy, aspirin, and ropegIFN (n = 64). The median follow-up was 12.1 months, and the primary end point was the proportion of responders—patients with median hematocrit level of less than 45% without disease progression—at 1 year of treatment.

More patients in the experimental arm achieved the composite primary end point than the standard arm, with 84% versus 60% responding by 1 year (odds ratio [OR], 3.5; 95% CI, 1.3-10.4; 

= .008). Additionally, 84% of patients receiving ropegIFN had hematocrit control compared with 66% receiving only phlebotomy and aspirin. No patients in the experimental arm had disease progression, however 8% of patients in the standard arm progressed. RopegIFN also demonstrated better symptomology for patients versus the standard of care.

After a patient with low-risk PV experiences symptomatic disease with potential indications for cytoreductive therapy, their disease is considered high risk and they need therapy. In high-risk disease, the NCCN guidelines recommend hydroxyurea or peginterferon alfa-2a in addition to the options suggested for low-risk PV.

Multiple studies have looked into using interferon treatments in PV, including the phase 3 PROUD-PV (2012-005259-18) and CONTINUATION-PV (2014-001357-17) trials. Treatment-naive patients who required cytoreduction were randomized 1:1 to receive ropegIFN (n = 127) versus hydroxyurea (n = 130) for 12 months in PROUD-PV. Twenty-one patients given ropegIFN discontinued treatment and 19 discontinued standard therapy.

In the CONTINUATION-PV trial, patient either continued on ropegIFN (n = 95) or best available therapy (BAT; n = 76). There were 16 patients who discontinued ropegIFN and 7 who discontinued BAT.

Patients treated with ropegIFN achieved complete hematologic response (CHR) at a higher rate than those on the standard arm after 3 years of therapy. The rate of phlebotomy-free patients was higher with ropegIFN, at 79.8% at 4 years compared with 60.0% (

“The most relevant of the responses obtained with interferon was the rate of patients who obtained a molecular response during the 3 years. It was clearly higher with ropegIFN versus hydroxyurea,” Passamonti said. The patients with lower JAK2 AB had a higher number of CHR at 1, 2, and 3 years as well.

The rate of major thromboembolic adverse events (3%) and myelofibrosis (1 case each) was similar between the 2 arms.

If a patient with high-risk PV experiences inadequate response or loss of response, physicians must decide on a second-line treatment. Options include clinical trial or ruxolitinib as preferred regimens, or hydroxyurea or ropegIFN as other recommendations if not previously used.

Peg-interferon-α2a (pegIFN) was investigated in the second line in the phase 2 MPD-RC 111 trial (NCT01259817) of 50 patients with high-risk disease. After 1 year, complete response was achieved in 22% of patients with PV, 46% had a hematocrit level of less than 45%, 37% were phlebotomy independent, 32% had splenomegaly normalization, and 41.3% had more than 20% variant allele frequency reduction. There were 2% of patients with major vascular events at 1 year and 5% at 2 years. Even after discontinuation of pegIFN, data have shown patients can have CHR over time.

“Interferons, either pegIFN or ropegIFN, provided evidence of efficacy in first- and second-line setting within 1- to 3-year follow-up, so the question is: Is 1- to 3-year follow-up enough for me to decide to use ropegIFN in a patient with PV,” Passamonti asked. “Probably not in [all patients], but I think in young patients, interferon is a good option for high risk.”

Currently, the only therapy approved for second-line treatment of high-risk PV is ruxolitinib. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) trials enrolled patient who were resistant or intolerant to hydroxyurea, required phlebotomy every 3 months, had palpable spleen with MRI-confirmed volume of over 450 cm3, and platelet count of less than 100,000. Patients were randomized 1:1 to ruxolitinib at 10 mg twice daily (n = 110) versus BAT (n = 112). There was a primary composite end point of hematocrit control in the absence of phlebotomy and 35% or more spleen volume reduction (SVR35) at week 32 in the RESPONSE trial.

In RESPONSE-2, patients did not have splenomegaly and did not require SVR35 as an end point. The end point in this trial was assessed at week 28.

There were 21% of patients who achieved the primary composite end point in the ruxolitinib arm versus 1% in the BAT arm (OR, 28.64; 95% CI, 4.50-1206; 

< .001). Separately, SVR35 was seen in 38% of patients receiving ruxolitinib and 1 patient receiving BAT; 60% and 20% achieved hematocrit control, respectively.

The RESPONSE-2 trial confirmed data for hematocrit control, with 62.2% of patients given ruxolitinib achieving control compared with 18.7% given BAT (OR, 7.28; 95% CI, 3.43-15.45; 

After 5 years of follow-up for the RESPONSE trial, 83% of patients on the ruxolitinib arm did not require phlebotomies. There were 41% with normalization of leukocytosis and 46% with normalization of thrombocytosis. There was a 67% 5-year probability of maintaining clinic-hematological response and 72% 5-year probability of maintaining SVR35.

In the ruxolitinib arm, the rate of thromboembolic events was 1.2 per 100 patient-years, 8.2 in the BAT arm, and 2.7 in patients who crossed over from BAT to ruxolitinib. Ruxolitinib also improved rates of second malignancies or nonmelanoma skin cancer compared with BAT but did not improve rates of transformation to myelofibrosis and acute myeloid leukemia, according to Passamonti.

Passamonti concluded that he hoped that in the future, new drugs will be able to control thrombosis as well as control the evolution from PV to post-PV myelofibrosis considering that is a more difficult condition to treat.

Mora B, Passamonti F. Polycythemia Vera: Is it Time to Rethink Treatment? Presented at: Society of Hematologic Oncology 2021 Annual Meeting; September 8-10. Accessed September 9, 2021.

Adapting therapy to patients using the available criteria may be the key to future treatment in patients with polycythemia vera. 

Rethinking the Treatment of PV Based on Efficacy and Toxicity

Zanubrutinib (Brukinsa) has been approved by the FDA to treat adult patients with Waldenström macroglobulinemia (WM), according to a press release by BeiGene, Ltd.

The approval was based on data from the phase 3 ASPEN trial (NCT03053440), a global, open-label trial. Results were presented at the 2020 American Society of Hematology Annual Meeting and published in 

This study demonstrated higher very good partial responses (VGPRs) with zanubrutinib versus ibrutinib (Imbruvica). There were also fewer Bruton’s tyrosine kinase (BTK)–associated toxicities with zanubrutinib compared with ibrutinib.

“The ASPEN trial provided compelling evidence that Brukinsa is a highly active BTK inhibitor in Waldenström’s macroglobulinemia, and compared to the first-generation BTK inhibitor, showed improved tolerability across a number of clinically important side effects. The approval of Brukinsa provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” said Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute and professor of Medicine at Harvard Medical School, in a press release.

“The approval of Brukinsa Waldenström’s macroglobulinemia, which is the second therapy approved specifically for the treatment of this rare type of lymphoma, is positive news for patients. Expanded treatment options offer new hope for those living with this disease and can potentially improve patient experience, especially oral therapies that can be given as a single agent,” said Pete DeNardis, chair of the Board at the International Waldenström’s Macroglobulinemia Foundation, stated in the press release.

In ASPEN, 164 patients with relapsed/refractory disease and 37 with treatment-naïve disease were randomized 1:1 to zanubrutinib at 160 mg twice daily or ibrutinib at 420 mg once daily in 28-day cycles until disease progression or intolerance. A second cohort looked at only zanubrutinib in patients with wild-type 

VGPR or CR per independent review committee (IRC) assessment was the primary end point of the trial. Secondary end points included major response rate (MRR) assessed by IRC, progression-free survival (PFS), duration of response, reductions in bone marrow and extramedullary tumor burden, and safety. Overall survival and changes in quality of life were investigated as exploratory end points.

The IRC-assessed VGPR rate with zanubrutinib was 28% versus 19% with ibrutinib. This result was not considered to be statistically significant although it was higher with zanubrutinib (2-sided 

= .09). The patients who had relapsed/refractory disease had a VGPR rate of 29% and 20% with zanubrutinib and ibrutinib, respectively (

= .12). The treatment-naïve population had a VGPR rate of 26% with zanubrutinib compared with 17% for those receiving ibrutinib (

=.54). The investigators assessment showed a 28% VGPR rate with zanubrutinib versus 17% with ibrutinib (

Fifteen percent of the zanubrutinib-treated population progressed on treatment or died after a median follow-up of 18.0 months, and 16% of those given ibrutinib progressed or died after a median 18.5 months. Neither arm was evaluable for median PFS, although both arms had comparable event-free rates of 85% with zanubrutinib and 84% with ibrutinib at 18 months. Patients with relapsed/refractory disease and treatment-naïve disease had 86% and 82% event-free rates at 18 months, respectively.

The most common AEs that occurred in 20% or more of patients with zanubrutinib were neutropenia, upper respiratory infection, and diarrhea. With ibrutinib, the most common were diarrhea, upper respiratory infection, contusion, and muscle spasms. There were 58% who had grade 3 or more AEs in the zanubrutinib group and 63% in the ibrutinib arm. The incidence of grade 3 or more pneumonia and hypertension were ≥5% higher in patients given ibrutinib compared with zanubrutinib. Grade 3 or more neutropenia had a ≥5% higher incidence in those receiving zanubrutinib.

In the zanubrutinib group, serious AEs occurred in 40% of patients compared with 41 in the ibrutinib group. Pneumonia, neutropenia, and febrile neutropenia were the most common serious AEs.

A phase 1/2 trial of zanubrutinib monotherapy in patients with B-cell malignancies led to the ASPEN study after it showed 45% of patients of the 73 patients with WM achieved complete response (CR) or VGPR. After 32.7-month median follow-up, 82% of those patients achieved major response. The safety profile showed that zanubrutinib was well tolerated, with relevant adverse events (AEs) of atrial fibrillation in 5%, major hemorrhage in 4%, and grade 3 or more diarrhea in 3%.

BeiGene, Ltd, announced that zanubrutinib’s supplemental new drug application was accepted by the FDA on February 17, 2021.

 This drug has also been used to treat patients with mantle cell lymphoma (MCL), small lymphocytic leukemia, and chronic lymphocytic leukemia, and has been approved in MCL for adult patients who have received at least 1 prior line of therapy.

“We are delighted by today’s FDA approval for Brukinsa in its second indication, offering a new treatment option with demonstrated efficacy and safety benefits for patients with Waldenström’s macroglobulinemia. As shown in the ASPEN trial, Brukinsa can improve treatment outcomes for these patients and potentially make a positive impact on their lives,” commented Jane Huang, MD, chief medical officer, Hematology at BeiGene, in a press release.

1. U.S. FDA Grants Brukinsa® (zanubrutinib) approval in waldenström’s macroglobulinemia. News release. BeiGene, Ltd. September 1, 2021. Accessed September 1, 2021. https://bwnews.pr/3kOax0v 

2. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. doi:10.1182/blood.2020006844

3. BeiGene Announces U.S. FDA acceptance of Supplemental New Drug Application for Brukinsa (zanubrutinib) in Waldenström’s macroglobulinemia. News release. BeiGene, Ltd. February 17, 2021. Accessed February 17, 2021. 

Zanubrutinib has been approved by the FDA to treat adult patients with Waldenström macroglobulinemia.




FDA Approves Zanubrutinib in Adult Waldenström’s Macroglobulinemia

In the wake of immunotherapy combinations becoming available in breast cancer, including triple-negative breast cancer (TNBC), the Society for Immunotherapy of Cancer (SITC) has published 

 for physicians treating in this setting.

“Immunotherapy is now offering some patients with breast cancer clinically meaningful benefit in early stage and advanced disease,” Jennifer Litton, MD, chair of the SITC Breast Cancer Immunotherapy Guideline Expert Panel, said in a statement.

 “It is important for clinicians and patients to understand that immunotherapy is very different from traditional breast cancer treatments, and this new guideline offers the expert guidance needed to safely consider these treatments.”

Trials investigating the use of immune checkpoint inhibitor (ICI) and chemotherapy combinations in advanced or metastatic TNBC have shown progression-free and overall survival for subsets of patients. Because of this clinical benefit, ICI combined with chemotherapy has been approved by the FDA for use in TNBC. These therapies include atezolizumab (Tecentriq) and pembrolizumab (Keytruda).

However, the optimal strategy for using immunotherapy in patients earlier in their disease, which chemotherapy backbone to use for the combination, appropriate selection of patients through biomarkers, and potential use in histological subtypes other than TNBC are all questions that remain. SITC convened a multidisciplinary panel of experts to guide the oncology community on these questions, among others, using published literature and clinical experience.

The clinical practice guideline contains evidence-based and consensus-based recommendations for healthcare professionals regarding different aspects of treatment with immunotherapy for patients with breast cancer. This includes immune-related adverse events, patients’ quality of life considerations, diagnostic testing, and treatment planning.

“Breast cancer has historically been a disease for which immunotherapy was largely unavailable,” SITC president Patrick Hwu, MD, said in a press release. “The new clinical practice guideline is the first to be published by SITC on breast cancer and is the twelfth manuscript published in SITC’s Cancer Immunotherapy Guidelines series.”

“This guideline serves as vital resource for oncologists managing the various unexpected adverse events that may arise with treatment. This is a pivotal step forward for SITC as the world leader in advancing the science and application of cancer immunotherapy and demonstrates a continued commitment to ensuring that breast cancer patients have the most optimal outcomes while receiving FDA-approved immunotherapies,” Hwu concluded.

The clinical practice guidelines first cover PD-L1 inhibitors in advanced or metastatic breast cancer. They subsequently discuss emerging data in the early-stage or locally advanced setting with PD-L1 inhibitors, diagnostics and biomarkers, evaluation and management of treatment response, toxicity considerations, patient education, and novel combination strategies and future directions, all with panel recommendations at the end of each section.

were modeled after the Institute of Medicine’s (IOM) Standard for Developing Trustworthy Clinical Practice Guidelines. As such, the guidelines were developed by a multidisciplinary expert panel, with funding sources and conflicts of interest readily reported.

“It’s an exciting time for immunotherapy in breast cancer,” Leisha Emens, MD, PhD, chair of the SITC Breast Cancer Immunotherapy Guideline Expert Panel, said in a statement. “This new guideline will help clinicians navigate the nuances of a dynamic and rapidly evolving field to offer their patients the benefits immunotherapy may provide.”

1. Emens LA, Adams S, Cimino-Mathews A

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of breast cancer. 

2. Society for Immunotherapy of Cancer published clinical practice guideline on immunotherapy for the treatment of breast cancer. New release. The Society for Immunotherapy of Cancer. Published August 18, 2021. Accessed August 23, 2021.

In the wake of immunotherapy combinations becoming available in breast cancer, including triple-negative breast cancer, the Society for Immunotherapy of Cancer has published clinical practice guidelines for physicians treating in this setting.

SITC Releases Immunotherapy Clinical Practice Guideline for Breast Cancer

To treat soft tissue sarcoma, a rare cancer type that can be found in any part of the body, patients can receive surgery, radiation, or chemotherapy in the first line.

 However, targeted therapy options are limited in this space because of the rarity of the disease type and a lack of funding.

“Doxorubicin-based chemotherapy still remains the gold standard for treatment in locally advanced metastatic soft tissue sarcoma in the first-line setting.” Dean Frohlich, PhD, director of scientific affairs at the Sarcoma Foundation of America, said in an interview with 

During the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, multiple trials for targeted treatments were presented for soft tissue sarcoma. Some of the most exciting data were from the phase 2 Spearhead 1 trial (NCT04044768) evaluating T-cell therapy in advanced and/or metastatic synovial sarcoma or myxoid/round cell liposarcoma (MRCLS).

 The therapy used in this single-arm, open-label study, afamitresgene autoleucel (formerly ADP-A2M4), targets melanoma-associated antigen 4 (MAGE-A4), an embryonic tumor antigen often expressed in patients with synovial sarcoma and MRCLS.

“The treatment of synovial sarcoma classically is with palliative chemotherapy. Where this really fits an unmet need is that this is a single infusion after chemotherapy,” Brian A. Van Tine, MD, PhD, one of the authors on this trial, said in an interview with 

. “After that one infusion, the modified T-cells continue to do their work, thus continuing to treat the patient. This provides the highest quality of life you can possibly have, because you're not coming back every 2 to 3 weeks for treatment or on a pill every day.”

In a previous signal-finding, phase 1 trial (NCT03132922), patients with HLA-A*02-positive tumors and MAGE-A4 expression demonstrated an “unusually high signal in this first trial that was both durable and the response rate was high,” according to Van Tine, an associate professor of medicine at Washington University School of Medicine in St Louis. Spearhead 1 is the confirmatory next-phase trial following these encouraging responses.

To be enrolled in Spearhead 1, patients went through screenings to see whether they had the correct HLA genotype and to find whether they had MAGE-A4 expression in 30% or more of their tumor cells. Patients between ages 16 and 75 years also needed an ECOG performance status of 0 or 1 and prior therapy with an anthracycline- or ifosfamide-containing regimen.

A total of 37 patients treated with 1×10

 transduced T cells included in the adverse event (AE) and baseline characteristics data. There were 33 patients in the modified intent-to-treat population who had at least 1 scan by the time of the data cutoff. These 33 evaluated for overall response rate (ORR) per RECIST v1.1 by independent review, overall survival, progression-free survival (PFS), duration of response (DOR), and time to response.

“I think the data that are coming out of this early interim analysis of the Spearhead 1 trial is noteworthy for a few things,” Van Tine said. “First, the ORR of the patients in the trial is nearly 40%, with 13 out of 33 patients responding. It’s a little higher in the synovial sarcoma arm at 41.3% [n=12/29], because there were patients with MRCLS who were allowed in the trial.” There was a 25.0% ORR in the MRCLS population (n=1/4).

Two patients with synovial sarcoma achieved complete response. The disease control rate was 84.8% in the modified intent-to-treat population. The median DOR was not reached (range, 4.3+ to 38.0+ weeks). “The responses are durable up to almost a year in a subset of patients. These are early data and I think it’s only going to get better as more patients enroll,” Van Tine said.

Any-grade treatment-related AEs (TRAEs) were seen in 95% of patients and grade 3 or more were seen in 92%. The most common grade 3 or more TRAES were lymphocyte count decrease in 84%, neutrophil count decrease in 68%, and white blood cell count decrease in 62%. Cytokine release syndrome was considered an AE of special interest and was observed in 59% of patients at any grade and in 3% at grade 3 or more. Van Tine noted that the number of serious AEs compared with the phase 1 trial have come down.

“It’s still in its early stages,” Frohlich said. “We may be able to see that [therapy being used] down the line, but those results are promising at least.” Van Tine hopes that an FDA approval will eventually follow these positive results, especially after longer-term follow-up, and the investigators can then try to expand this therapy to all patients with synovial sarcoma and MRCLS.

Another trial upcoming in patients who are HLA-A*02 and MAGE-A4 positive is the Surpass trial evaluating ADP-A2M4CD8 (NCT04044859). Those with urothelial carcinoma, head and neck, non–small cell lung, gastric, and esophageal cancer and esophagogastric junction disorder are eligible for enrollment. This phase 1 dose-escalation study “will show the utility of this therapy beyond synovial sarcoma and will be useful to any patient with a biomarker that can be used as an identifier. If you have the identifier to help the HLA, this will then allow you to, in a potentially tumor-agnostic way, move forward,” Van Tine said.

Additionally, data for catequentinib (anlotinib, AL3818), an oral tyrosine kinase inhibitor (TKI), were presented by Van Tine at ASCO 2021. This was in patients with metastatic or advanced synovial sarcoma from arm C of the phase 3 APROMISS trial (NCT03016819).

 Patients were randomized 2:1 to 12 mg/d of catequentinib for 2 weeks of a 3-week cycle (n=52) versus dacarbazine (DTIC-Dome; n=27). Crossover was allowed on this trial.

The primary end point of median PFS for patients receiving catequentinib was 2.89 months compared with 1.64 months with dacarbazine (HR, 0.449; 95% CI, 0.270-0.744; 

=.0015). The PFS rate at 4, 6, and 12 months was 48.1%, 42.3%, and 26.9% with catequentinib versus 14.9%, 11.1%, and 3.7% with dacarbazine, respectively.

“What’s interesting about catequentinib is it’s just like what we do with gastrointestinal stromal tumors. It’s a second oral TKI where the prior use of pazopanib didn’t seem to affect outcomes, so you can go from one to the other. It gives you a second oral medication to try,” Van Tine explained.

Catequentinib also demonstrated less toxicity than pazopanib, according to Van Tine. The most common grade 3 or more TRAEs for catequentinib were diarrhea at 5.8% and hypertension at 3.8%.

“The trial with catequentinib [showed] some efficacy,” Frohlich said. “That still has more progress to go. We have hope, but we still have a little way to go before we think that we will see those [therapies] in the clinic.”

Other early-phase studies have shown promise in the soft tissue sarcoma setting as well, including the phase 2 trial (NCT03880019) of olaparib (Lynparza) and temozolomide (Temodar) in patients with advanced uterine leiomyosarcoma.

 With a median follow-up of 10.8 months, the ORR was 27%, the median PFS was 6.9 months (95% CI, 5.4–not estimable), and the median DOR was 12.0 months (95% CI, 9.5–not estimable).

“That’s going to a phase 3 trial from a very small trial given the unusual high rates of response. Where I think this comes back to is funded basic science led to an observation that then focused a trial in just 1 [type of] sarcoma. This field, which used to just be the field of doxorubicin, may need hundreds of different therapies. But if you put the right therapies in the right box, you see the [efficacy],” Van Tine said.

Currently, the financial support for sarcoma research is not comparable to other, more common cancers. Van Tine felt the National Institutes of Health investments in adult sarcoma grants have been minimal. “There’s an entire group of young investigators who are coming up that will be bringing you the next treatments. But until they also get funded, there’s an unmet need for money and there’s an unmet need for new ideas. There needs to be an openness to allowing some of these novel ideas to move forward so that we can at least test them in patients,” Van Tine said.

However, the Sarcoma Foundation of America was offering grants in 2020 to be distributed in 2021 for research in immunotherapy, omic patterns of sensitivity and resistance to existing agents, omic characterization of sarcomas and definition of novel targets, systemic therapy combinations, and gene therapy.

“Because sarcoma is a group of rare cancers, sarcoma researchers haven’t had the funding to develop the immunotherapies and personalized treatments like they have in more frequently occurring cancers,” Frohlich said. “But in the last few years, we have seen progress in those areas and that was reflected in the research that was discussed at ASCO 2021.”

Van Tine and Frohlich agreed that patients’ willingness to participate in clinical trials is imperative to moving forward in this setting. “Our field only advances because of the partnership with patients,” Van Tine commented. “There are so many patients who have traveled so far to go on these trials that they are equally responsible for the results we’re seeing today. Their open-mindedness and their willingness to participate in novel therapies is the reason I think we’re going to have some advancement.”

Going forward, more targeted therapies will be investigated, and the current trials of catequentinib, afamitresgene autoleucel, olaparib plus temozolomide, and more will have longer follow-up and hopefully enough positive results for an approval to create more options for patients with soft tissue sarcomas. “I think that the future of sarcoma is an out-of-the-box way of approaching treatment. I think the first thing you must think about is that we know what chemotherapy does; we know what the limits of chemotherapy are. I think that we need novel ideas. There are a number of trials at ASCO showing me novel ideas this year,” Van Tine said.

1. What is a soft tissue sarcoma? American Cancer Society. Updated May 8, 2019. Accessed July 15, 2021. https://bit.ly/3eq7VDW

2. D’Angelo SP, Van Tine BA, Attia S, et al. SPEARHEAD-1: A phase 2 trial of afamitresgene autoleucel (formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma. 

2021;39(suppl 15):11504. doi:10.1200/JCO.2021.39.15_suppl.11504

3. Van Tine BA, Chawla SP, Trent JC, et al. A phase III study (APROMISS) of AL3818 (catequentinib, anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma.

2021;39(suppl 15):11505. doi:10.1200/JCO.2021.39.15_suppl.11505

4. Ingham M, Allred JB, Gano K, et al. NCI protocol 10250: A phase II study of temozolomide and olaparib for the treatment of advanced uterine leiomyosarcoma.

2021;39(suppl 15):11506. doi:10.1200/JCO.2021.39.15_suppl.11506

5. Sarcoma Foundation of America research grants – 2021 funding opportunity announcement. Sarcoma Foundation of America. Accessed July 19, 2021. https://bit.ly/3wKxEgA

During the 2021 American Society of Clinical Oncology Annual Meeting, multiple trials for targeted treatments were presented for soft tissue sarcoma. Dean Frohlich, PhD, and Brian A. Van Tine, MD, PhD, discuss the the results of some of these presentations, including the Spearhead 1 trial.