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Perspectives on 2019’s New Hematology Drug Approvals

December 30, 2021

In 2019, the FDA approved several new therapies – or new indications for previously approved therapies – for people living with blood disorders, including two disease-modifying treatments for sickle cell disease (SCD), the first anticoagulant for venous thromboembolism (VTE) management in children, and the first agent approved under the new international initiative of the agency's Oncology Center for Excellence, Project Orbis. In addition, the agency approved numerous new molecules and additional indications for leukemia, lymphoma, and myeloma.

With new agents poised to reshape the treatment landscape for many hematologic disorders, the American Society of Hematology (ASH) and the FDA partnered to bring hematologists practical information about using these agents during the "ASH-FDA Symposium on New and Late-Breaking Drug Approvals" at the 2019 ASH Annual Meeting. Experts convened to offer clinical and regulatory perspectives on the newly available therapies in two sessions focusing on malignant and classical hematology approvals, featuring FDA representatives offering insight into the drug review process and clinicians with significant experience with these agents discussing treatment challenges.


On November 21, the FDA approved acalabrutinib for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), after a review conducted under the agency's Project Orbis. As Nicholas Richardson, DO, MPH, a clinical reviewer for the FDA, explained, the initiative "creates a framework for concurrent submission and review of oncology drugs among international partners." Initial partners include Australia and Canada, but the agency is looking to expand the reach to include regulatory agencies in Singapore and Switzerland.

The decision was based on a review of results from the ELEVATE-TN and ASCEND trials. ELEVATE-TN included 535 patients with previously untreated CLL to receive either acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, or obinutuzumab plus chlorambucil. ASCEND randomized 310 patients with relapsed or refractory CLL to receive either acalabrutinib or investigator's choice. In each trial, acalabrutinib was associated with longer progression-free survival, compared with other treatment arms.

Thanks to recent therapeutic developments in the treatment of CLL/SLL, 5-year survival has climbed from 66% to 85%, noted Jacqueline Barrientos, MD, MS, from Northwell Health in New York, who discussed the clinical application of acalabrutinib.

However, Dr. Barrientos outlined several areas where acalabrutinib provides an important therapeutic option. First, a high proportion of patients with CLL/SLL are older (≥60 years) and have comorbidities that make it difficult for them to tolerate certain intense chemoimmunotherapeutic regimens. Second, if patients relapse after frontline therapy, "every subsequent next line of therapy [gives] us a shorter overall response rate, [meaning] we sometimes run out of options." Third, acalabrutinib provides an option for patients with disease that is intolerant to ibrutinib (the preferred regimen for young, fit patients). As Dr. Barrientos noted, "[Ibrutinib] is a really good drug, if you can take it."

Despite the improvements seen with acalabrutinib and the seemingly more manageable toxicity profile, Dr. Barrientos recommended patients be made aware of supportive care issues that may arise with treatment, including the potential for tumor flares, arthralgia, neutropenia, and opportunistic infections that may require prophylaxis.

Polatuzumab Vedotin-piiq

On June 10, the FDA approved the CD79b-directed antibody drug conjugate polatuzumab vedotin-piiq, in combination with bendamustine and rituximab (BR), to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received at least 2 prior therapies. The decision was based on results from the open-label phase II GO29365 study, which randomized 80 adults to receive either BR alone or BR with polatuzumab vedotin-piiq. The complete response rate was 40% in the polatuzumab + BR group, compared with 18% in the BR-alone group. Among the 25 patients who responded to treatment with polatuzumab vedotin-piiq, 16 (64%) had response durations of ≥6 months and 12 (48%) had response durations of ≥12 months.

As noted by FDA reviewer Yvette Kasamon, MD, in her discussion, this approval relied on data from a small randomized trial, which presented several regulatory challenges. In the analysis for survival endpoints, for example, the small sample size and lack of prespecified hypothesis limits drawing definitive conclusions, so that "a difference of 1 or 2 events might have substantial changes in the results."

Still, the combination of polatuzumab vedotin-piiq plus BR was found to have a favorable risk-benefit profile, and, as discussant Jonathan Friedberg, MD, MMSc, from Wilmot Cancer Institute at the University of Rochester in New York, said, this new drug fills "a major unmet need" for patients with relapsed/refractory DLBCL. While novel treatment combinations have failed to improve on the standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) approach for most patients, the treatment for patients with relapsed disease who are considered ineligible for hematopoietic cell transplantation or chimeric antigen receptor (CAR) T-cell therapy, treatment is largely palliative and consists of various types of chemotherapy. Therefore, "[polatuzumab vedotin-piiq plus BR] is a useful regimen to consider as second- or third-line therapy in transplant-ineligible patients," Dr. Friedberg stated.

The safety results from the pivotal trial suggest that most of the toxicity that led to withdrawal was associated with the BR component of the regimen, not with polatuzumab vedotin-piiq, which leads to questions of whether BR is necessary in this approach – particularly given the promising efficacy seen with polatuzumab vedotin-piiq monotherapy.

Dr. Friedberg recommended monitoring closely for neuropathy and cytopenias in patients treated with this novel approach. "I always remind people that this is palliative therapy and you are trying to make patients feel better," he said. "If toxicity is an issue, you can stop treatment earlier [than the 6 cycles evaluated in the pivotal trial]."


Acute graft-versus-host disease (aGVHD) remains a leading cause of nonrelapse mortality in patients with hematologic malignancies who undergo allogeneic hematopoietic cell transplantation, according to FDA reviewer Emily Jen, MD, PhD, who discussed the approval of the JAK inhibitor ruxolitinib for the treatment of steroid-refractory aGVHD in adult and pediatric patients ≥12 years.

While steroids are the standard frontline therapy option for treating aGVHD, a large portion of patients do not respond to or have recurrence of GVHD after steroids. "Despite durable response rates of only 40% to 60%, corticosteroids remain the only standard initial treatment for aGVHD," added clinical discussant Betty Ky Hamilton, MD, from Cleveland Clinic. Several agents are used off-label, but none have been proven more effective than steroids, meaning the treatment choice often depends on physician preference and side effect profile.

The approval was based on results from the REACH-1 trial, which enrolled 49 patients with aGVHD. All patients with grade 2 aGVHD responded to treatment by day 28, as well as 41% of those with grade 3 aGVHD, and 44% of those with grade 4 aGVHD. Responses lasted for a median of 16 days (range = 9-83). In addition, no new safety signals were identified, although the most common non-hematologic adverse events (AEs) included infections and edema.

Ruxolitinib is the first drug approved for this indication, so longer-term follow-up is needed to assess durability of response, survival, and other AEs such as infection, Dr. Hamilton said. "The pathogenesis of GVHD is very biologically complex and the phenotype of GVHD is quite heterogeneous, so well-designed clinical trials of novel agents are needed to identify subsets of patients who respond to specific agents," she concluded.


On November 20, the FDA approved givosiran for the treatment of acute hepatic porphyria (AHP), a rare disease that affects approximately 5 to 10 people per 100,000 in the U.S. The disease is characterized by painful neurovisceral attacks, with or without cutaneous manifestations, which often require hospitalization, supportive care, and narcotics to manage.

One drug, hemin for injection, is approved to ameliorate recurrent porphyria attacks in women, but, as FDA reviewer Andrew Dmytrijuk, MD, explained, its use is challenging for several reasons, such as the potential for iron overload and the fact that it is not routinely stocked in hospital pharmacies.

In his discussion of the role of givosiran in the clinic, Michael Linenberger, MD, from the Seattle Cancer Care Alliance, highlighted the complicated manifestations of AHP. "Abdominal pain is the hallmark but is not always present, and patients can have a broad range of neurologic manifestations, including sensory and motor peripheral neuropathy and central nervous system involvement," he explained. The episodic attacks characteristic of AHP develop over hours and can persist for days, but there are few clues to etiology. "Triggers like drugs, P450 inducers, progesterone, and alcohol use are not always present," he continued.

In the pivotal ENVISION study, 94 patients with AHP were randomized to receive either once-monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo to determine givosiran's effect on reducing the rate of porphyria attacks that require hospitalization, an urgent health care visit, or intravenous hemin administration at home. Over 6 months, the rate of attacks in the givosiran-treated group was 1.9, compared with 6.5 in the placebo group. In addition, givosiran treatment led to dramatic decreases in biomarkers of AHP (urinary delta-aminolevulinic acid and porphobilinogen).

In what Dr. Dmytrijuk called "a victory of integration of structural biology and medicine," the drug was approved for adults, and givosiran's manufacturer has committed to a postmarketing analysis in pediatric patients ages 12-17.

"Givosiran offers a highly effective and durable intervention for severely affected patients with AHP," Dr. Linenberger added. While patients may still require hemin to manage attacks or even opioids to manage pain, he noted that, "with proper diagnosis, genetic screening, preventive measures, and intermittent hemin, we can now effectively manage mild and/or infrequently symptomatic patients."

Crizanlizumab-tmca and Voxelotor

November saw 2 new approvals for patients with SCD: crizanlizumab-tmca to reduce the frequency of vaso-occlusive crises (VOC) in patients ≥16 years and voxelotor to potentially interrupt the molecular pathogenesis of SCD in patients ≥12 years.

Crizanlizumab-tmca, a monoclonal antibody targeted against the P-selectin glycoprotein that is expressed on activated endothelial cells and platelets, was approved based on results from the SUSTAIN trial, explained FDA reviewer Patricia Oneal, MD. A total of 198 patients with SCD and a history of VOC were randomized to receive either placebo or crizanlizumab-tmca at 2.5 or 5.0 mg/kg.

Treatment with crizanlizumab-tmca 5 mg/kg led to a significant reduction in the annual rate of VOCs leading to a health care visit (1.63 vs. 2.98) and a larger portion of patients had no episodes during follow-up (35% vs. 17%). "Treatment with crizanlizumab resulted in a 3-fold delay in time to first VOC and a 2-fold delay in time to second VOC," Dr. Oneal reported, noting that "longer-term studies are required to evaluate risks of infusion-
related reactions, bleeding complications, and infections."

Voxelotor, a once-daily oral therapy that modulates hemoglobin (Hb) affinity for oxygen to prevent the sickling of cells, was approved based on results from the phase III, placebo-controlled HOPE trial. Participants were randomized to receive voxelotor 900 mg per day, voxelotor 1,500 mg per day, or placebo. More voxelotor-treated patients achieved the primary endpoint of Hb response, defined as an increase of >1 g/dL from baseline to week 24 (51.1% in the voxelotor 1,500 mg group, 32.6% in the voxelotor 900 mg group, and 6.5% in the placebo group). As FDA reviewer Rosanna Setse, MD, PhD, noted in her discussion, this was the first time that accelerated approval was granted to a drug with an SCD indication.

"For the first time, we are in the position of having more than one disease-modifying sickle cell drug," said Caterina Minniti, MD, from Albert Einstein College of Medicine in New York. "We have 4 now and more are on their way." However, these approvals have brought more questions than answers, she added, including how to select the patient population that would most benefit from the 2 new drugs. Patient phenotype, genotype, age, preference, and insurance status may all affect treatment choices, she noted.

Jane Hankins, MD, MS, from St. Jude Children's Research Hospital in Memphis, tackled these questions from the perspective of a pediatric provider. Because voxelotor increases Hb concentration and crizanlizumab-tcma reduces VOC, it is reasonable to prescribe voxelotor to patients with more severe anemia and crizanlizumab-tcma to those with a high frequency of painful events, at least until data on organ preservation and other acute complications are available, she said. Information on combination therapy is not yet available.

Despite the fact that these agents have a different mechanism of action and non-overlapping toxicity profiles, Dr. Minniti outlined some concerns with each drug, including the prevention of vasculopathic complications with voxelotor and managing infection risk and antibody production with crizanlizumab-tmca.

It also is still unclear whether the new agents can be used in combination. However, Dr. Hankins offered a definitive answer on the question of whether either of the new agents should eventually take the place of hydroxyurea. "The answer is no, but the combination should be studied long term," she said, adding that curative therapies such as transplant and gene therapy also should still be offered to patients with available donors or with severe disease.

In discussing the challenges of implementing these new drugs into the clinical management of patients with SCD, Dr. Minniti also pointed to the uptake of hydroxyurea, which, despite being a standard of care for decades, has only reached 31%. Strategies to improve adherence are needed. "Drugs are not enough to improve outcomes in SCD," she said. "Standardization of supportive and ancillary care has been instrumental in improving outcomes in oncology, and I don't see why it shouldn't work in sickle cell."

Dr. Hankins also drew attention to the costs of crizanlizumab-tmca and voxelotor, which average $8,000 to $10,000 per month – much higher than hydroxyurea, which typically costs $50 to $100 per month. Although this might suggest that hydroxyurea is a more effective option, that would "miss the point of cumulative problems," she commented. "Starting [treatment with new agents] earlier to prevent complications would save money in the long term."

Dalteparin Sodium

On May 16, the FDA approved dalteparin sodium to reduce the recurrence of symptomatic VTE in pediatric patients (≥1 month). Dalteparin sodium, a type of low-molecular-weight heparin (LMWH), initially was approved in 1994 to prevent VTE in adult patients, and the label has been extended several times since then, including reduction of recurrence of cancer-associated VTE in adults in 2007. Prior to this recent pediatric-specific approval, options for VTE management in pediatric patients were extrapolated from data from adult trials, with modifications for age, weight, and anti–factor Xa therapeutic targets.

In the pivotal FRAG-A001-201 trial, 38 patients between 1 month and 18 years of age with symptomatic VTE received dalteparin sodium. Twenty-one patients (55%) achieved resolution of the qualifying VTE by study completion; another 7 patients showed regression, and 2 patients showed no change. No patients experienced progression of VTE, while 1 patient experienced recurrence of VTE.

Based on these findings, the recommended starting doses of dalteparin sodium differed by age: 150 IU/kg for those aged 1 month to <2 years; 125 IU/kg for those aged 2 to 8 years; and 100 IU/kg for those aged 8 to 17 years. The safety analysis uncovered no new unexpected safety findings, and rates of bleeding events were similar to those observed in adult clinical trials (minor bleeding in 40% of participants and major bleeding in 2%). Approximately two-thirds of patients enrolled in FRAG-A001-201 had cancer, suggesting that these findings can be applied to the management of children with cancer-associated thrombosis, as well.

In his discussion of dalteparin sodium's approval, Neil Goldenberg, MD, PhD, from Johns Hopkins All Children's Hospital in St. Petersburg, Florida, underscored the importance of having a pediatric-specific indication for VTE management. "So much in pediatric care ends up being not FDA-approved, even though it becomes standard of care," he said. This recent approval "gives parents and patients more confidence [in the treatment decision]."

However, Dr. Goldenberg recommended discussing the limited experienced with dalteparin sodium in this setting with patients and their families, because the literature about LMWH is dominated by enoxaparin. "It is important to inform parents and patients, and assess and support their values and preferences," he said.


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