ASH 2019 Clinical Findings: CAPTIVATE, CANDOR, Blinatumomab, and More

Three-Quarters of Patients on Ibrutinib-Venetoclax Combo in CLL Achieve Undetectable MRD in CAPTIVATE

Most patients with previously untreated chronic lymphocytic leukemia (CLL) who received a combination of ibrutinib and venetoclax achieved undetectable minimal residual disease (MRD), according to partial results from the phase 2 CAPTIVATE trial¹ presented on December 7, 2019, at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.

Patients in the study, who were under age 70, received a daily oral dose of 420 mg of ibrutinib (Imbruvica, Janssen) for 3 cycles (28 days each), followed by 12 cycles of ibrutinib with an escalating dose of venetoclax (Venclexta/Venclyxto) up to 400 mg. Of the evaluable patients, 75% achieved undetectable MRD in their peripheral blood at some point after baseline, whereas 72% achieved undetectable MRD in their bone marrow.

Lead investigator Constantine Tam, MD, of the Peter MacCallum Cancer Centre, Victoria, Australia, presented results from the MRD cohort prior to randomization based on their MRD status. Results presented at ASH involved 164 patients who began the trial and 151 who were able to complete all 12 cycles. In the next phase of the trial, to be reported later, patients with undetectable MRD were randomized 1:1 to receive ibrutinib or placebo, whereas those with detectable MRD will be randomized to receive ibrutinib or ibrutinib with venetoclax.

Based on the successful results to date, Tam added, “We have now accrued a third [group of] 159 patients in a separate, fixed-duration cohort,” and these patients will receive the combination therapy “without any further treatment.”

Ibrutinib has transformed CLL care as the only daily inhibitor of Bruton tyrosine kinase.² Its benefi ts have been seen in patients with first-line CLL in both the RESONATE-2³ and ECOG-1912⁴ trials; investigators for these studies reported additional data during ASH 2019. Venetoclax is an oral inhibitor of BCL2, proteins that regulate cell death, or apoptosis. As CAPTIVATE investigators discussed in their abstract, the 2 therapies are believed to have synergistic properties, given the ability of ibrutinib to draw CLL cells from lymphoid tissue into the blood, where they would rely on BCL2.¹ Tam is also leading studies of the 2-drug combination in mantle cell lymphoma.

MRD is an increasingly important measure of the small number of cancer cells remaining in the body after treatment. These cells can be hard to detect, but they are important because they can be indicators of which patients will relapse. The use of MRD as a guide for treatment will be the focus of CAPTIVATE when the next results are reported, and this will help answer one of the important questions the trial is designed to address, Mark Wildgust, PhD, vice president, Global Medical Affairs, Oncology, Janssen, said in an interview with Evidence-Based Oncology™.

Before ibrutinib, he said, the reason patients with CLL would only be treated with 6 cycles of the regimen known as FCR—fl udarabine, cyclophosphamide, and rituximab—was because they could not tolerate any more therapy. Ibrutinib “changed the paradigm,” Wildgust said; he noted that new data from ECOG-1912 presented at ASH show that continuously treating patients with ibrutinib is better than the old “gold standard” of 6 cycles of FCR.⁵

With CAPTIVATE, the question of stopping therapy is raised not because patients can no longer tolerate treatment, but because once they are MRD negative, it might be possible to stop therapy without CLL progressing. Thus, he said, the study seeks to answer (1) Can patients who have 15 cycles of therapy reach a point where MRD cannot be measured, and (2) If therapy is stopped, is it safe?

Clinicians were aff orded an early glimpse at CAPTIVATE data in June 2018 during the annual meeting of the American Society of Clinical Oncology, where 77% of the first 30 patients had undetectable MRD after 6 cycles of the combination treatment.⁶ Presenters explained at that time the lead-in with ibrutinib alone helps prevent tumor lysis syndrome; this protocol is also seen in the CLARITY trial for patients with relapsed or refractory CLL.⁷

In the results presented at ASH 2019, the median treatment duration was 14.7 months (range, 0.5-19.9 months) with ibrutinib and 12 months (range, 0.8-12.7 months) with venetoclax.¹ The most common adverse events (AEs) of any grade were diarrhea (31%) with single-agent ibrutinib and diarrhea (60%), neutropenia (40%), and nausea (34%) with the combination. AEs leading to dose reductions occurred in 20% of patients, and AEs that caused patients to stop therapy occurred in 7% of patients (ibrutinib 5%, venetoclax, 4%).

“This study was not intended to enroll high-risk patients,” Tam said during his presentation, but many in the original 164Šenrollees (median age, 58 years) had genetic risk factors:

• 16% had deletion 17p.

• 20% had deletion 17p or TP53 mutation.

• 16% had deletion 11q without deletion 17p.

• 19% had complex karyotype.

• 59% had unmutated immunoglobin heavy chain gene mutation.

Tam noted the high rate of undetectable MRD was seen across subgroups, including these high-risk patients: deletion 17p, 75%; deletion 17p or TP53 mutation, 70%; deletion 11q, 84%; complex karyotype, 83%; and unmutated immunoglobin heavy chain gene mutation, 81%.

Of the patients who reached the combination therapy cycles:

• Undetectable MRD in peripheral blood rose over time, from 57% after 6 cycles to 68% after 9 cycles, and 73% after 12 cycles

• Undetectable MRD was achieved in 75% of patients (122 of 163) in peripheral blood when measured and 72% (111 of 155 patients) in bone marrow

“We are encouraged by these data and the potentially potent combination of ibrutinib plus venetoclax treatment for CLL and potentially other blood cancers in the future,” Tam said in a statement.

NEW ANALYSIS FROM EARLIER STUDIES.

An integrated analysis⁸ of the RESONATE and RESONATE-2 studies, which includes up to 6 years of follow-up, covered a total of 271 patients, including 136 patients who received ibrutinib as fi rst-line therapy and 135 who received it for relapsed or refractory CLL. The analysis shows that using ibrutinib earlier in the treatment of CLL results in better progression-free survival, overall survival, and overall risk reduction. Results include the following:

• A higher share of patients treated with ibrutinib in earlier lines remained progression-free or alive at 60 months (fi rst line, 70%; 1-2 lines prior, 60%; 3 or more, 33%).

• First-line treatment brought a 34% reduction in risk of disease progression or death compared with 1 to 2 prior lines, with a hazard ratio (HR) of 0.66 (95% CI, 0.40-1.09).

• Progression-free survival was prolonged for first-line treatment versus 3 or more lines, with an HR of 0.32 (95% CI, 0.21-0.49) and 1 to 2 lines versus 3 or more lines, with an HR of 0.48 (95% CI, 0.30-0.77).

Wildgust said Janssen will continue to support research to explore questions of whether patients can safely stop therapy for CLL, and if so, what is the best way.

“We’re at a point where ibrutinib has 5 frontline studies that show a survival benefit,” he said, including the new RESONATE analyses that show earlier treatment is better. “Now the question is whether we can look at potential ways of stopping—and as a company, we’re looking at all those diff erent ways of stopping.”

References

1. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at: 61st†American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 35. ash.confex.com/ash/2019/webprogram/Paper121424.html. Accessed December 8, 2019.

2. Bauer A. Cancer advance of the year: transformation of CLL treatment. Cancer.net website. cancer.net/blog/2015-01/cancer-advance-year-transformation-cll-treatment. Published January 20, 2015. Accessed December 10, 2019.

3. Berger JA, Tedeschi A, Barr PM, et al for the RESONATE-2 investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437. doi:10.1056/NEJMoa1509388.

4. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOGACRIN cancer research group (E1912) Blood. 2018;132(suppl 1):LBA-4.

5. Shanafelt TD, Wang V, Kay NE, et al. Ibrutinib an rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. Outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 61st†American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 33. ash.confex.com/ash/2019/webprogram/

Paper126824.html. December 8, 2019.

6. Helwick C. Ibrutinib plus venetoclax in CLL: high MRD-negativity rates, reduced risk for tumor-lysis syndrome. The ASCO Post. ascopost.com/issues/july-10-2018/ibrutinib-plus-venetoclax-in-cll/. Published July 10, 2018. Accessed December 8, 2019.

7. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. JClin Oncol. 2019;37(30):2722-2729. doi: 10.1200/JCO.19.00894.

8. Barr PM, Tedeschi A, Munir T, et al. Using ibrutinib in earlier lines of treatment results in better outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 61st†American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract. 3054. ash.confex.com/ash/2019/webprogram/Paper123327.html. December 8, 2019.

Adding Daratumumab to Carfilzomib, Dexamethasone Improves PFS in Relapsed/Refractory Multiple Myeloma

Using the monoclonal antibody daratumumab with carfilzomib and dexamethasone boosts survival benefi ts for patients with relapsed or refractory multiple myeloma (RRMM), including those who have taken lenalidomide, according to findings from CANDOR,¹ a phase 3 study presented on December 10, 2019, at the 61st American Society of Hematology Annual Meeting and Exposition in Orlando, Florida.

The triple-therapy combination led to a 37% reduction in the risk of disease progression or death compared with those taking carfi lzomib and dexamethasone alone. Carfilzomib, a selective proteasome inhibitor, is sold as Kyprolis by Amgen; a once-weekly†combination with dexamethasone was approved for patients with RRMM in October 2018.² Amgen funded the CANDOR trial.

Although survival rates for multiple myeloma have improved as treatment options have increased, the disease remains incurable, and some patients must stop current agents such as lenalidomide or bortezomib due to toxicity.^3,4 Thus, fi nding new therapies or combinations is a priority, according to Saad Z. Usmani, MD, of Atrium Health, lead author of the CANDOR study.

“The majority of patients have disease progression on lenalidomide, and of the 6 treatment combinations that are currently approved in this setting, 4 have lenalidomide as part of their treatment combination,” Usmani said in a statement.⁵ “It makes little sense to rechallenge a patient with something they are progressing on just by adding other drugs. So, there is a need for novel therapeutic options for patients with multiple myeloma who have relapsed or are refractory to lenalidomide-based treatments.”

CANDOR is a phase 3, open-label trial in which 466 patients treated with 1 to 3 prior therapies were randomized 2:1 to receive the triple combination (KdD) or carfi lzomib and dexamethasone (Kd).1 In an earlier phase I study, investigators found that adding daratumumab improves survival in patients with RRMM.⁶

Daratumumab (Darxalex, Janssen) targets CD38, causing cell death.

Results of the trial showed the following:

• After a median follow-up of 17 months, the median progression-free survival (PFS) had not been reached for KdD, whereas median PFS was 15.8 months for Kd; the hazard ratio (HR) was 0.63 (95% CI, 0.46-0.85; P = .0014).

• At this point, Usmani said there are no diff erences in overall survival.

• The patients receiving triple therapy had a better overall response rate, or 84.3% compared with 74.7% for Kd.

• Complete response rates were 28.5% for KdD versus 10.4% for Kd.

• Rates of undetectable minimal residual disease at 12 months were 12.5% for KdD versus 1.3%.

• Patients on triple therapy were in treatment for 70.1 weeks, compared with 40.3 weeks for the Kd group.

Patients in the CANDOR trial had a median age of 64 years; 42.3% previously had lenalidomide therapies, and 90.3% underwent regimens with bortezomib. In a press briefing, Usmani pointed out results for those previously treated with lenalidomide. “This is perhaps one of the more important subgroups,” he said.

In patients with prior lenalidomide exposure, the median PFS was not reached in the triple- therapy group, whereas it was 12.1 months for the Kd group (HR, 0.52; 95% CI, 0.34-80). Among patients who were lenalidomide refractory, the median PFS for the triple-therapy group was not reached; it was 11.1 months for the Kd group (HR, 0.45; 95% CI, 0.28-74).

“So, the PFS benefit was maintained not just in other subgroups, but in these 2 clinically meaningful subgroups as well,” Usmani said.

Patients in the triple-therapy group had higher rates of serious adverse events, including 5 treatment-related deaths due to pneumonia, sepsis, septic shock infection, and cardiac arrest. The most common adverse events were thrombocytopenia, anemia, diarrhea, hypertension, upper respiratory tract infection, fatigue, and shortness of breath.

Investigators reported cardiac events in 5% to 8% of patients, consistent with prior studies, but heart failure was lower in the triple-therapy group.¹

In a statement, Usmani pointed out that multiple myeloma is a heterogenous disease, so multiple treatment options are needed to address different patient needs. “Even within a single patient, we see many diff erent clones, at an average of 10 to 15 clones at the time of diagnosis—so if you want optimal disease control, you have to target diff erent mechanisms of action to control the disease more effectively.”⁵

References

1. Usmani SZ, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): primary analysis results from the randomized, open-label, phase 3 study CANDOR. Presented at: 61stŸAmerican Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract LBA-.Ÿash.confex.com/ash/2019/webprogram/Paper132629.html.

Accessed December 9, 2019.

2. Joszt L. FDA approves once-weekly dose of Kyprolis for R/R multiple myeloma. The American Journal of Managed Care® website. ajmc.com/newsroom/fda-approves-onceweekly-dose-of-kyprolis-for-rr-multiple-myeloma. Published October 3, 2018. Accessed December 7, 2019.

3. Bnello F, Pulini S, Ballanti S, et al. Lenalidomide maintenance with or without prednisone in newly diagnosed myeloma patients: a pooled analysis. Cancers. 2019;11(11):1735. doi.org/10.3390/cancers11111735.

4. Field-Smith A, Morgan GJ, Davies FE. Bortezomib (Velcade) in the treatment of multiple myeloma. Ther Clin Risk Manag. 2006;2(3):271-270. doi:Ÿ10.2147/tcrm.2006.2.3.271.

5. Triple drug combination delays disease progression in people with stubborn multiple myeloma [press release]. Orlando, FL: American Society of Hematology. hematology.org/Newsroom/Press-Releases/2019/10107. aspx. Accessed December 10, 2019.

6. Chari A, Martinez-Lopez J, Mateos MV. Daratumumab (DARA) in combination with carfilzomib and dexamethasone (D-Kd) in lenalidomide-refractory patients with relapsed multiple myeloma (MM): subgroup analysis of MMY1001. J Clin Oncol. 2018; 36(suppl 15):8002. doi: 10.1200/JCO.2018.36.15_suppl.8002.

Oral Azacitidine in AML Maintenance Boosts Overall Survival by 31%

Older patients with acute myeloid leukemia (AML) who achieved remission with chemotherapy saw significant improvements in both relapse-free and overall survival (OS) with Celgene’s investigational oral azacitidine, CC-486, a result that investigators say finally validates the role of maintenance therapy in this disease.

Phase 3 findings from the QUAZAR trial,¹ presented on December 10, 2019, at the 61st American Society of Hematology Annual Meeting and Exposition in Orlando, Florida, showed the therapy brought OS improvements across a range of subgroups, including with or without consolidation, and those older and younger than age 65.

AML is a common form of adult leukemia and tends to strike elderly patients, with less than 30% of those who develop this cancer surviving for 5 years.² The 472 study patients ranged from 55 to 86 years of age (mean age, 68). Participants had to achieve a complete response (CR) or CR with incomplete recovery count after induction chemotherapy.¹ They could not be candidates for a bone marrow transplant. With 4 months of CR, patients were randomized 1:1 to receive 300 mg of CC-486 or placebo for 14 days of a 28-day cycle until relapse.

After a median follow-up of 41.2 months, investigators reported the following results³:

• The primary end point, OS, was 24.7 months for the study drug group versus 14.8 months for placebo, for a 31% lower risk of death; hazard ratio, 0.69 (95% CI, 0.55-

0.86, PŸ= .0009).

• Risk of relapse was 35% lower among those taking CC-486: 10.2 months for those on the study drug versus 4.8 months on placebo; hazard ratio, 0.65 (95% CI, 0.52-0.81, PŸ= .0001).

• Patients on CC-486 were more likely to attain undetectable minimal residual disease.

• Serious adverse events (AEs) were reported for 34% of the CC-486 group and 25% of the placebo arm, with the most common AE in both groups being neutropenia or gastrointestinal events.

• Treatment discontinuation due to AEs was infrequent.

• CC-486 did not adversely aff ect quality of life compared with placebo.

Because AML is not considered a curable disease, investigators believe the fi ndings off er the opportunity for prevention of progression instead of waiting for a relapse to treat the disease.

“The AML community has been trying to val idate the role of maintenance therapies to extend initial treatment responses for many decades and—until now—without success,” lead study author Andrew H. Wei, MBBS, PhD, of Alfred Hospital, Melbourne, Australia, said in a statement.⁴ “While several agents have been studied and shown to increase relapse-free duration, demonstration of a survival benefit has been elusive.”

Robert Brodsky, MD, director of the Division of Hematology at Johns Hopkins School of Medicine, said CC-486 could offer a maintenance therapy for patients with AML who really have not had a good option. For these patients, “It’s pretty easy to get into remission, but it’s very short-lived—there’s never any consolidation that’s really been effective,” he said.

A viable maintenance option in treating AML could bring significant savings to the healthcare system, especially Medicare. An analysis of the cost burden of AML presented at the 2017 ASH meeting found that relapse brings frequent and costly hospitalizations; the least expensive episode from low-intensity chemotherapy was $53,081; the one with the highest cost was a bone marrow transplant at $329,621.⁵

Brodsky and Wei both said having an oral drug for maintenance is benefi cial and convenient for patients. The drug is a cytidine nucleoside analogue that contributes to hypomethylation, or modification of DNA, and cytotoxicity of hematopoietic cells in the bone marrow, leading to cell death. Renal toxicities have been reported in the intravenous version of azacitidine in the treatment for myelodysplastic syndrome, but this was among the AEs reported in the QUAZAR-AML-001 trial.

Wei said he anticipates that CC-486 will become “a fundamental building block” of more effective drug combinations in AML, perhaps with venetoclax. When Celgene announced topline results for QUAZAR AML-001 in the fall of 2019, company offi cials said regulatory fi lings would occur in the first half of 2020.⁶ Celgene, which was recently acquired by Bristol-Myers Squibb, funded the study.

References

1. Wei AH, Dohner H, Pocock C, et al. The QUAZAR AML-001 maintenance trial: results of a phase 3 international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. Presented at the 61st American Society of Hematology Annual Meeting and Exposition, Orlando, Florida; December 7-10; Abstract LBA-3. ash.confex.com/ash/2019/webprogram/Paper132405.html.

2. National Institutes of Health. Cancer stat facts—leukemia: acute myeloid leukemia (AML). Surveillance, Epidemiology and End Results website. seer.cancer.gov/statfacts/html/amyl.html. Accessed December 10, 2019.

3. Wei A. The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 in patients with acute myeloid leukemia (AML) in first remission. American Society of Hematology online press kit slides. ASH website. https://apps.hematology.org/presskit/19.aspx. Accessed December 9, 2019.

4. New drug markedly improves overall survival in patients with AML in remission [press release]. Orlando, FL: American Society of Hematology. apps.hematology.org/presskit/37.aspx. Accessed December 10, 2019.

5. Rosenberg J. Significant economic burden associated with various AML treatment episodes. The American Journal of Managed Care® website. ajmc.com/conferences/ash-2017/significant-economic-burden-associated-with-various-aml-treatment-episodes. Published December 8, 2017. Accessed December 11, 2019.

Use Blinatumomab, Not Standard Chemo, for Children With Relapsed B-ALL, Study Finds

6. Caffrey M. Celgene announces topline results for maintenance therapy in acute myeloid leukemia. The American Journal of Managed Care® website. ajmc.com/newsroom/celgene-announces-topline-results-for-maintenance-therapy-in-acute-myeloid-leukemia. Published September 17, 2019. Accessed December 9, 2019.Children with a first relapse of B-cell acute lymphoblastic leukemia (B-ALL) avoided infections and were more likely to receive a bone marrow transplant if treated with the immunotherapy blinatumomab instead of standard chemotherapy, according to a study presented on December 10, 2019, at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.

Use of blinatumomab improved survival by 20%, and the drop in minimal residual disease (MRD) was so dramatic that an independent review panel stopped the phase 3 trial of children and young adults early, after it was clear that the drug’s benefits were enough to set a new standard of care. Investigators had planned to randomize 220 patients when the study began in January 2015, but randomization was halted in September 2019 at 208 patients.1

Blinatumomab, marketed by Amgen as Blincyto, is approved for use in relapsed and refractory B-ALL,² but this trial from the Children’s Oncology Group sought to confirm its benefits in pediatric patients who have still have MRD after a month of chemotherapy following a relapse. Trial participants were aged between 1 and 30 years.

Patrick A. Brown, MD, of Johns Hopkins University’s Kimmel Comprehensive Cancer Center and the study’s lead author, explained during a press briefing that prognosis is poor for the 15% of children and young adults with B-ALL who have a relapse within the first 3 years of diagnosis. Getting these patients to transplant off ers the best chance for a cure, but this has required a 2-part chemotherapy protocol that threatens survival if infections or other complications arise during the process, which can take up to 4 months.

“This is a new standard of care,” said Robert Brodsky, MD, ASH secretary and director of the Division of Hematology at Johns Hopkins, who moderated the briefing on the ASH late-breaking session. Pediatric B-ALL patients can be challenging to treat, he said, because “when they relapse, it’s very hard to get them back into remission.” Driving down MRD levels is essential for a bone marrow transplant to work, and the results presented on December 10 show that blinatumomab greatly improves those odds, Brodsky said.

In this study, all patients who had a relapse received the standard 1-month chemotherapy reinduction. They were stratifi ed by risk level, based on the timing of their relapse or a measurement of MRD. Brown explained that those with early relapse, or late relapse but elevated MRD levels, proceeded to the consolidation phase that leads to transplant; these patients were randomized 1:1 to receive either 2 blocks of chemotherapy or 2 cycles of blinatumomab.

After a median follow-up of 1.4 years, the results showed¹:

• 59% of the patients in the blinatumomab group had disease-free survival, which was the primary end point, compared with 41% for the chemotherapy group.

• Overall survival also favored the blinatumomab group over the chemotherapy group, 79% versus 59%

• 73% of the blinatumomab group were able to proceed to transplant, compared with 45% of the chemotherapy group.

• For patients with detectable MRD after the month of chemotherapy reinduction, 79% of those receiving blinatumomab achieved undetectable MRD, compared with 21% of those who continued chemotherapy.

“Based on our study, it appears that blinatumomab is a much more eff ective bridge to transplant for this patient population, leading to a much larger portion of patients who are actually able to receive a bone marrow transplant,” Brown said³in a statement.³ “We believe that is the reason for the striking improvement in survival among patients who received blinatumomab.”

A bispecific T cell engager, or BiTE, blinatumomab binds specifically to CD19, a protein on the surface of B cells, and to CD3, a protein expressed on the surface of T cells, causing the T³cells to kill leukemia cells. When it was approved, blinatumomab reached the market at a list price of $178,000 for 2 cycles, making it one of the most expensive cancer drugs on the market at the time.4 However, a July 2017analysisin theJournal of Medical Economicsfound it to be cost-effective based on its survival and quality-of-life benefits.⁵

Importance of Reducing Infection Risk

In response to a question fromThe American Journal of Managed Care®, Brown explained that studies show the burden of life-threatening infection from chemotherapy in B-ALL falls more heavily on the adolescent and young adult (AYA) population compared with older patients. “It’s likely that the impact of improvement in survival with immunotherapy in the relapse setting may be particularly important in the AYA population, since the burden of infection seems to be greatest in those

patients,” he said.

Brown said during the press briefing that the survival benefi ts for blinatumomab were driven in part by the reduced infection risk, as there were 4infection-related toxicity deaths among patients in the traditional chemotherapy group and none in the blinatumomab group. The researchers also compared adverse events (AEs) of grade 3 or higher for the fi nal 2 cycles of chemotherapy in the control group and the 2 cycles of blinatumomab, tallying these results¹:

• Febrile neutropenia: chemotherapy 44% (1st cycle)/46% (2nd cycle) vs blinatumomab 4%/0%; P<.001 for both cycles

• Infections: chemotherapy 41%/61% vs blinatumomab 10%/11%; P<.001 for both cycles

• Sepsis: chemotherapy 14%/21% vs blinatumomab 1%/2%; P<.001 for both cycles

• Mucositis: chemotherapy 25%/7% vs blinatumomab 0%/1%; P<.001 for fi rst cycle/P = .16 for second cycle.

In the blinatumomab group, notable AEs included cytokine release syndrome (CRS). In the first cycle, CRS affected 22% overall, with 1% grade 3 or higher; in the second cycle, 1% overall, 0% grade 3 or higher. For other neurotoxicities, the rate was 14% overall, with 2% grade 3 or higher in the fi rst cycle, and the rate was 11% overall and 2% grade 3 or higher in the second cycle. Investigators reported that all AEs were fully resolved.

Brown said future research in this area of treating pediatric B-ALL will include combining blinatumomab and checkpoint inhibitors, using immunotherapy to replace or augment reinduction chemotherapy, and using chimeric antigen receptor T cells to replace or augment hematopoietic stem cell transplant.

References

1. Brown PA, Ji L, Xu X, et al. A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) first relapse of B-acute lymphoblastic leukemia (B-ALL) in children and adolescents/young adults (AYAs) demonstrates superior efficacy and tolerability of blinatumomab: a report from Children’s Oncology Group Study AALL1331. Presented at: 61stAmerican Society of Hematology Annual Meeting and Exposition; Orlando, Florida; December 7-10, 2019. Abstract LBA-1. ash.confex.com/ash/2019/webprogram/Paper132435.html.

2. FDA approves BLINCYTO™ (blinatumomab) immunotherapy for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia [news release]. Thousand Oaks, CA, and South San Francisco, CA: Amgen; December 3, 2014. investors.amgen.com/news-releases/news-release-details/fda-approves-blincytotm-blinatumomab-immunotherapy-treatment. Accessed December 10, 2019.

3. Immunotherapy superior to chemotherapy for children with relapsed B-ALL [news release]. Orlando, FL: American Society of Hematology; December 10, 2019. hematology.org/Newsroom/Press-Releases/2019/10106.aspx . Accessed December 10, 2019.

4. Pierson R. Exclusive: Amgen’s new leukemia drug to carry $178,000 price tag. Reuters website. reuters.com/article/us-amgen-cancer-exclusive/exclusive-amgens-new-leukemia-drug-to-carry-178000-price-tagidUSKBN0JV1YU20141217. Published December 17, 2014. Accessed December 9, 2019.

5. Delea TE, Amdahl J, Boyko D, et al. Cost-effectiveness of blinatumomab versus salvage chemotherapy in relapsed or refractory Philadelphia-chromosome-negative B-precursor acute lymphoblastic leukemia from a US payer perspective. J Med Econ. 2017;20(9):911-922. doi: 10.1080/13696998.2017.1344127.

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