New Approvals Continue to Shift Treatment Landscape in Hematologic Malignancies

Kathryn Maples, PharmD, BCOP

New drug approvals, new indications, and drug removals have continued to add novel treatment options for patients with hematologic malignancies, according to Kathryn Maples, PharmD, BCOP, a clinical pharmacy specialist in multiple myeloma at the Winship Cancer Institute with Emory Healthcare in Atlanta, Georgia.¹

“A lot of these drugs are getting approved through accelerated approval pathways, which is really great and exciting for our patients because they need these therapies now,” she said. “But [their approvals] are contingent upon those confirmatory studies. If that doesn't happen, then those drugs get removed.”

Maples recently presented at the 27th Annual International Congress on Hematologic Malignancies^®: Focus on Leukemias, Lymphomas, and Myeloma.. Her talk, “Pharmacology in Oncology: New Updates in Hematologic Malignancies” touched on the updated indications of asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze), Brentuximab vedotin (Adcetris), and zanubrutinib (Brukinsa), along with the new approvals of olutasidenib (Rezlidhia; FT2102), mosunetuzumab-axgb (Lunsumio), and teclistamab (Tecvayli). She also highlighted the removal of belantamab mafodotin (Blenrep) from the United States market.

Although Maples noted that the expanded indications and new approvals are very exciting, she added that there are still many unmet needs. “We still have a giant need for novel therapies at this time, and I think we will see more to come in 2023.”

Leukemia

Asparagine is very critical to the cell survival process and asparaginase is a core component of multiagent treatment regimens in acute lymphoblastic leukemia (ALL) as well as lymphoblastic lymphoma (LBL).² Asparaginase converts serum asparaginase into aspartic acid and ammonia, this in turn stops the leukemia cells from acquiring asparagine. Without asparagine, the leukemia cells do not have RNA or protein synthesis and are no longer able to proliferate and survive. Maintaining periods of asparaginase activity is therefore key in the treatment of ALL and LBL. Survival estimates for ALL have been steadily improving since asparaginase was first introduced in 1978.²

Maples noted that the most common form of asparaginase is E. coli derived, however 10% to 15% of patients will develop hypersensitivity to that product.

Asparaginase erqinia chrysanthemi (Recombinant) was indicated as part of a multi-agent chemotherapy regimen for adult and pediatric patients who are 1 month or older with ALL/LBL who have developed a hypersensitivity to E.coli-derived asparaginase . This agent was approved in the US in June 2021 with a dosing schedule of 25 mg/m² every 48 hours. However, this dosing was challenging for patients, especially since infusion centers are not open on the weekends.³

She noted that many patients who receive this treatment are pediatric patients, and coming in every other day may be unrealistic for both them and working parents. So, in November 2022, the FDA label was expanded to include a Monday/Wednesday/Friday dosing schedule. This was approved based on data from the phase 2/3 trial JZP458/ AALL1931 trial (NCT04145531) and the new dosing regimen consists of 25/mg² on both Monday morning and Wednesday morning followed by a 50 mg/m² dose on Friday afternoon. In the trial, the dosing schedule demonstrated a favorable benefit-to-risk profile and over 90% of patients achieved nadir serum asparaginase activity greater than 0.1 U/mL by simulation.^3,4

“This has been pretty impactful in our practice by allowing patients to have this Monday/Wednesday/Friday dosing schedule; they no longer have to worry about coming [in] on weekends, and we are able to not miss a dose [and] eliminate a very critical part to the survival for ALL patients,” Maples said.

IDH Mutations

IDH1 or IDH2 mutations are detected in approximately 20% of patients with acute myeloid leukemia (AML). Accordingly, enasidenib (IDHIFA) was approved in 2017 for IDH2-mutated relapsed/refractory (R/R) AML, and ivosidenib (Tibsovo) was approved in 2018 for IDH1-mutated R/R AML. Ivosidenib was also subsequently approved in May 2022 in combination with azacitidine for patients with newly diagnosed disease and an IDH1 mutation who were unfit for intensive chemotherapy. This approval applies to patients who are 75 years or older and who cannot tolerate intensive therapy.^5,6

IDH1 mutations typically are present in between 7% to 14% of patients with AML. Moreover, they are present in approximately 3% to 4% of patients with myelodysplastic syndrome. IDH1 functions by catalyzing oxidative decarboxylation of isocitrate to a-ketoglutarate.⁷

Olutasidenib

Olutasidenib was approved by the FDA for relapsed/refractory AML in December 2022. It is indicated at a dose of 150-mg by mouth twice daily. It crosses the blood-brain barrier, which makes it different from other IDH1 inhibitors, according to Maples, who added that more data is needed in terms of best sequencing practices. It is included in National Comprehensive Cancer Network (NCCN) guidelines, and there is ongoing research evaluating olutasidenib in comparison with azacitidine.^7,8

Maples described olutasidenib as a potent, selective, oral small molecule of mutant IDH1. This quinolinone-based allosteric, non-competitive inhibitor of mutant IDH1 binds in hydrophobic pocket near the IDH1 homodimer interface. It holds the therapeutic potential to restore normal cellular differentiation.^7,8

Olutasidenib was assessed in a phase 2 trial (NCT02719574) which enrolled patients with relapsed or refractory AML harboring a mutant IDH1 mutation. These 153 IDH1-inhibitor treatment-naïve patients were prescribed olutasidenib monotherapy at 150-mg twice daily. The trial’s primary end point was complete remission plus completion remission with partial recovery of peripheral blood counts (CR + CRh) rate—which came out to 35% (n = 51; 95% CI, 27.0%-43.0%). The overall response rate (ORR) was 48% (n = 71; 95% CI, 40.0%-56.7%). The median time to CR/CRh was 1.9 months (range, 0.9-5.6), the median duration of response (DOR) was 11.7 months (95% CI, 6.9-25.9), and the median overall survival (OS) was 11.6 months (95% CI, 8.9-15.5).^7,8

The most common adverse events (AEs) of any grade on the trial were gastrointestinal-related, including nausea (38%), constipation (26%), and diarrhea (20%). This agent needs to be taken on an empty stomach, Maples said. Cytopenias are also seen with olutasidenib, and the rate of febrile neutropenia was 22%.^7,8

“We need to mindful of giving our patients that prophylaxis, especially if they have that partial hematologic count recovery,” Maples said.

Moreover, differentiation syndrome occurred in 22 (14%) of patients, and 9% of these cases were grade 3 or worse. Olutasidenib does have a boxed warning for this differentiation syndrome. This may present as leukocytosis fever, pulmonary infiltrates dyspnea. Most cases did, however, resolve with treatment interruption, dexamethasone, and or supportive care, she noted.⁸

Additionally, hepatic AEs also occurred in 38 patients, with grade 3 events occurring in 12% and grade 4 occurring in 3% of patients, respectively. Monitoring for hepatic AEs, and responding accordingly, is advised.⁸

Lymphoma

Previously, there were 3 PI3K inhibitors available but now there is only 1 still on the market. Intravenous copanlisib (Aliqopa) is still approved, although idelalisib (Zydelig) and duvelisib (Copiktra) were removed from the guidelines and lost their approval after data on their benefit/risk profile proved unfavorable in long-term confirmatory studies.⁹

There is an EZH2 Inhibitor, tazemetostat (Tazverik), approved for R/R follicular lymphoma, as well as 2 CD19-directed CAR T-cell therapies. These are axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah).⁹

Mosunetuzumab

Mosunetuzumab, which was approved late in 2022, is the first CD20/CD3 T-cell-engaging bispecific antibody approved in this setting and represents a new class of fixed-duration cancer immunotherapy, according to Maples. Patients receive 8 cycles. If they achieve CR, then you can “stop and observe” but if not, treatment can continue up to 17 cycles before stopping and observing. It is an off-the-shelf product, and its indication is for adults with R/R follicular lymphoma who have already seen 2 or more lines of systemic therapy.¹⁰

“The way I describe our bispecific antibodies to my patients is that it has one arm that reaches out and grabs the target itself and then it has one arm that reaches out and grabs your CD3 T- cells [and] activates those T cells to then find and target the lymphoma cells,” Maples said.

Mosunetuzumab’s approval was supported by findings from a phase 2, single-arm, multicenter study (NCT02500407), which enrolled a total of 90 patients with grade 1-3a, follicular lymphoma, who had undergone 2 or more prior lines of therapy, including CD20 monoclonal antibodies and anthracycline. After a median follow-up of 18.3 months, the ORR was 80% (95% CI, 70.3-87.7), and the CR rate was 60% (95% CI, 49.1%-70.2%). The median time to CR was 3 months (range, 1.4-5.7) and the median progression-free survival (PFS) was 17.9 months (95% CI, 10.1-not reached [NR]). The median duration of response was 22.8 months (95% CI, 9.7-NR).

Cytokine release syndrome (CRS) is the biggest concern with this treatment. Forty out of 90 patients in this trial experienced CRS (44%), 26% had grade 1 severity and 17% had grade 2 severity. CRS typically occurred in cycle 1 on day 1 (23%), as well as on day 15. The median time to CRS was 5 hours (range, 3-9 hours). The symptoms observed with CRS included pyrexia (98%), hypotension (38%), chills (35%), headache (28%), tachycardia (28%), and hypoxia (20%).

Moreover, neutropenia occurred in 27% of patients, hypophosphatemia in 17%, hyperglycemia in 8%, and anemia in 8%.

Its administration is on a 21-day cycle. Premedication is advised prior to the first 2 cycles. If CRS does not occur during that time, then premedication can be stopped at the beginning of cycle 3.

“The administration with Cycle 1 is over 4 hours. Starting with Cycle 2, the administration can be as short as 2 hours,” Maples explained. “The dose is 60-mg on day 1 only, and then [for] cycles 3 and beyond, the doses are 30 mg on day 1 only.”

Moreover, “this agent is easy to prepare,” she explained. “It's already in solution.It doesn't take long to mix and the administration is relatively easy thinking in contrast to other agents. This is something that can easily be done in the outpatient setting.”

Brentuximab vedotin

Brentuximab vedotin received its first pediatric approval in November 2022. It was approved in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide, as a treatment for pediatric patients 2 years of age and older with previously untreated high-risk classical Hodgkin lymphoma.¹¹

This approval was supported by findings from a randomized, open-label, actively controlled phase 3 trial (NCT02166463) which enrolled 600 patients to receive either brentuximab vedotin or bleomycin—both in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide. High-risk disease was defined as Arbor Stage IIB with bulk disease, stage IIIB, stage IVA, and stage IVB.

At a follow-up of 42.1 months (range, 0.1-80.9), the 3-year event-free survival (EFS) rate was 92.1% (95% CI, 88.4%-94.7%) vs 82.5% (95% CI, 77.4%-86.5%) in the brentuximab and standard-of-care arms, respectively (HR, 0.41, 95% CI, 0.25-0.67). The median EFS was not reached in either group, but the OS rate at 3 years was 99.3% in the brentuximab vedotin group vs 98.5% in the standard of care group. Toxicity profiles were reportedly similar between the 2 groups.

“[It was] very exciting to see Brentuximab vedotin receive this new pediatric approval,” Maples said.

Zanubrutinib

The SEQUOIA study was a phase 3 trial (NCT03336333) which assessed zanubrutinib vs rituximab and bendamustine (R-benda) in untreated CLL or SLL in patients who are older, have comorbidities, and whose disease did not harbor the high-risk genomic abnormality del (17)(p13.1). This trial was built off of previous studies which demonstrated zanubrutinib superiority in this setting. A total of 590 patients were enrolled, 241 of whom received zanubrutinib and 238 of whom received R-benda. The median follow-up was 26.2 months.¹²

Overall, median PFS was significantly improved with zanubrutinib compared with R-benda (HR, 0.42; 95% CI; 0.28-0.63). Of note, the median PFS per independent review committee was not reached in either group. The rate of neutropenia was much lower with zanubrutinib than with R-Benda (11% vs 51%, respectively).

This data led to the approval of zanubrutinib as frontline therapy for patients with CLL or SLL.

According to Maples, zanubrutinib has many practical implications. It is an oral option for patients for whom chemoimmunotherapy may be a challenge. Moreover, zanubrutinib was associated with a low rate of atrial fibrillation (3%), especially compared to ibrutinib in the relapsed setting in the ASPEN (NCT03053440) and ALPINE (NCT03734016) trials. It is considered a less toxic option than some of the other options approved in this setting.

There are currently ongoing studies seeking to explore the combination with other agents to deepen responses.

“At our institution zanubrutinib has become our preferred BTK inhibitor of choice,” Maples said. “If we are using it in the frontline setting for these patients, the only time where we will sometimes consider acalabrutinib (Calquence) is in a patient with uncontrolled blood pressure.”

Multiple Myeloma

Maples began her update on multiple myeloma by noting that treating this malignancy should be viewed as a “marathon not a sprint.” Tolerability is just as important as efficacy in choosing combination regimens, she said.¹³

Multiple myeloma is an incurable malignancy characterized by uncontrolled plasma cell proliferation. These malignant plasma cells will secrete M-protein into the blood or urine, and it is associated with end-organ dysfunction. It is a rare malignancy but it’s the second most common hematologic malignancy.

However, according to Maples “we have seen significant growth” in the treatment of multiple myeloma, particularly since the approval of bortezomib (Velcade) in the early 2000s. Prior to that approval, the 5-year relative survival date was estimated to be nearer to 25.5%, since autologous or allogeneic stem cell transplant were the only standard of care treatments. However, since then, a slew of agents have received indications, including numerous since 2015 alone—daratumumab (Darzalex), elotuzumab (Empliciti), isatuximab (Sarclisa), ixazomib (Ninlaro), selinexor (Xpovio), ciltacabtagene autoleucel (Carvytki), idecabtagene vicleucel (Abecma), teclistamab, and belantamab mafodotin—and the current 5-year relative survival rate is 57.9%.

Teclistamab

The MajesTEC-1 Trial (NCT04557098) was a phase 1/2 study design which enrolled 165 patients with R/R multiple myeloma who had received no prior BCMA-directed therapy and 77.8% of whom had triple-class refractory disease. Patients received teclistamab at a dose of 1.5 mg/kg subcutaneously once weekly, with a step-up dose of 0.06 mg/kg and 0.3 mg/kg. The primary end point was ORR. Secondary end points included PFS, OS, minimal residual disease (MRD) negativity, and DOR.¹⁴

The findings showed an ORR of 63%, which included a 58.8% very good partial response rate and a 39.4% CR rate. The median DOR was 18.4 months, the median time to first response was 1.2 months and the median time to best response was 3.8 months. MRD negativity was 26.7%, median PFS was 11.3 months, and median OS was 11.3 months.

This data led to an FDA approval for patients with R/R multiple myeloma who have received at least 4 prior lines of therapy, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. It was added to the NCCN guidelines for this setting. A confirmatory phase 3 trial is still ongoing.

“The biggest thing [with bispecifics] is going to be CRS,” Maples said, regarding the safety profile of teclistamab. In the trial, the rate of all-grade CRS was 72.1% (n = 119). The median time to onset was 2 days (range, 1-6) and the median duration as also 2 days (range, 1-9). Managing infections is also key, as these occurred in 76.4% of patients (n = 126), and 44.8% (n = 7) had grade 3 or 4. Hypogammaglobulinemia occurred in 123 patients (74.5%) and the rate of injection-site reactions occurred in 36.4% (n = 60).

“I think the most notable AEs that we see in practice are going to be related to the cytopenias and infections,” she added. “The other most common AEs that we see are injection site reactions.”

Moreover, because of the risks of CRS and neurologic toxicities, this agent is only available under a Risk Evaluation and Mitigation Strategy (REMS), called the Tecvayli REMS.

Health care facilities need to have an Authorized Representative, and all prescribers must be enrolled in the REMS program and take a knowledge assessment. Moreover, Authorized Representatives must generate a REMs dispense authorization for each dose, and these records should be maintained indefinitely.

REMS does not require hospitalization, however patients must be monitored for 48 hours following each step up dose on days 1 and 4, and after the first dull treatment dose on day 7. Patients will also need to be given a wallet card prior to their first treatment.

Belantamab mafodotin

Belantamab mafodotin was removed from the US market in November 22, 2022. Following findings from the phase 3 DREAMM-3 trial (NCT04162210), which showed that the agent did not meet its primary end point of PFS.^15,16

However, belantamab mafodotin is still available via compassionate use, and RNs and APPs should therefore be aware that the agent is associated with keratopathy. Patients receiving this agent should undergo ophthalmic exams at baseline, prior to each dose, and promptly thereafter if symptoms, including rye eye, blurred vision, or more, occur. Patients should also be counseled to use preservative-free lubricant eye drops and avoid contact lenses unless directed by an ophthalmologist. She stressed that prophylactic steroid eye drops will not prevent or reduce the risk of keratopathy. If keratopathy occurs, treatment should be held until improvement. Treatment may be resumed, or permanently discontinued based on severity.

Research is still ongoing, and belantamab mafodotin is being investigated in combination with numerous other regimens.

“So more to come on this agent to see if we see it come back around,” Maples concluded.

Editor’s Note: Maples has served as a consultant for Pfizer, and discusses off-label and non=FDA approved medications. Her slides on lymphoma updates were co-created with her colleague Aseala Abousand, PharmD, BCOP.

References

1. Maples K. Pharmacology in oncology: new updates in hematologic malignancies. Presented at: 27th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma; Miami, FL; February 24-27, 2023.
2. Egler RA, Ahuja SP, Matloub Y. L-asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016;7(2):62-71. doi:10.4103/0976-500X
3. Rylaze. Prescribing information. Jazz Pharmaceuticals; 2022. Accessed February 27, 2023. https://pp.jazzpharma.com/pi/rylaze.en.USPI.pdf
4. Efficacy and safety of intramuscular (IM) recombinant Erwinia asparaginase in acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): The Children’s Oncology Group (COG) AALL1931 study. J Clin Oncol. 2022;40(suppl 16):7001. doi:10.1200/JCO.2022.40.16_suppl.7001
5. Idhifa. Prescribing information. Celgene Corporation; 2022. Accessed February 27, 2023. https://packageinserts.bms.com/pi/pi_idhifa.pdf
6. Tibsovo. Prescribing information. Servier Pharmaceuticals LLC; 2022. Accessed February 27, 2023. https://www.tibsovopro.com/pdf/prescribinginformation.pdf
7. Watts JM, Baer MR, Yang J. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol. 2023;10(1):e46-e58. doi:10.1016/S2352-3026(22)00292-7.
8. Rezlidhia. Prescribing information. Rigel Pharmacueticals Inc; 2022. Accessed February 27, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf
9. NCCN Guidelines for B-Cell Lymphomas V.2.2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
10. Lunsumio. Prescribing information. Genentech, Inc; 2022. Accessed February 27, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761263s000lbl.pdf
11. Adcetris. Prescribing information. Seagen, Inc; 2022. Accessed February 27, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125388_s056s078lbl.pdf
12. Tam CS, Brown JR, Kahl BS. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5.
13. Cancer Stat Facts: Myeloma. National Cancer Institute. Surveillance, epidemiology, and end results program. Accessed February 27, 2023. https://seer.cancer.gov/
14. Tecvayli. Prescribing information. Janssen Biotech, Inc; 2022. Accessed February 27, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761291s000lbl.pdf
15. Blenrep. Prescribing information. GlaxoSmithKline; 2022. Accessed February 27, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761158s006lbl.pdf
16. GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News release. GlaxoSmithKline. November 22, 2022. Accessed February 27, 2023. https://www.gsk.com/en-gb/media/press-releases/