When it comes to chimeric antigen receptor (CAR) T-cell therapy, the waiting may hardest part for revolutionary, lifesaving treatment for certain leukemias and  lymphomas. Manufacturing personalized treatments from a patient’s own cells can take up to 3 weeks, and payer approval can add more time. The process itself is complicated and costly—at least $373,000 before administration costs&mdash;and reimbursement has sometimes been slow.

That’s why results highlighted December 7, 2019, at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, Florida, focused on the next wave of innovation, which features allogeneic, or “off-the-shelf,” treatments that could offer greater convenience and lower costs—and make treatment available to more patients.

Gary Schiller, MD, of University of California, Los Angeles, Health, who moderated a press briefing on several abstracts presented at the meeting, said that advances in CAR T-cell therapy are overcoming multiple barriers:

• Although first-generation therapies primarily target the protein CD19, the next wave of treatment will attack multiple targets.

• Therapies in the pipeline will treat more blood cancers, including multiple myeloma.

• A uniform product will replace the complex manufacturing process.

“When we approach unmet needs in medicine, we solve one and we create another,” said Stephen J. Schuster, MD, of Penn Medicine’s Abramson Cancer Center in Philadelphia, Pennsylvania, who presented results on a novel therapy, mosunetuzumab. CAR T-cell therapy, Schuster said, has been a major advance—he led the JULIET trial in refractory B-cell lymphomas that resulted in approval of the first therapy, Novartis’ tisagenlecleucel (Kymriah).

 “However, the two-thirds of patients that don’t respond to CAR T-cell therapy are now our new unmet need,” he said. 

Because patients eligible for CAR T are already quite ill, about a third of those enrolled in clinical trials never make it to the point of getting therapy, ASH Secretary Robert A. Brodsky, MD, director of the Division of Hematology at Johns Hopkins School of Medicine, said during a preview of the meeting. 

Cost also poses a significant barrier to treatment.

 Academic medical centers and Medicare have been locked in a struggle over how to pay for CAR T-cell therapy, because traditional reimbursement designs were not created with this expensive, 1-time treatment in mind.

 Although CMS announced in August that 2020 would bring a modest increase in the new technology add-on payment, a November commentary in the 

 pronounced that “this quick fix does not go far enough.”

 The authors estimated that hospitals lose $300,000 for every patient treated with this technology.

Schuster presented results from a dosing study involving mosunetuzumab, a bispecific antibody tested in 270 patients with B-cell lymphomas that had returned or not responded to at least 3 therapies, including some patients who relapsed or failed to respond to CAR T-cell therapy.

The group included 30 patients previously treated with CAR T-cell therapy. In a press preview ahead of the 2019 meeting, ASH leaders speculated that bispecific antibodies could supplant first-generation CAR T-cell treatments in some cancers if they can treat patients quickly at a lower cost.

Unlike CAR T-cell therapy, mosunetuzumab does not require individualized genetic modification of a patient’s T cells. Instead, this therapy redirects T cells to engage and eliminate B cells, Schuster said. The new therapy produced durable responses in 37% of the patients with aggressive non-Hodgkin lymphoma (NHL), a group that would benefit most from not having to wait for individualized manufactured cells. Higher exposure to mosunetuzumab brought better responses, and a higher-dose study is now enrolling patients, Schuster said.

Across the studies presented at the meeting, patients generally experienced lower grades of cytokine release syndrome (CRS) than seen in the first generation of CAR T-cell therapy. Hospitalization due to CRS has been a significant contributor to cost in the first generation of CAR T-cell therapy; estimates of managing severe cases range from $56,000 to more than $200,000.

However, Schiller said, ease of access will likely be the top selling point of these new therapies in the coming years. “An off-the-shelf product is attractive because of feasibility issues,” Schiller said. For patients previously treated with CAR T-cell therapy, it appears this new wave of treatments may salvage responses after a relapse,

he said: “It all depends on durability.

“[For a] simple clinician…who needs to take care of patients with desperate diseases, tolerability is secondary to access and feasibility,” Schiller continued. “So whatever product—be it cellular or bifunctional&mdash;that we have access to tomorrow will be better and easier for us to use.”

Abstracts presented at the briefing highlighted what’s in the pipeline:

 Schuster reported on complete remission (CR) in patients with relapsed/refractory NHL who were treated with the study drug. In this phase 1/1b open-label study, according to the abstract, mosunetuzumab is given with step-up dosing on days 1, 8, and 15 of cycle 1, then as a fixed-dose on day 1 of each subsequent 21-day cycle, for a maximum of 17 cycles. Outcomes are best objective response rate (ORR), maximum tolerated dose (MTD), and tolerability.

• The treatment produced promising responses in patients with aggressive NHL. Among 124 patients (diffuse large B-cell lymphoma, follicular lymphoma), ORR was 37.1% (46 patients) and CR was 19.4% (24 patients) (

• As expected, responses were better for patients with indolent NHL. Among the 67 patients, ORR was 62.7% (42 patients), and 29 (43.3%) had a CR. 

• Among the first 18 patients with prior CAR T-cell therapy, ORR was 38.9% (7 patients), and 4 patients (22.2%) had a CR.

• Four patients were able to be retreated with mosunetuzumab; among these, 3 (75%) had an ORR, and 1 had a CR.

“I have stopped therapy in some patients after 6 months, and they have remained in remission,” Schuster said. “Some patients have remained in remission without additional therapy for more than a year.” 

Bob Valamehr, PhD, of Fate Therapeutics, presented proof-of-concept data on an off-the-shelf cellular immunotherapy that targets 2 proteins on the surface of lymphoma cells.

 The treatment, a targeted CAR natural killer (NK) cell, would be enhanced with features to take advantage of the properties of NK cells—their ability to attack and kill many types of cells&mdash;while extending the cells’ durability. “NK cells are multifaceted and can be viewed as a jack-of-all-trades when it comes to protecting the host, whereas T cells can act in only 1 way,” Valamehr said.

Fate Therapeutics developed a master line of NK cells induced from specialized stem cells (iNK cells), known as FT596, which overcomes a challenge of CAR T therapy: lack of uniformity that can occur with individualized products. “When you [manufacture] the product, not every cell is engineered, and not every engineered cell is pristine,” Valamehr said.

According to the abstract,8 FT596 cells are designed to carry 3 genes at once:

• An NK cell-calibrated CAR that targets CD19 • Noncleavable CD16, which enhances binding activity

• A recombinant fusion of interleukin (IL) 15 and IL-15 receptor-α (IL-Rα) that extends persistence of the cells

Investigators did experiments in both in vitro and in mouse models and found that iNK cells engineered with both CD19-CAR and IL-Rα “were curative against B-cell lymphoma” compared with iNK cells either alone or modified only with CD19-CAR. The investigators next performed tests using various combinations with rituximab and reported that “only FT596 was able to effectively eliminate the CD19 antigen escaped target cell.”

According to the abstract, experiments using the allogeneic therapy on a mouse model showed that FT596 “demonstrated improved survival and safety over primary CAR19 T cells,” whether used as alone or in combination with rituximab. Experiments with rituximab showed great potential for that combination.

 If successful, this approach could be administered much like traditional therapies, according to Valamehr. The process creates “a homogeneous, high-quality product that’s low cost,” he said. “Each dose is $2500. It’s directly infused; there is no processing needed, so it becomes a true, administered off-the-shelf product in an outpatient setting.”

The session also covered a pair of CAR T-cell therapies for multiple myeloma, taking advantage of the dual target approach. Results from CARTITUDE-1,

 funded by Janssen, confirm results from the LEGEND-2 study

 for a therapy containing 2 proteins designed to target the B-cell maturation antigen. Deepu Madduri, MD, of Mount Sinai in New York, New York, shared the news that the FDA granted JNJ-4528 breakthrough therapy designation on the eve of the ASH meeting—December 6, 2019.

“We know that there have been a lot of advances over the last few years [in] multiple myeloma,” Madduri said, “and so people are living longer.” However, for patients who have failed all available therapies, “median overall survival is less than 12 months,” he said.

This study involved 29 patients, 25 of whom had at least 3 prior therapies, including autologous transplantation. The investigators said the results show that JNJ-4528 at a dose of 0.75 x 106 CAR-positive cells/kg brings an early and deep response, featuring minimal residual disease negativity “in all evaluable patients tested.”

• Not only were CRS events of lower grade than in first-generation CAR T therapies, but the median time of onset was 7 days, >90% between 5 and 9 days, later than in the past.

• Neurotoxicity was infrequently observed and generally low grade.

• Early and deep responses were seen: 100% ORR, with ≥CR 69% at 6 months.

• The median time to first response was 1 month, as was the median time to ≥CR; 27 of 29 patients were progression free at 6 months. 

1. Andrews M. Staggering price slow insurers’ coverage of CAR-T cancer therapy. Kaiser Health News. khn.org/news/staggering-prices-slow-insurers-coverage-of-car-t-cancer-therapy/. Published July 17, 2018. Accessed December 10, 2019.

2. Schuster SJ, Bishop MR, Tam CS, et al; JULIET investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi: 10.1056/NEJMoa1804980.

3. Worcester S. Barriers to CAR T use in the spotlight at first European meeting. MDedge website. mdedge.com/hematology-oncology/article/195404/immuno-oncology/barriers-car-t-use-spotlight-first-european. Published February 28, 2019. Accessed December 10, 2019.

4. Caffrey M. NCCN panel digs into reality of CAR T-cell reimbursement. The American Journal of Managed Care® website. ajmc.com/conferences/nccn-2019/nccn-panel-digs-into-reality-of-car-tcell-reimbursement. Published March 21, 2019. Accessed December 10, 2019.

5. Manz CR, Porter DL, Bekelman JE, et al. Innovation and access at the mercy of payment policy: the future of chimeric antigen receptor therapies [published online November 1, 2019]. 

6. Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies, and is active in treatment through multiple lines. Presented at: 61st American Society of Hematology Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 6. ash.confex.com/ash/2019/webprogram/Paper123742.html.

7. Mulcahy N. What’s the total cost of one CAR T-cell treatment? Medscape website. medscape.com/viewarticle/895735. Published April 26, 2018. Accessed December 7, 2019.

8. Goodridge JP, Mahnood S, Zhu H, et al. Translation of first-of-kind multi-antigen targeted off-the-shelf CAR-NK cell with engineered persistence for the treatment of B-cell malignancies. Presented at: 61st American Society of Hematology Meeting & Exposition; December 7-10, 2019; Orland, FL. Abstract 301. ash.confex.com/ash/2019/webprogram/Paper129319.html.

9. Madduri D, Usmani SZ, Janannath S. Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). Poster and abstract presented at: 61st American Society of Hematology Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 577. ash.confex.com/ash/2019/webprogram/Paper121731.html.

10. Xu J, Chen LJ, Yang SS, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci U S A. 2019;116(19):9543-9551. doi:10.1073/pnas.1819745116.

11. House D. J&J CAR T nabs accelerated review status in US for multiple myeloma. Seeking Alpha website. seekingalpha.com/news/3524575-jand-j-car-t-nabs-accelerated-review-status-in-u-s-for-multiple-myeloma. Published and accessed December 6, 2019.

Articles

Evidence-Based Oncology

Coverage from the 61st American Society of Hematology Annual Meeting and Exposition in Orlando, Florida, featured results for allogeneic or "off the shelf" CAR T-cell treatments and bispecific antibodies. 

CAR T-Cell Therapy and Beyond: Off-the-Shelf Therapies Among Innovations at ASH 2019

Update on UCART19 Arrives Amid News on Allogeneic CAR T Therapy

Despite all the buzz about allogeneic or “off -the-shelf” chimeric antigen receptor (CAR) T-cell therapy at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, Florida, the concept was not new to ASH meetings.

At the 2018 gathering in San Diego, California, the French biotech Servier presented data on its universal anti-CD19 therapy, UCART19.

The product made news amid reports that“in pooled data from a pair of ongoing phase 1 studies (1 with adults, 1 with pediatric patients), 82% of patients who received a novel lymphodepletion regimen had achieved remission.

“This is done by knocking out the CD52 gene, allowing the therapy alemtuzumab to be used in this process.

UCART19 is manufactured from healthy donor T cells and features a safety switch, the CD20 mimotope RQR8, that lets rituximab bind to the CAR T cells. This halts the runaway responses associated with CAR T treatment, dramatically reducing adverse events such as cytokine response syndrome. This mechanism was initially developed by Servier’s collaborator,“Cellectis,“which exclusively licensed UCART19 to Servier.

 Because the product is created from donor cells, the therapy features technology to deal with graft-vs-host disease—notably, a T-cell receptor (TCR) knockout that disrupts the “TRAC" gene.

Results reported at the 2019 ASH meeting show that healthy donor CAR T cells (n = 11) expanded signifi cantly during the manufacturing process compared with those derived from B-cell acute lymphoblastic leukemia (B-ALL; n = 9), chronic lymphocytic leukemia (CLL; n = 8), or diff use large B-cell lymphoma (DLBCL; n = 8).

 Investigators said in their abstract that median CAR expression level was higher for patients with CLL using the CAR T-cell product compared with B-ALL patients and healthy donors.

The TCR knockout led to the following results:

• CD3 expression was lost on healthy donor TCR-negative CAR T cells, except for a distinct population called γδ CAR T cells.

• CLL and DLBCL CD8-CAR cells expressed higher levels of PD-1 than healthy donor CD8- CAR T cells.

• In 2018, CAR-CD8-CD27-PD-1 T cells we re described as “functionally important” and correlated with clinical outcomes in patients who got the CLL CAR T cells.

• Healthy donor and healthy donor TCR CAR T cells had more CD8, CD27, and PD-1 CAR T cells compared with those derived from CLL and DLBCL but similar to the amount of those in patients with B-ALL.

)  posed questions about UCART19 to Patrick Therasse, MD, PhD, head of Research & Development, Oncology, at Servier Group. Under a“licensing agreement with Pfizer, if successfully developed and then approved by the FDA, the product would be marketed in the United States through Allogene Therapeutics. Pfi zer bought a 25% stake in Allogene in 2018.

The approach of UCART19 appears to strike a balance: You use healthier cells to overcome weaknesses that develop due to prior treatments and cancer itself, while guarding against the potential for rejection through modifi cation, via knockouts of TRAC and CD52. Is this the basic concept? What are the advantages and disadvantages compared with the current approach to CAR T-cell treatment?

 Yes, this is basically the approach: overcoming the limitations associated with the use of autologous CAR T approaches including lengthy vein-to-vein time, manufacturing failure, variable potency, and high production cost. We believe that the use of innovative technology to modify nonmatched allogeneic healthy donor T cells may allow the treatment of a broad patient population with a product of consistent quality standards. If UCART19 is approved, the treatment could begin soon after diagnosis, which could be vital in a fast-progressing disease such as acute lymphoblastic leukemia [ALL].

UCART19 uses trademarked technology called TALEN. What does TALEN stand for, and can you discuss the basic mechanism? 

 TALEN“is a gene-editing technology pioneered and owned by our partner Cellectis. It stands for “transcription activator-like eff ector nuclease.” TALEN products are designed by fusing the DNA cutting domain of a nuclease to TALE domains, which can be tailored to specifi cally recognize a unique DNA sequence.

These fusion proteins serve as readily targetable “DNA scissors” for gene-editing applications that enable us to perform targeted genome modifi cations such as sequence insertion, deletion, repair, and replacement in living cells.

 How does UCART19 stand apart from other allogeneic treatments presented at the 2019 meeting?

UCART19 is the most advanced allogeneic CAR T product in clinical development. It entered clinical development in 2016, and encouraging clinical data from the fi rst 21 patients were presented during ASH [in 2018].

 “Today, 3 clinical trials are ongoing in pediatric and adult ALL and non-Hodgkin lymphoma. 

 Will this approach be less costly than current CAR T-cell treatments—not just in the therapy itself but also in administrative/hospitalization costs? Have estimates been developed? If so, what are the potential benefits to payers, especially Medicare?

 Cost is clearly a key parameter with regard to CAR Ts. By using the allogeneic approach, we hope to be able to treat 10 to 100 patients from a single manufacturing run. This will certainly allow to decrease the cost of treatment compared with the autologous approach.

There have already been discussions that CAR T-cell therapy should be given earlier, before cells are depleted by prior treatments. Is there potential for allogeneic treatments to jump ahead of the current CAR-T offerings in the treatment guidelines?

: Using CAR-T cell therapy earlier in the management of ALL patients has been discussed. One of the benefi ts could be to avoid the long-term toxicity that may be associated with the use of chemotherapies, especially in pediatric patients. It is too early to tell if allogeneic CAR Ts would behave diff erently than autologous

Is it possible yet to say what the difference would be in toxicity compared with current CAR T treatments?

 Improving the toxicity profi le of CAR T-cell therapies is also one of our objectives when developing next-generation allogeneic CAR Ts. It is too early today to make any conclusion, but preliminary data suggest that toxicity may diff er between autologous and allogeneic CAR T-cells.

Improving the efficacy while preserving the toxicity profi le of CAR Ts, together with optimizing the manufacturing process, are our main objectives today. For the future, challenges will be to extend CAR T-cell therapies to other targets and indications, including solid tumors.

1. Benjamim R, Graham C, Yallop D, et al. Preliminary data on safety, cellular kinetics and anti-leukemic activity of UCART19, an allogeneic anti-CD19 CAR T-cell product, in a pool of adult and pediatric patients with high-risk CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia. Blood.†2018;132(suppl 1):896. doi: 10.1182/blood-2018-99-111356.

2. Servier and Allogene Therapeutics present pooled data from phase 1 trials of allogeneic UCART19 in relapsed/refractory acute lymphoblastic leukemia [press release]. Paris, France, and South San Francisco, CA: Servier; December 4, 2018. servier.com/en/communique/servier-and-allogene-therapeutics-present-pooled-data-from-phase-1-trials-of-allogeneic-ucart19-in-relapsed-refractory-acute-lymphoblastic-leukemia/. Accessed December 9, 2019.

3. Cellectis and Servier announce collaboration in allogeneic cell therapy: UCART19 to treat leukemia and 5 product candidates targeting solid tumors [press release]. Paris, France: Cellectis website; February 17, 2014. cellectis.com/en/press/cellectis-and-servier-announce-collaboration-in-allogeneic-cell-therapy-ucart19-to-treat-leukemia-and-5-product-candidates-targeting-solid-tumors. Accessed December 10, 2019.

4. Graham C, Jozwik A, Quartey-Papafio R, et al. Allogeneic anti-CD19 CAR T cells manufactured from healthy donors provide a unique cellular product with distinct phenotype characteristics compared to CAR T cells generated from patients with mature B cell malignancies. Presented at: 61st American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 3228. ash.confex.com/ash/2019/webprogram/Paper123018.html.

5. Pfizer hands UCART19, allogenic CAR-T portfolio rights to $300M startup. Genetic Engineering & Biotechnology News website. genengnews.com/topics/drug-discovery/pfizer-hands-ucart19-allogenic-car-t-portfolio-rights-to-300m-startup/. Published April 3, 2018. Accessed December 10, 2019.

Persistence of CAR T Cells Seen in “Next-Generation” Anti-BCMA Therapy, bluebird bio’s Ide-cel

Although results for Janssen's investigational chimeric antigen receptor (CAR) T-cell therapy directed against B-cell maturation antigen (BCMA) appeared on the press program at the 61st American Society of Hematology (ASH) in Orlando, Florida,

 with results for a competing anti-BCMA from bluebird bio and Bristol-Myers Squibb.

The company presented updated phase 1 results

for a revamped version of bb2121 that point to sustained responses for patients with relapsed/refractory multiple myeloma (RRMM). Both versions are built on the idecabtagene vicleucel (ide-cel; bb2121). Separately, bluebird bio and Bristol-Myers Squibb also announced positive topline results for a phase 2 pivotal trial called KarMMa.

The updated phase 1 dose escalation trial (CRB-402) is a first-in-human study of bb21217, so called because ide-cel is enhanced with the phosphoinositide 3-kinase inhibitor bb007 to create “memory-like” T cells. As of September 4, 2019, the study included data for 38 patients with a median of 6 prior lines of therapy; 82% had at least 1 autologous stem cell transplant:

• 24 patients received the therapy at 3 dose levels: 12 at 150 x 10

• 14 patients received therapy in the dose expansion cohort at 2 dose levels: 8 at 300 x 106†CAR+ T cells and 6 at 450 x 10

) discussed the results and CAR T-cell therapy for multiple myeloma with bluebird bio’s Liviu Niculescu, MD, PhD, senior vice president for global medical affairs.

: We’ve been hearing about CAR T-cell therapy in multiple myeloma for a while. What are the challenges of using a CAR T-cell approach for this particular blood cancer?

 The fundamental challenge associated with the treatment of multiple myeloma is the relentlessness of the disease. Treatment outcomes have decidedly improved for myeloma patients over the last decade, which is refl ective of the introduction and availability of many new eff ective treatment options. However, the disease remains incurable with the majority of patients experiencing relapse, at which time the patient’s disease becomes more and more difficult to treat.

CAR T therapies are shown to provide relapsed and refractory myeloma patients with durable remissions after a single administration, allowing these patients additional time to live without their disease getting worse. However, many of these patients relapse and require further treatment. Understanding the underlying mechanism of relapse after CAR T therapy is a key challenge today. When we begin to understand this incredibly complex question, we can further explore ways to improve CAR T therapies. This question of how to improve CAR T therapy in order to increase outcomes for patients is what led to the development of bb21217.

These therapies are promising and at the forefront of innovative science, but there are also practical challenges. Many patients with multiple myeloma are treated in community practice settings and CAR T therapy is only administered in specialized centers. So, finding the right treatment centers and providing a smooth experience for the patient is a key focus as we potentially bring CAR T therapy to patients with multiple myeloma. 

BCMA-based immunotherapies for multiple myeloma have received lots of attention. Can you discuss the value of this approach [bb21217] generally and how bluebird bio’s concept of enriching T cells to improve “memory” improves persistence?

bb21217 is an investigational BCMA-targeted CAR Tcell therapy that uses the idecabtagene vicleucel (ide-cel; bb2121) CAR molecule and is cultured with the PI3 kinase inhibitor (bb007) to enrich for T cells displaying a memory-like phenotype with the intention to increase the 

persistence of CAR T cells. Evidence suggests that memory like T cells may persist in patients for a longer time than other types of T cells, and it is hypothesized that the persistent memory like CAR T cells may be important for increasing durability of response  As of September 4, 2019, CAR T-cell persistence in CRB-402 was observed in 8 of 10 patients with ongoing response and evaluable at six months, and 2 out of 2 patients with ongoing response and evaluable at 18 months. Initial data, based on limited follow-up, suggest that enrichment for memory-like CAR T cells in bb21217 drug product was associated with both increased peak CAR T expansion and achievement of sustained clinical response at 6 months.

Longer follow-up is needed to defi ne any association with long-term persistence and response. It is important to note that these are early data and analyses of long-term CAR T-cell persistence require additional follow-up. We continue to assess the functional persistence of bb21217 in this ongoing study, as well as its potential correlation with durability of response.

Toxicity has been an issue with the first generation of CAR T-cell therapy, although this seems to be improving with the next generation of treatments. How does bb21217 compare in toxicity relative to both the first generation of CAR T and some of the newer treatments on the horizon?

A pair of interviews on investigational therapies whose sponsors reported updates at the 61st American Society of Hematology Annual Meeting and Exposition: UCART19 from Servier and a revamped anti-BCMA therapy ide-cel from bluebird bio.

CAR T-Cell Therapy and Beyond: UCART 19 and Anti-BCMA Therapy

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 trial

 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.

 Its benefi ts have been seen in patients with first-line CLL in both the RESONATE-2

 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.

 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 

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&mdash;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.

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.

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.

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.

 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:

• 20% had deletion 17p or TP53 mutation.

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

• 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.

 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.”

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/

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. JClin 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,

 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.

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.

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.

“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.

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; 

• 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.

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.”

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.

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.

Results from clinical trials presented at the 2019 American Society of Hematology Annual Meeting and Exposition in Orlando, Florida. 

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

Apixaban Is Linked to Large Reductions in Major Bleeding, Recurrent VTE in Active Cancer

Patients with cancer who took apixaban to prevent blood clots had a 37% reduction in major bleeding (MB) and a 39% reduction in recurrent venous thromboembolism (VTE) compared with those taking low-molecular weight heparin (LMWH), according to data presented on December 7, 2019, at the 61st American Society of Hematology Annual Meeting & Exposition in Orlando, Florida. Apixaban also had large reductions in VTE (32%) relative to warfarin.

A subgroup analysis presented alongside the main study found that apixaban’s benefi ts relative to LMWH held up across different types of cancer regardless of the risk level they present for VTE.

 Apixaban is sold as Eliquis by Bristol-Myers Squibb/Pfizer. Patients with active cancer—for this study, defined as cancer diagnosis or treatment in the 6 months before or 30 days after a VTE diagnosis&mdash;have a 4 to 7 times greater risk of developing VTE.

To gain more real-world evidence on the eff ectiveness and safety of LMWH compared with vitamin K antagonists, which emerged in the last decade as a treatment of VTE, and non-VKA anticoagulants, a team of researchers led by Alexander T. Cohen, MBBS, MSc, MD, of King’s College, London, evaluated the effi cacy of apixaban, LMWH, and warfarin among patients with active cancer. 

The investigators examined 3 groups of patients who started treatment within 30 days of their first VTE: 3393 apixaban users, 6108 LMWH users, and 4585 warfarin users. The mean ages were 65, 64, and 64 years, respectively. To evaluate rates of MB, clinically relevant non-MB (CRNMB), and recurrent VTE, the patients were followed to the earliest of 1 of 6 time points: health plan disenrollment, death, index therapy discontinuation, switch to another anticoagulant, study end, or a maximum of 6 months.

• Apixaban had lower risks of MB, CRNMB, and recurrent VTE compared with LMWH, with a hazard ratio (HR) of 0.63 (95% CI, 0.47-0.86; P = .003) for MB, an HR of 0.81 (95% CI, 0.70-0.94; P = .006) for CRNMB, and an HR of 0.61 for recurrent VTE (95% CI, 0.47-0.81; P = .001).

• Apixaban had lower rates of recurrent VTE and modest reductions of MB and CRNMB compared with warfarin, with an HR of 0.68 (95% CI, 0.52-0.90; P = .007) for recurrent VTE, an HR of 0.73 (95% CI, 0.53-1.0; P = 0.51) for MB, and an HR of 0.89 (95% CI, 0.77-1.04; P = 0.145) for CRNM. 

“Real-world evidence analyses such as this have the potential to provide additional insights into complex patient populations such as those with VTE and active cancer,” Cohen said in a statement.

“Results from these analyses are a welcomed addition to the growing body of data around recurrent VTE in patients with active cancer.”

In the second presentation, results from the subgroup analysis examined how apixaban aff ected recurrent VTE, MB, and CRNMB risk across diff erent cancer types relative to warfarin and LMWN.  Hematologic cancer, as well as those of the brain, pancreas, stomach, liver, lungs, and kidneys, are associated with a higher risk of VTE. Researchers used the Khorana risk score based on cancer type, blood counts, and body mass index to evaluate risk level and assess the safety of each therapy based on cancer type. Patients were categorized as having a very high risk of VTE, high risk of VTE, or other.

Results from the same real-world data set as the fi rst abstract showed that those taking apixaban had a lower risk of recurrent VTE compared with warfarin and a lower risk of MB, CRNMB, and recurrent VTE compared with LMWH, consistent with the overall results. Researchers called for more studies to evaluate the role of anticoagulants in high-risk subgroups of patients with cancer who have VTE.

Besides the risk of VTE, real-world evidence can be evaluated for other factors. Asked by 

™ if the patient data could be evaluated to see whether those with comorbidities had diff erent responses, Danny Wiederker, HEOR team lead at Pfi zer, said in an email, “Comorbidities are always an important consideration in real-world evidence, given some may be important confounders that impact both the treatment decision and the outcomes of interest. That’s why the Pfizer/BMS Alliance leverages the best research practices recommended by organizations like the International Society of Pharmacoeconomics and Outcomes Research that look to adjust for both comorbidities and patient factors, like age, gender, etc, that may impact outcomes.” 

He said the study being presented is the inverse probability of treatment weighting to adjust for confounding while including the broadest possible patient population.

Reviews of apixaban in active cancer, Medicare costs after CAR T-cell therapy, and the need for financial assistance for novel therapies.

January 2020

CAR T-Cell Therapy and Beyond: Off-the-Shelf Therapies Among Innovations at ASH 2019

CAR T-Cell Therapy and Beyond: UCART 19 and Anti-BCMA Therapy

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

ASH 2019: Real-World Evidence and Cost of Care

ASH 2019: Patient-Reported Outcomes, From MOST to FDA Clinical Reviews

ASH 2019 Interview: Data Show Fixed-Dose Daunorubicin Plus Cytarabine Leads to Fewer Inpatient Days for Patients With sAML

Biosimilars at ASH 2019: Data on Truxima and Competitors for Eculizumab

AJMCtv Interviews: ASH19 Edition