The FDA approved avapritinib (Ayvakit) for the treatment of adults with advanced systemic mastocytosis (AdvSM), including those with mast cell leukemia (MCL), aggressive systemic mastocytosism (ASM), or systemic mastocytosis with an associated hematological neoplasm (SM-AHN), according to the agency.1

The approval marks the first targeted therapy that inhibits D816V mutant KIT, which is a main driver of AdvSM.

"Advanced systemic mastocytosis is a debilitating disease characterized by extensive damage in multiple organ systems due to mast cell infiltration, and new treatment options are urgently needed to address these life-threatening complications," said Daniel DeAngelo, MD, PhD, Chief of the Division of Leukemia at Dana-Farber Cancer Institute, in a statement.2 "Avapritinib will clearly establish a new standard of care for patients with advanced systemic mastocytosis. The FDA approval was based on data showing robust and durable responses, including complete remissions, and a favorable safety profile. For advanced SM patients, the approval of avapritinib shifts the treatment paradigm toward precision therapy that targets the primary driver of mastocytosis."

The approval was based on findings from the multi-center, open-label, single-arm EXPLORER and PATHFINDER clinical trials. The primary endpoint was overall response rate (ORR) per modified IWG-MRT-ECNM criteria, as adjudicated by a central committee. Other endpoints included duration of response (DOR), time to response, and changes in individual measures of mast-cell burden.

The trials included 53 patients who received daily avapritinib at doses up to 200 mg.

"As shown in two clinical trials, AYVAKIT provides remarkable clinical efficacy to patients with advanced systemic mastocytosis, and this approval solidifies the therapy's strong value proposition in this population. With a deep commitment to driving continued research innovation in collaboration with the mast cell disease community, we are now building on this progress with the goal of bringing the benefits of precision therapy to a broader range of patients through our ongoing and planned clinical trials for non-advanced systemic mastocytosis,” said Jeff Albers, CEO of Blueprint Medicines, the manufacturer or avapritinib, in a statement.

Between both trials, there was a 57% IRR (95% CI, 42,70), which included 28% complete remissions and 28% partial remissions. Average DOR Was 38.3 months (95% CI 19-not estimable), and the median time to patient response was 2.1 months.

Most common adverse events that occurred in 20% or more of patients were edema, diarrhea, nausea, and fatigue/asthenia.

"This milestone is also the culmination of many years of work across the systemic mastocytosis community, and we're proud of the contributions The Mast Cell Disease Society has made to improve the understanding of this disease, pioneer new approaches to measuring the impact of therapeutic interventions, and support the development of important medicines like AYVAKIT," said Lauren Denton, Executive Director of The Mast Cell Disease Society.

FDA. FDA approves avapritinib for advanced systemic mastocytosis. June 16, 2021. 

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avapritinib-advanced-systemic-mastocytosis?utm_medium=email&utm_source=govdelivery

Blueprint Medicine. FDA Approves Blueprint Medicines’ AYVAKIT (avapritinib) for the Treatment of Adults with Advanced Systemic Mastocytosis. June 16, 2021

Articles

The FDA approved avapritinib (Ayvakit) for the treatment of adults with advanced systemic mastocytosis (AdvSM), including those with mast cell leukemia (MCL), aggressive systemic mastocytosism (ASM), or systemic mastocytosis with an associated hematological neoplasm (SM-AHN). 

FDA Approves Avapritinib for Rare Blood Disease


A presentation at the European Hematology Association 2021 Virtual Congress demonstrated that discrepancies exist between actual patterns of care and recommendations based on clinical trials, according to a study of treatment patterns in adult patients with mantle cell lymphoma (MCL).


MCL is most commonly treated in younger patients (≤65) with chemoimmunotherapy with or without autologous stem cell transplantation (SCT), and in older patients (≥65) with bendamustine-rituximab (Rituxan; BR) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

“Our understanding of how clinical study findings are reflected in routine clinical practice is limited,” lead investigator, Peter Martin, MD, associate professor of medicine and chief of the Lymphoma Program at Weill Cornell Medicine, New York, said. “These data highlight the need to develop treatment regimens that can be delivered effectively in routine and community practices, and treatments may not need to be centered around SCT intent in young patients.”

The retrospective analysis included patients (n = 4216) with a confirmed MCL diagnosis in the Flatiron Health de-identified database between January 2011 and January 2021 by the Flatiron Health database; 3614 had a record of frontline treatment for MCL. All the patients were 18 years or older and had at least 2 recorded clinic visits. Data originated from 280 cancer clinics representing 800 sites of care; most patients (86.6%) were treated in community oncology settings.

Patient characteristics, treatment patterns, real-world time-to-next treatment (rwTTNT), and real-world overall survival (rwOS) were evaluated. rwTTNT was defined as the time from start of first-line treatment to subsequent treatment or death, whichever came first; rwOS as time from start of first-line treatment to death.

“This was a retrospective analysis,” Martin said. “There were missing data in the baseline characteristics. The tumor response and disease progression data were not available to evaluate overall response rate or progression-free survival. And the intention for choosing treatments (eg, transplantation or maintenance) was not captured in the database.”

Still, significant data were revealed: in patients under 65 years, only 30.5% received a cytarabine-containing regimen; 23.3% received SCT. In patients over 65 years, about 65% received BR or R-CHOP. Median rwTTNT was 28 months in patients under 65 and 22.3 months in patients 65 years or older, which, according to Martin, “appears worse than what has been reported with standard therapies in this population. Older age and high-risk disease features were predictive of worse outcome in the real world, while [rituximab] maintenance appeared to be associated with better outcome. Among the SCT-eligible patients, there was no clear rwTTNT or rwOS benefit associated with receipt.”

Median follow-up in patients with documented first-line MCL treatment was 45.5 months (range, 0.033-119.4) and median rwTTNT was 24 months (28 months in patients <65 years and 22.3 months in patients ≥65 years). At 36 months, the rwTTNT was 41% (95% CI, 39%-43%) for all patients, 46% (95% CI, 43%-49%) for patients <65 years, and 38% (95% CI, 36%-41%) for patients ≥65 years. The 36-month rwOS rate was 68% (95% CI, 66%-69%) in all patients, 78% (95% CI, 75%-81%) in younger patients, and 62% (95% CI, 60%-65%) in older patients.

The 36-month rwTTNT rate was comparable for patients under 65 years treated with SCT (65%; 95% CI, 59%-71%) compared with those did not receive SCT (59%; 95% CI, 55%-64%; log-rank 

= .082). At 3 years, the rwOS rate was 87% (95% CI, 83%-92%) in younger patients who received SCT and 84% (95% CI, 81%-88%) in those who did not receive SCT (log-rank 

= .387). For patients 65 years or older who were not treated with SCT, the 36-month rate of rwTTNT was 37% (95% CI, 35%-40%).

Among eligible patients with a record of treatment, 2340 patients (64.7%) were 65 years or older and 1274 (35.3%) were under age 65. Of the younger group, 971 patients were SCT eligible and 291 received SCT. A total of 23.1% received rituximab maintenance therapy.

Overall, the median age for the study was 69.4 years (range, 27.7-84.6), with 64.7% of patients over age 65, 71.5% male, and 86.6% treated in a community oncology setting. Patients treated with cytarabine-containing regimens (n = 514) and SCT (n = 291) were younger (median, 60.1 and 59.6 years, respectively) than those treated with R-CHOP (n = 636; median age, 66.3) or BR (n = 1502; median age, 72.7) and were less likely to be treated in the community. Patients treated with cytarabine-based regimens were also more likely to have blastoid/pleomorphic morphology (20%) than the overall patient group (10%) but had a low-risk MCL International Prognostic Index (MIPI) score. Those treated with SCT were more likely to have a lower MIPI score than the overall population as well as those treated with BR or R-CHOP.

Martin P, Wang M, Kumar A, et al. Real-world treatment patterns and outcomes of 4216 previously untreated mantle cell lymphoma patients in US routine clinical practice. Presented at: European Hematology Association 2021 Congress; June 9-12, 2021; Virtual. Abstract EP798.

This article was originally published on OncLive.com as “

Real-World Treatment Reveals Discrepancy Between Actual Care and Clinical Trial


A presentation at the European Hematology Association 2021 Virtual Congress demonstrated that discrepancies exist between actual patterns of care and recommendations based on clinical trials, according to a study of treatment patterns in adult patients with mantle cell lymphoma (MCL). 


Discrepancies Exist Between Actual Care and Trial-Based Recommendations in MCL

The use of integrative palliative care can improve coping skills, thus bettering quality of life in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy. That said, it is essential that oncology nurses advocate for palliative care for patients who could benefit from it.

“Often what we have found in our practice – and certainly in our studies – is that nurses and nurse clinicians are begging for palliative care specialists to be invited to see these patients, and it’s often the attending physicians who are saying, ‘we don’t really need that’ or ‘the patient isn’t ready for that yet,” said Thomas W. LeBlanc, MD, associate professor of medicine at the Duke University School of Medicine, noting that some people still believe the misconception that palliative care is synonymous with end-of-life care (hospice).

LeBlanc recently presented his research on palliative care in patients with AML at the 2021 ASCO Annual Meeting.

The study analyzed quality of life, depression, and anxiety symptoms for patients with AML who are in their second week of treatment with induction therapy. Researchers chose the second week of treatment because that is when patients tend to feel the worst. Two groups were compared: the integrated palliative and oncology care (IPC) cohort that saw palliative care clinicians at least twice a week while hospitalized (n=86) versus usual care (n=74).

Findings showed that the patients randomized to IPC had more approach-oriented coping skills and less avoidant-oriented coping skills. The interventions effects on those given IPC who had approach-oriented coping were sustained all the way up until week 24.

An improvement in coping skills was correlated with improved quality of life and decreased depression and anxiety symptoms.

Nurses treating this patient population can understand how life-changing improved quality of life can be for patients with AML.

“Nurses are often the ones who are seeing and witnessing the suffering of these patients and their families because they’re in the room 11 out of the 12 hours of their shift,” LeBlanc said. “The nurses have an incredible opportunity and really also (a) responsibility to be the voice of the patient, who maybe doesn’t know how to articulate that they’re really suffering with something that we’re not doing a good job managing.”

Not only do nurses have to advocate for palliative care to the clinicians and other members of the treatment team, but they must also ensure that patients and their families understand the benefit of receiving palliative services as well.

“The mistake that often is made is that we kind of go in with our tail between our legs, because we’re afraid that patients are going to get freaked out when they hear the P-word. Even though most [patients] have heard it, they don’t know what it means,” LeBlanc said.

LeBlanc recommends clinicians approach the conversation with a script similar to this:

“We’re going to call another group of specialists to come and see you. They’re called palliative care specialists, and they’re experts in helping patients and families deal with the stresses and symptoms that go along with having a serious illness like AML. I have found that they often can really help people feel better with symptom management and help improve or maintain quality of life or help you cope with anxieties that can come along with having this diagnosis and getting treatment.”

Laying down the basics for what palliative care actually is – and what it is not – can greatly sway patients’ opinions.

“We know from other studies that when patients and families hear an explanation of what palliative care is, and how it might be helpful to them, they just about universally want it,” LeBlanc said.

LeBlanc TW, Kavanaugh A, Webb J, et al. Palliative care and coping in patients with acute myeloid leukemia receiving intensive induction therapy: A Mediation analysis of data from a randomized trail. Presented at: 2021 ASCO Annual Meeting. June 4-8, 2021. Virtual

Learn how to approach palliative care discussions with both physicians and patients. 

Nurses Have the Responsibility to be the ‘Voice of the Patient’ in Palliative Care Advocacy

Treatment with the second-generation 4-1BB bi-specific chimeric antigen receptor (CAR) T-cell therapy C-CAR039 led to improved response rates – as well as a favorable safety profile – in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL), according to phase 1 data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

“C-CAR039 has demonstrated a favorable safety profile and highly promising efficacy in patients with relapsed/refractory B-NHL,” Aibin Liang, MD, Tongji Hospital of Tongji University, Shanghai, China, said during an oral presentation of the data.

According to the safety data, 100% of patients experienced at least 1 adverse event (AE) of any grade.

In total, 92.9% of patients reported cytokine release syndrome (CRS); however, Liang noted, that most were grade 1 or 2 and all events were reversible. Only 1 patient, who was treated in the 2.5x106 CAR T cells/kg, experienced grade 3 CRS. The most common symptoms were pyrexia (100%) and hypotension (23.1%).

The median time to onset of CRS events was 2.5 days (range, 0-10), with a median time to resolution of 4 days (range, 1-25). CRS cases were treated with tocilizumab (14.3%), corticosteroids (3.6%), or a combination of the 2 (3.6%).

Two cases of neurologic events – both in the 5.0x106 CAR T cells/kg group – occurred at a median time of onset of 16 days (range, 4-28). The median time to resolution was 31.5 days (range, 11-52).

“CRS in higher dose groups showed shorter time to onset and longer resolution time,” Liang said.

Cytopenias were common, “mostly related to Cy/Flu lymphodepletion and are reversible,” he added, noting that infection was also common, occurring in 53.6% of patients, with only 1 grade 3 event.

The most common grade 3 or higher AEs included lymphopenia (96.$%), leukopenia (89.3%), neutropenia (89.3%), anemia (32.1%), and thrombocytopenia (25%).

For efficacy, median follow-up was 7 months (range, 1.9-17.2).

The overall response rate (ORR) was 92.6% for the entire population, including an 85.2% complete response (CR) rate, 7.4% partial response (PR) rate, 3.7% with stable disease (SD), and 3.7% with progressive disease (PD). Broken down by disease subtype, ORR in those with diffuse large B-Cell Lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), and tFL were 91.7% (CR, 83.3%; PR, 8.3%), 100% (CR, 100%), 100% (CR, 100%), and 100% (CR, 100%), respectively. Liang noted that the CR rate was consistent among key subgroups, including dose level, disease type, cell or origin of cancer, age, sex, stage, IPI, double expressors, extranodal disease, prior lines of therapy, previous response status, previous ASCT, and bridging treatment.

The median time to first response was 1 month (range, 0.9-1.6), as was median time to CR (range, 0.9-6.0). Four patients relapsed at 3, 6, 8, and 9 months, respectively, after achieving CR. Median duration of response (DOR) has not been reached. The 6-month progression-free survival (PFS) was 83.2% (95% CI, 69.1-100).

“C-CAR039 proliferation and expansion in the peripheral blood correlated with B cell depletion,” Liang added.

C-CAR039 – a novel second generation 4-1BB bi-specific CAR T-cell therapy that targets both CD19 and cd20 antigens – has demonstrated in vitro anti-tumor activity against both single- and double-positive CD20/CD19-expressing tumors, as well as superior anti-tumor activity in both in vitro and in vivo to the bi-specific CAR T-cell therapy with the tandem linked scFvs of Leu16 and FMC63, Liang explained.

“This data strongly support moving this CAR design to clinic use as the lead asset,” he added.

Manufacturing the CAR T-cell therapy was carried out in a functionally closed, highly automated serum free system within a median of 6 days (range, 5-11). Median vein-to-vein time was 19 days (range, 12-67).

Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen.

The phase 1 study is an open-label, dose escalation and expansion study conducted across 4 sites in China – designed to evaluate the safety and efficacy of this approach in patients with relapsed/refractory B-NHL.

Investigators administered C-CAR039 as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen.

Eligibility criteria included patients aged 18 to 75 years; relapsed/refractory B-NHL, including DLBCL, FL, and mantle cell lymphoma (MCL); either CD19- or CD20-positive disease; no active central nervous system (CNS) involvement; and have received anti-CD20 monoclonal antibodies.

The safety assessment included the incidence and severity of treatment-emergent adverse events (TRAEs), while the efficacy assessment was comprised of ORR, DOR, PFS, and OS.

In the trial, patients were treated across 3 doses: 1.0x106 CAR T cells/kg (DL1), 2.5x106 CAR T cells/kg (DL2), and 5.0x106 CAR T cells/kg (DL3).

As of April 20, 2021, 34 patients were infused with C-CAR039. In total, 28 were evaluable for safety, including 4 in the DL1 arm, 15 in the DL2 arm, and 9 in the DL3 arm; while 27 were evaluable for efficacy, including 4 in the DL1 arm, 15 in the DL2 arm, and 8 in the DL3 arm.

Median age was 55.5 years (range, 28-71). The majority of patients were male (89.3%), had diffuse large B-cell lymphoma (89.3%), an ECOG performance score of 0 (64.3%), and were Ann Arbor stage III/IV (75%). Moreover, 8 patients (28.6%) had double-expressor lymphoma.

The median number of prior lines of therapy was 3 (range, 1-5), including ASCT (17.9%), a BTK inhibitor (28.6%), and lenalidomide (Revlimid; 32.1%). Eight patients (28.6%) had never experienced a CR to prior therapies and 5 patients (17.9%) received bridging therapy.

“The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR T and peer therapies,” the study authors concluded. “These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response.”

Liang A, Zhou L, Li P, et al. Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). 

. 2021;39:suppl 15; abstr 2507. doi: 10.1200/JCO.2021.39.15_suppl.2507.

The second-generation 4-1BB bi-specific CAR T-cell therapy was efficacious and safe in treating patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Second-Generation CAR T-Cell Therapy Is ‘Highly Promising’ in Relapsed/Refractory B-NHL

In previously treated patients with chronic lymphocytic leukemia (CLL) that harbors del(17p) or del(11q), acalabrutinib (Calquence) had similar survival rates but fewer adverse events than ibrutinib (Imbruvica), according to findings presented at the 2021 ASCO Annual Meeting.

“Acalabrutinib is a more selective inhibitor of [Bruton tyrosine kinase (BTK)] and has been known to have less adverse events (AEs) when compared across trials. [Until] today, no clinical trial has directly compared ibrutinib to acalabrutinib in previously treated CLL. Our trial presented here does this,” said John C. Byrd, MD, professor of hematology at The Ohio State University.

Byrd presented findings from an open-label, randomized, noninferiority, phase 3 trial that compared acalabrutinib and ibrutinib in 533 patients.

 Patients were randomized to receive the BTK inhibitor acalabrutinib or ibrutinib until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS), and secondary endpoints were (in hierarchical order): all-grade atrial fibrillation, grade 3 or higher infection, Richter transformation, and overall survival (OS).

Overall, 268 patients received acalabrutinib and 265 received ibrutinib. Median age was 66 years and on average patients had 2 prior lines of therapies; 45.2% of patients had del(17p) and 64.2% had del(11q).

At a median follow-up of 40.9 months, acalabrutinib was noninferior to ibrutinib, with a PFS of 38.4 months in both arms (HR 1.00; 95% CI, 0.79-1.27).

Acalabrutinib was superior in all-grade atrial fibrillation incidence compared to ibrutinib (9.4% versus 16.0%, respectively; 

“When considering de-novo atrial fibrillation flutter occurring in patients who had never had this before, the difference between ibrutinib and acalabrutinib was greater,” Byrd explained. “Patients with acalabrutinib had a 6.2% incidence, whereas ibrutinib was 14.9%. Among patients developing atrial fibrillation and flutter, prior history of this and other risk factors were more common in the acalabrutinib arm.”

Other end points were comparable between the 2 treatments: 30.8% of patients on acalabrutinib and 30.0% of patients on ibrutinib experienced grade 3 or higher infection; 3.8% of patients on acalabrutinib versus 4.9% of those on ibrutinib had Richter transformation.

Average OS was not reached in either arm. There were 63 (23.5%) deaths in the acalabrutinib arm and 73 (27.5%) in the ibrutinib arm.

When it came to frequent (≥20%) all-grade AEs, the acalabrutinib arm had a lower instance of hypertension than ibrutinib (9.4% vs 23.2%, respectively), arthralgia (15.8% vs 22.8%), and diarrhea (34.3% vs 46.0%). Acalabrutinib, however, did have a higher incidence of headache (34.6% vs 20.2%, respectively) and cough (28.9% vs 21.3%) than ibrutinib.

“Despite a similar [independent review committee] progression-free survival, survival non-statistically favored acalabrutinib with 10 fewer deaths,” Byrd said. “These results demonstrate that acalabrutinib is better tolerated and safer than ibrutinib [and has] similar efficacy in previously treated patients with CLL.”

Byrd JC, Hillmen P, Ghia P, et. Al. First results of head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 7501.

Study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk CLL. ClinicalTrials.gov Updated May 20, 2021. Accessed June 2, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02477696

Survival rates were similar between the 2 drugs, but acalabrutinib had fewer adverse events.

Acalabrutinib: Same Survival Rates, But Better Tolerated Than Ibrutinib in CLL Treatment

The FDA has granted a breakthrough therapy designation to teclistamab for the treatment of patients with relapsed/refractory multiple myeloma, according to Janssen, the developer of the bispecific antibody.

The designation was based on data from a phase 1 study (NCT03145181), an open-label, multicenter trial evaluating the safety and efficacy of teclistamab in adults with relapsed/refractory disease.

Primary data from the phase 1 study, which were presented at the 2020 ASCO Virtual Scientific Program, showed that teclistamab led to a 67% objective response rate (ORR) and a very good partial response rate (VGPR) or better of 50% in patients with relapsed/refractory myeloma at a dose of 270 µg/kg.

Updated results from the study showed that at the recommended phase 2 dose (RP2D), which was 1500 μg/kg given subcutaneously (SC), the ORR with teclistamab was 73% and the VGPR or better was 55%; the complete response (CR) rate or better was 23%.

The agent was also well tolerated at the RP2D; the maximum-tolerated dose (MTD) was not identified, and all reports of cytokine release syndrome were of grades 1/2 and were mostly a result of step-up doses and the first full doses of treatment.

“We are pleased to have received Breakthrough Therapy and PRIME Designations for our novel bispecific antibody, teclistamab,” said Peter Lebowitz, MD, PhD, Global Therapeutic Area Head of Oncology at Janssen Research & Development, LLC. “This program exemplifies our commitment to advancing science for patients living with multiple myeloma, and it builds upon our robust portfolio in this disease.”

Teclistamab is an off-the-shelf, T-cell redirecting, bispecific antibody that targets BCMA and CD3. Teclistamab redirects CD3-positive T cells to BCMA-positive myeloma cells to induce malignant cell death. Preclinical data have shown that teclistamab kills myeloma cell lines and bone marrow–derived myeloma cells from heavily pretreated patients.

To be eligible for enrollment in the phase 1 study, patients had to have measurable myeloma that was relapsed/refractory to standard therapies or be intolerant to standard treatments, hemoglobin that was at least 8 g/dL, platelets that were at least 75 x 109/L, and white blood cell counts that were at least 1.0 x 109/L. Patients could not have received prior BCMA-targeted treatment.

The study comprised 2 cohorts: intravenous (IV; n = 84) and SC (n = 65) administration. The dosing schedule in each cohort comprised 1 to 3 step-up doses prior to week 1, followed by full doses in weeks 1 to 3. In the IV cohort, doses increased following 0.3 to 19.2 μg/kg with a maximum dose of 720 μg/kg; the SC cohort started at 80 μg/kg and increased up to 3000 μg/kg. The initial every-2-week IV dose was switched to weekly IV or SC plus or minus step-up dosing.

Premedication with dexamethasone were limited to the step-up doses and the first full dose, and there was no steroid requirement following the first full dose.

In the overall study population (n = 149), the median age is 63 years (range, 24-84), and 22% of patients were 70 years and older; 54% of patients were male. Twenty-five percent of patients had at least 60% of bone marrow plasma cells, 12% had at least 1 extramedullary plasmacytomas, and the median years since diagnosis was 7 years. A total 32% of patients had high-risk cytogenetics, and 85% had prior transplantation.

The median number of prior lines of therapy was 6 (range, 2-14); most patients (96%) were exposed to 3 classes of therapy, and 69% were penta-refractory. Patients were refractory to carfilzomib (Kyprolis; 66%), pomalidomide (Pomalyst; 77%), and anti-CD38 antibodies (93%), and 91% of patients were refractory to their last line of therapy.

The primary end point in part 1 of the trial was the RP2D; in part 2, the key objective was safety and probability at the RP2D, as well as antitumor activity, pharmacokinetics, and pharmacodynamics.

The updated findings also showed that at the RP2D, the median time to first confirmed response was 1 month (range, 0.3-3); 70% of patients who were triple-class refractory responded to treatment, and 75% of patients who were penta-refractory responded.

Most of the active doses were reported to be between 270 to 720 μg/kg given IV and 720 to 3000 μg/kg given SC. At these doses, the ORR was 69%, 59% of patients had a VGPR or greater, and a CR or better occurred in 26% of these patients. In the IV cohort (n = 27) and SC cohort (n = 41), the ORRs were 67% and 71%, respectively.

In the SC cohort, the ORR was 46% at the 80 μg/kg plus 240 μg/kg dose (n = 13), 60% at the 720 μg/kg dose (n = 15), and 73% at the 1500 μg/kg dose (n = 22), in which the VGPR or better was 55%.

Of 11 evaluable patients across the IV and SC doses thus far, 8 patients had a minimal residual disease–negative (MRD) CR at 10-6 and 1 patient experienced this at 10-5 sensitivity.

Responses were durable and deepened over time. Among responders who received the RP2D (n = 16), and at a median follow-up of 3.9 months, 94% of patients are alive and progression free. Of those in the SC cohorts (n = 35), 91% of patients are on treatment with ongoing responses; the median follow-up is 6.5 months.

Patients receiving the active IV and SC doses (n = 47) remained on treatment with ongoing responses (94%) at a median follow-up of 6.5 months. All 5 evaluable patients across the IV and SC cohorts showed sustained MRD negativity.

The pharmacokinetic and pharmacodynamic data supported the RP2D.

The safety profile was similar in both the overall and RP2D population. Overall, the most common (≥20%) all-grade and grade 3 or higher adverse effects (AEs) were neutropenia (57% and 46%, respectively), anemia (55% and 32%), thrombocytopenia (40% and 22%), and leukopenia (28% and 14%). Nonhematologic all-grade AEs were all-grade CRS (55%), pyrexia (30%), diarrhea (23%), nausea (22%), fatigue (22%), headache (22%), and cough (21%). Grade 3 or higher AEs were cough (2%), and diarrhea, nausea, and fatigue (1% each).

There were 2 dose-limiting toxicities across all doses, but no DLTs were at the RP2D. These were grade 4 delirium, which occurred at the 20 μg/kg IV step-up dose, and grade 4 thrombocytopenia, at the 180 μg/kg IV dose.

Infections occurred in 52% of patients, and 27% occurred at the RP2D; 15% percent of these patients had grade 3 or higher infections across all doses, and 6% had grade 3 or higher infections at the RP2D.

Neurotoxicity occurred in 7 patients (5%), 1 (3%) which occurred at the RP2D. Two events of grade 3 or higher neurotoxicity occurred at the IV dose, and none of which were reported with SC dosing. Injection-site reactions occurred in 32% of patients, 36% occurred at the RP2D, all of which were grades 1/2. One treatment-related AE, grade 5 pneumonia at 80 μg/kg after 16 cycles, led to death; no treatment-related deaths occurred at the RP2D.

CRS occurred in 55% of patients overall; the median time to CRS onset was 2 days (range, 1-5 days) and the median duration of CRS was 2 days (range, 1-8). Fifty-one percent of patients had supportive interventions to treat CRS: tocilizumab (Actemra; 23%), steroids (13%), low flow oxygen (6%), and single low-dose vasopressor (1%).

There were no treatment discontinuations because of CRS; CRS was generally confined to the step-up and first full doses. CRS occurred in 54%, 57%, and 64% of patients in the IV, SC, and RP2D groups, respectively. Step-up dosing was implemented to reduce the risk of severe CRS, and no cases of grade 3 or higher CRS.

Teclistamab is also under study in a phase 2 trial (NCT04557098) for the treatment of patients with relapsed/refractory multiple myeloma and in several combination studies (NCT04586426; NCT04108195; NCT04722146).

Updated results of the phase 1 trial will be presented at the 2021 ASCO Annual Meeting.

Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for Teclistamab for the Treatment of Relapsed or Refractory Multiple Myeloma. News release. Janssen. June 1, 2021. Accessed June 1, 2021. 

Usmani SZ, Mateos M, Nahi H, et. al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). Presented at: 2020 ASCO Virtual Scientific Program. May 29-31, 2020. Abstract 100.

Garfall AL, Usmani SZ, Mateos M-V, et al. Teclistamab, a B-cell maturation antigen (BCMA) X CD3 bispecific antibody, in relapsed and/or refractory multiple myeloma (RRMM): updated phase 1 results. Presented at: 2nd European Myeloma Network Meeting; March 3-6, 2021; virtual. Abstract B11.

Krishnan Amrita Y., Garfall AL, Mateos MV, et al. Updated phase 1 results of teclistamab, a B-cell maturation antigen (BCMA) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). 

. 2021;39(suppl 15):8007. doi:10.1200/JCO.2021.39.15_suppl.8007


This article was originally published on OncLive as, "

FDA Grants Breakthrough Status to Teclistamab for Relapsed/Refractory Multiple Myeloma

The FDA has granted a breakthrough therapy designation to teclistamab for the treatment of patients with relapsed/refractory multiple myeloma.

Teclistamab Granted Breakthrough Status for Relapsed/Refractory Myeloma

Age was associated with overall survival (OS) and the time to Richter transformation in adolescent and young adult (AYA) patients with chronic lymphocytic leukemia (CLL), according to findings from a single-institutional, retrospective study published in the 

The results showed that there was a significant difference in OS when sub-stratifying patients into younger than 30, 30 to 34, and 35 to 39 years age groups (

 = .049). The HR for OS was 1.72 (95% CI, 1.10-2.70) when comparing patients aged less than 30 years vs 35 to 39 years, and 2.33 (95% CI, 0.83-6.25) when comparing patients aged less than 30 years vs 30 to 34 years.

 = .03) were associated with a shorter time to developing Richter transformation. The probability of being free from Richter transformation at 5 years from diagnosis was 86%, 92%, and 99% for patients aged less than 30, 30 to 34 and 35 to 39 years at diagnosis, respectively.

“CLL presents very rarely in AYA patients younger than 40. Here, we found that the same validated prognostic biomarkers, such as 

mutation status and FISH abnormalities, used for all CLL patients could also predict outcomes in this rare subset, which included AYA patients treated with novel oral targeted therapies. Richter transformation into an aggressive lymphoma and need for allogeneic stem cell transplant were significant sources of mortality for this young population,” said Hua-Jay J. Cherng, MD, of The University of Texas MD Anderson Cancer Center, in a statement to 

Patients included in the review included those with a diagnosis of CLL or small lymphocytic lymphoma (SLL) who had been evaluated at least once at The University of Texas MD Anderson Cancer Center.

Patients with monoclonal B-cell lymphocytosis were excluded. AYA patients, defined as those aged between 15 and 39 years old at the time of diagnosis, were selected from all patients diagnosed between January 1, 2000, and December 31, 2019.

Complex karyotype was defined as 3 or more chromosomal abnormalities. Second primary malignancies were defined as any neoplasm diagnosed after CLL diagnosis, excluding non-melanoma skin cancers. Novel oral targeted therapy was defined as any therapy containing an oral targeted agent, including a BTK inhibitor, BCL-2 inhibitor, or PI3K inhibitor.

The majority of patients were between the ages of 35 and 39 years (n = 159; 70%) and male (n = 140; 62%). Moreover, most patients had mutated 

 (n = 82; 52%) and non-complex karyotype (n = 114; 84%).

Of 6074 patients who had been diagnosed with CLL between the prespecified period and seen at MD Anderson, 227 (3.7%) AYA patients were selected for analysis.

The median age at the time of diagnosis was 37 years (range, 17-39). The median follow-up time from diagnosis was 7.1 years (range, 0.1-19.3) with a data cutoff of June 30, 2020.

Six (3%) patients had a first-degree relative with CLL. A total of 161 (71%) patients received CLL treatment, and the median time to first treatment was 2.2 years. A total of 39 patients died, and the 5- and 10-year OS rates were 90% and 78%, respectively.

Beta 2-microglubin of at least 3.5 mg/L was the only significant predictor of OS in the reduced model (HR, 2.34; 95% CI, 1.63-3.38; 

 < .001) because of the small number of death events.

Reduced model multivariate analysis indicated that beta 2-microglubin of at least 3.5 mg/L (HR, 1.72; 95% CI, 1.36-2.16; 

 <.001), Rai stage I to IV vs 0 (HR, 2.01; 95% CI, 1.07-3.79; 

 =.03), and del(17p) or del(11q) vs del(13q) or negative FISH (HR, 1.89; 95% CI, 1.03-3.45; 

 =.04) were significantly associated with a shorter time to first treatment.

There were no differences in baseline characteristics or rate of receipt of oral targeted therapy between the age groups.

 mutations by next-generation sequencing was not associated with outcomes, likely because of the small numbers of patients with available pre-treatment somatic gene mutation data.

Of the 161 treated patients, 72 (45%) patients received oral targeted therapy at any time during their disease course. A total of 30 of the 72 oral targeted therapy-treated patients (42%)

received an oral targeted therapy as part of their first treatment.

Within the subgroup of the 72 patients who received oral targeted therapy at any time, hemoglobin of less than 11 g/dl (

 <.001), presence of del(17p) or del(11q; 

The median time to second treatment from start of first-line therapy was 4.2 years.

There was a significant difference in time to second treatment when sub-stratifying by type of first-line therapy (

The HR for oral targeted therapy vs purine/alkylator combination therapy was 0.51 (95% CI, 0.12-2.19) and for oral targeted therapy vs other therapies was 0.42 (95% CI, 0.20-0.85).

“The advent of oral targeted therapy in CLL has revolutionized treatment, including for AYA patients. We did find that patients treated with oral targeted therapy in the first-line setting enjoyed the longest time to second treatment. However, this advantage was not statistically significant compared with classic chemoimmunotherapy regimens such as FCR. AYA patients are much more likely to tolerate chemotherapy better than their older counterparts. For now, some clinicians may still offer FCR to young patients with low-risk disease as a treatment option,” said Cherng.

A total of 18 (8%) patients underwent allogeneic stem cell transplant (allo-SCT), 4 for Richter transformation and 14 for relapsed or refractory disease. Patients with del(11q) or del(17p; 

 = .006) were more likely to undergo allo-SCT in their treatment course. A total of 10 (4%) patients developed Richter transformation a median of 2.7 years (range, 0-16) after their diagnosis of CLL.

The median OS after diagnosis of Richter transformation was 8 months. Therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML) developed in three (1%) patients; they had received fludarabine, cyclophosphamide, and rituximab (Rituxan) chemoimmunotherapy 2.8, 3.3 and 10.3 years prior to diagnosis of t-MDS/AML. A second primary malignancy occurred in eight (4%) patients a median of 9.0 years from CLL diagnosis.

“Our findings stress the importance of vigilance for disease-related complications such as second cancers and Richter transformation and therapy-related complications such as MDS and AML. The risk of developing these [diseases] increases over time. AYA patients may live a long time with respect to their CLL, so age-appropriate cancer screening and monitoring for other complications is needed,” said Cherng.

Of the total of 39 patients who died, 19 (49%) developed Richter transformation and/or underwent allogeneic stem cell transplant, and 4 (10%) developed t-MDS/AML or a second primary malignancy. Of the 6 patients younger than 30 years who died, 5 (83%) developed Richter transformation and/or underwent allogeneic stem cell transplant, and none developed t-MDS/AML or a second primary malignancy.

“It is worth taking a look at this data again with longer follow-up so we can again investigate how AYA patients are doing on newer oral therapies compared with chemotherapy,” concluded Cherng.

Cherng HJJ, Jammal N, Paul S, et al. Clinical and molecular characteristics and treatment patterns of adolescent and young adult patients with chronic lymphocytic leukaemia. 

. Published May 10, 2021. doi:10.1111/bjh.17498

This article was originally posted on OncLive as, "

OS and Time to Richter Transformation Linked With Age in Adolescent and Young Adults With CLL.

Age was associated with overall survival and the time to Richter transformation in adolescent and young adult patients with chronic lymphocytic leukemia, according to findings from a single-institutional, retrospective study.

Age Associated With Survival, Time to Richter Transformation in AYA Patients With CLL

Melphalan flufenamide (Pepaxto) has been shown to be noninferior to pomalidomide (Pomalyst) in the treatment of patients with relapsed/refractory multiple myeloma, according to data from the phase 3 OCEAN trial (NCT03151811).

The hazard ratio (HR) for progression-free survival (PFS), per independent review committee assessment, favored melphalan flufenamide over pomalidomide, at 0.817 (95% CI, 0.659-1.012; 

 = .0640). The HR for PFS per investigator assessment was 0.790 (95% CI, 0.639-0.976). In both assessments the median PFS for the investigative arm proved to be over 40% higher than for the control arm. Moreover, the overall response rates (ORRs) with melphalan flufenamide and pomalidomide were 32.1% and 26.5%, respectively.

“The efficacy and safety data from the OCEAN study are very encouraging, and the results will be of importance in physicians’ treatment decisions for patients with relapsed and refractory multiple myeloma,” Pieter Sonneveld, MD, PhD, professor of hematology at Erasmus University of Rotterdam and principal investigator of the OCEAN study, stated in a press release. “Melphalan flufenamide has a unique mode of action, which in addition with its tolerability profile, makes the drug on attractive treatment option for many patients.”

In the open-label, global phase 3 trial, investigators set out to examine the safety and efficacy of melflufen flufenamide and dexamethasone vs pomalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma.

 To be eligible for enrollment, patients needed to have previously received 2 to 4 treatments and have been refractory to both lenalidomide (Revlimid) and their last treatment received. If patients previously received pomalidomide, they were excluded.

The primary end point of the trial was progression-free survival (PFS), while key secondary end points include ORR, duration of response (DOR), and overall survival.

Regarding safety, discontinuation rates due to toxicity were noted to be comparable between the melphalan flufenamide and pomalidomide arms. The toxicity profile of melphalan flufenamide also proved to be in line with what has been seen in prior studies; it was also consistent across age subsets.

“The outcome from the phase 3 OCEAN study is very good news for patients with relapsed refractory multiple myeloma,” Klaas Bakker, MD, PhD, executive vice president and chief medical officer at Oncopeptides, added in the release. “This head-to-head comparison was a bold study with an optimal design for demonstrating melphalan flufenamide’s true isolated treatment effects.”

Based on the data, Oncopeptides announced plans to submit a supplementary new drug application to the FDA in Q4 2021. Data from the trial will be presented at an upcoming medical conference.

In February 2021, the FDA approved melphalan flufenamide for use in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma, who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. The decision was based on findings from the phase 2 HORIZON trial (NCT02963493), where the doublet elicited an ORR of 23.7% in heavily pretreated patients with relapsed/refractory multiple myeloma, with a median DOR of 4.2 months.

Moreover, the ongoing phase 3 LIGHTHOUSE trial (NCT04649060) is examining the safety and efficacy of melphalan flufenamide plus daratumumab (Darzalex) vs daratumumab alone in patients with relapsed/refractory multiple myeloma.

Phase 3 OCEAN study demonstrates that melphalan flufenamide is at least as efficacious as pomalidomide, the most used medicine in relapsed refractory multiple myeloma. News release. Oncopeptides Inc. May 26, 2021. Accessed May 26, 2021. 

Schjesvold F, Robak P, Pour L, et al. OCEAN: a randomized phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma. 

. 2020;16(11):631-641. doi:10.2217/fon-2020-0024

FDA approves Oncopeptides' PEPAXTO (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides AB (publ). February 26, 2021. Accessed May 26, 2021. http://cisn.co/3q2bZgq

Melphalan Flufenamide Noninferior to Pomalidomide in Relapsed/Refractory Myeloma

Melphalan flufenamide was noninferior to pomalidomide in patients with relapsed or refractory myeloma. 

Melphalan Flufenamide Is Efficacious and Tolerable in Relapsed/Refractory Myeloma

The FDA has granted priority review to the biologics license application (BLA) for ciltacabtagene autoleucel (cilta-cel) for the treatment of patients with relapsed/refractory multiple myeloma.

The BLA is supported by data from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), which demonstrated that the investigational BCMA-directed CAR T-cell therapy induced an objective response rate (ORR) of 96.9%, when administered at the recommended phase 2 dose in this patient population.

 Among those who responded to treatment with cilta-cel, the stringent complete response (sCR) rate was 67.0%, the very good partial response (VGPR) rate was 25.8%, and the partial response (PR) rate was 4.1%.

The regulatory agency is expected to make a decision on the application by November 29, 2021, under the Prescription Drug User Fee Act.

“Cilta-cel has shown great promise in the treatment of patients with heavily pretreated multiple myeloma according to study findings reported to date,” Ying Huang, PhD, chief executive officer and chief financial officer of Legend Biotech, stated in a press release. “Today’s priority review designation marks another significant milestone for this cell therapy. We look forward to our continued collaborative efforts with Janssen and in working with the FDA to bring this transformative therapy to patients who are in need of new treatment options.”

In the open-label, multicenter phase 1b/2 trial, investigators set out to examine the safety and efficacy of cilta-cel in adult patients with relapsed and/or refractory multiple myeloma. To be eligible for enrollment, patients needed to be at least 18 years of age, have measurable disease, and an ECOG performance status of 0 or 1. They also needed to have previously received at least 3 regimens or were double refractory to a proteasome inhibitor and an immunomodulatory drug and had received an anti-CD38 antibody.

The FDA has granted priority review to the biologics license application for ciltacabtagene autoleucel for the treatment of patients with relapsed/refractory multiple myeloma.

Hematology