On December 11, 2023 Physicians and scientists with City of Hope, one of the largest cancer research and treatment organizations in the United States, reported data on potential new treatment options for blood cancers at this year’s American Society of Hematology (ASH) (Free ASH Whitepaper) conference in San Diego, California, Dec. 9 to 12 (Press release, City of Hope, DEC 11, 2023, View Source [SID1234638468]).

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City of Hope researchers discussed the creation of personalized DNA vaccines that can trigger the immune system to resist the growth of early lymphoplasmacytic lymphoma, also called Waldenström macroglobulinemia; targeting and eliminating leukemic stem cells with innate lymphoid cells (ILC1s); and intriguing approaches for overcoming resistance to CAR T cell therapy.

"The exciting findings presented at the ASH (Free ASH Whitepaper) 2023 conference illustrate the exceptional science unfolding across a wide spectrum of hematologic malignancies and the welcome optimism these discoveries can bring to our patients," said Eileen Smith, M.D., City of Hope’s Francis & Kathleen McNamara Distinguished Chair in Hematology & Hematopoietic Cell Transplantation. "City of Hope and our colleagues at Translational Genomics Research Institute and City of Hope Phoenix, Atlanta and Chicago continue to pursue advances that will enhance the survival and quality of life for people with blood cancers."

Highlights of City of Hope research presented at the ASH (Free ASH Whitepaper) conference include:

Promising safety and anti-lymphoma efficacy of autologous Pmb-CT01 (BAFFR CAR T cell) therapy in a first-in-human Phase 1 Study

CD19 chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment landscape of B cell lymphoma. By genetically altering patients’ T cells in the lab, scientists can program the immune cells to seek and destroy cancer cells with the CD19 antigen.

Unfortunately, a significant number of patients with aggressive B cell lymphoma, mantle cell lymphoma or follicular lymphoma still relapse or don’t respond after CAR T cell therapy.

Seeking an alternative approach to improve patient outcomes, Larry Kwak, M.D., City of Hope vice president and deputy director of its comprehensive cancer center and the Dr. Michael Friedman Professor in Translational Medicine, and his lab focused on B cell activating factor receptor (BAFFR) signaling, a driver of B cell and cancer growth. Reducing BAFFR expression, they hypothesized, could limit the ability of B cell tumors to dodge therapy.

Malignant B cells express BAFFR independently of CD19 expression, subsequent studies found, and CAR T cells targeting BAFFR were able to eliminate B cell tumors in a preclinical setting.

In a clinical trial lead by Elizabeth Budde, M.D., Ph.D., an associate professor of hematology and hematopoietic cell transplantation and the executive medical director for the Immune Effector Cell Therapy Program at City of Hope, the team treated three B cell lymphoma patients in a Phase 1 clinical trial evaluating the safety and efficacy of therapy with autologous BAFFR CAR T cells. All were male, ages 51 to 75 years old. Two faced a poor prognosis after prior CD19 CAR T cell therapy did not halt their tumor growth. A third patient did not have CD19 expressed on his lymphoma cells.

In an exciting reversal, all three patients had a complete response (100% complete response rate).

All three patients experienced robust CAR T-cell expansion, peaking on day 12 in patient #1 and day 14 in patients #2 and #3. The therapy also cleared lymphoma cells from the bone marrow 28 days after CAR T cell infusion.

While each patient developed low-grade side effects, these resolved safely with time or medication. No dose-limiting toxicities were seen. The study, sponsored by PeproMene Bio Inc., is now enrolling patients in its next cohort. (Kwak is PeproMene’s scientific founder, compensated chair of its Scientific Advisory Board and has an equity interest in PeproMene. City of Hope holds an interest in the investigational therapy ‘BAFFR(EQ)BBζ/EGFRt+ CAR T cells’, the therapy being studied in this research.)

"We were delighted to see complete remission of B cell lymphoma with this approach," Budde said. "Each of our three patients’ cancers had not benefited from several previous lines of treatment. We hope BAFFR-CAR T therapy offers a promising new option for lymphoma patients struggling with relapse or progression."

Early intervention and favorable biologic effects of personalized neoantigen vaccines on the tumor immune microenvironment in smoldering Waldenström macroglobulinemia

In lymphoplasmacytic lymphoma (LPL), abnormal white blood cells multiply rapidly in the bone marrow, displacing healthy blood cells and reducing the immune system’s ability to make new blood cells.

No therapies currently exist for patients in the cancer’s early asymptomatic stage, called smoldering Waldenström macroglobulinemia. Believing that early treatment does not enhance patient survival, the current standard of care advises oncologists to postpone treatment until the disease progresses.

Now City of Hope scientists have conducted the first clinical trial of a personalized therapeutic DNA vaccine as an early intervention for patients with asymptomatic LPL.

Developed in Kwak’s laboratory, the personalized DNA vaccine platform encodes a protein derived from the patient’s lymphoma cells fused to a molecule that targets the vaccine to antigen-presenting cells in the body. The vaccine was designed to trigger T cell immunity against the patient’s lymphoma cells.

In 8 out of 9 patients, the vaccine slowed the cancers’ growth in the bone marrow. This extended their median time to disease progression to 5.1+ years versus a median time to progression of 3.9 years in earlier studies. The vaccine was well tolerated with no dose-limiting toxicities.

"Therapeutic anti-cancer vaccines offer a promising strategy for harnessing a patient’s own immune system to fight cancer at the disease’s start," explained Szymon Szymura, Ph.D., first author and City of Hope staff scientist. "Our study suggests that a personalized vaccine provides a feasible early intervention for patients with asymptomatic LPL."

Lisocabtagene maraleucel (liso-cel) in relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: 24-month median follow-up of TRANSCEND CLL 004

No standard of care exists for patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma who develop resistance to treatment with venetoclax or Bruton tyrosine kinase inhibitor (BTKi). These patients often face poor outcomes, underscoring a critical unmet need for effective new therapies.

Now a new study presented at ASH (Free ASH Whitepaper) found that liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell therapy product, showed efficacy in resolving heavily pretreated chronic lymphocytic leukemia and small lymphocytic lymphoma.

"Our findings suggest liso-cel offers a promising alternative for high-risk patients whose cancers have not benefited from previous traditional approaches," said principal investigator Tanya Siddiqi M.D., medical director of lymphoma at City of Hope Orange County and director of the Chronic Lymphocytic Leukemia Program at the Toni Stephenson Lymphoma Center, City of Hope.

Siddiqi led the testing of liso-cel in a Phase 1/2, single-arm, multicenter TRANSCEND CLL 004 clinical trial. To qualify, patients must have received at least two prior lines of therapy, including a BTKi. Of 118 total patients, 54 had previously failed BTKi and venetoclax therapies. Participants underwent chemotherapy to lower their white blood cells and prepare the body for CAR T cells before receiving liso-cel in one of two target doses.

"A single dose of liso-cel produced rapid, deep and durable responses in this difficult-to-treat patient population and had a manageable safety profile," said Siddiqi. "We were pleased to see these measurable results."

The primary endpoint of complete remission rate was met at 20%, with high undetectable minimal residual disease rates at approximately 60% in the blood and bone marrow. Of nine patients who experienced a best overall response of complete remission in this subgroup, eight have ongoing complete remission.

After four years of follow up, one patient completed the last assessment of the study in complete remission. Another patient — who had best overall response of partial remission at primary analysis — improved without additional therapy to complete remission with incomplete count recovery at 18 months.

The median follow-up was 23.5 months. With longer follow-up, Siddiqi observed, liso-cel may continue to elicit complete remissions and high undetectable minimal residual disease rates.

IL 1 RAP-specific T cell engager antibody efficiently depletes acute myeloid leukemia and leukemic stem cells

Leukemic stem cells lack a specific membrane-surface antigen that distinguishes them from normal stem cells. Without a molecular target, it’s been challenging for scientists to develop a therapy to eliminate leukemic stem cells and overcome treatment failure.

To find a therapeutic workaround for acute myeloid leukemia (AML), City of Hope researchers created a mouse-human chimeric bispecific T cell engager called BiF002 that incorporates a human form of immunoglobulin G. The research was presented as an oral abstract at ASH (Free ASH Whitepaper).

The approach equips the chimeric antibody to simultaneously bind to IL1RAP, a protein linked to inflammation during cancer development, and to the CD3 protein on T cells. The two proteins’ close proximity triggers the T cells to kill the leukemic stem cells expressing IL1RAP.

In three different mouse models, BIF002 significantly impeded disease progression and prolonged the lives of mice with human AML, all without causing side effects, observed researcher Yi Zhang, Ph.D., a visiting scholar of hematologic malignancies translational science in the lab of Guido Marcucci, M.D.

"Our treatment not only killed leukemic stem cells in the first set of mice but prevented the cells from starting disease after we transplanted them into a second set of mice," Zhang said. "The second group of mice survived 200-plus days without further treatment. In contrast, the control mice lived only 26 days."

Despite the latest therapies, only 30% of people with AML survive five years after diagnosis. Patients are often extremely sick and must remain hospitalized because their blood and immunity are compromised by the leukemia and the treatments. While stem cell transplants can prolong life, many patients don’t qualify due to their age, other medical issues or the inability to find a matched donor.

BIF002 targets the cancer-causing stem cells that most AML treatments do a poor job of eliminating, Zhang emphasized.

"If we succeed in bringing our findings into the clinic, we could create a treatment that targets the leukemia stem cells responsible for the dismal survival odds of AML patients," she said. "Because our approach relies on an antibody, it eliminates the toxicity of chemotherapy and the need for a stem cell transplant donor."

On December 11, 2023 Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global biotechnology company developing, manufacturing, and commercializing novel therapies to treat life-threatening diseases, reported patient-reported outcome (PRO) data from the Phase 3 CARTITUDE-4 study from an oral presentation at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #1063). These data showed clinically meaningful improvement in health-related quality of life following a single CARVYKTI (ciltacabtagene autoleucel; cilta-cel) infusion in adults lenalidomide-refractory multiple myeloma (MM) who received one to three prior lines of therapy (LOT), compared to patients treated with the standard of care (SOC) treatment regimens of either pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd).1 The PRO data also demonstrated meaningful reductions in disease-specific symptoms after a single infusion for patients in the CARVYKTI arm, while patients in the SOC treatment arm trended toward worsening or lower degrees of improvement from baseline for most domains and symptoms.

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"We believe the safety and efficacy data presented from the CARTITUDE Clinical Development program at the 2023 ASH (Free ASH Whitepaper) Annual Meeting support our continuous efforts to bring CARVYKTI to myeloma patients in various stages of disease progression"

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Eligible patients in the CARTITUDE-4 study had lenalidomide-refractory MM, and had one to three prior LOT, including a proteasome inhibitor (PI) and an immunomodulatory drug. Four hundred nineteen patients were randomized, with 208 patients in the CARVYKTI arm and 211 patients in the SOC arm. At the clinical cut-off on November 1, 2022, 99 patients in the CARVYKTI arm and 66 patients in the SOC arm had baseline and 12-month PRO assessments, representing data prior to disease progression. When compared to SOC, patients who received the CARVYKTI infusion exceeded clinically meaningful thresholds for average improvement from baseline to 12 months in global health status (10.1 points vs. -1.5 points), pain (-10.2 points vs. -3.9 points), and the visual analogue scale (8.0 points vs. 1.4 points).1

"The CARTITUDE-4 data presented today reinforce the impact that a single infusion of CARVYKTI may provide to patients," said Roberto Mina, Assistant Professor, Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy.

When compared to SOC, the PRO data for CARVYKTI neared clinically meaningful thresholds when evaluating improvements in fatigue (-9.1 points vs. 2.8 points) and emotional functioning (9.5 points vs. 2.2 points), and numerically favored CARVYKTI for all other domains established by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; 100-point scale). The median time until MM symptom worsening in the CARVYKTI arm was 23.7 months compared to 18.9 months in the SOC arm (hazard ratio [HR], 0.42), as measured with the Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q; 5-point scale).1

CARTITUDE-4 As-Treated Analysis Illustrated Favorable Progression-Free Survival (PFS) Rate

An additional analysis of the CARTITUDE-4 study data was presented as a poster (Abstract #4866) at the ASH (Free ASH Whitepaper) Annual Meeting. At the clinical cut-off, 176 of the 208 patients were randomized to the CARVYKTI treatment arm. The median age of this patient population was 61 years and 34 percent had received 1 prior LOT. At a median follow-up of 16 months following randomization, 22 percent of patients received one bridging therapy cycle, 59 percent received two cycles and 18 percent received 3 cycles, and disease burden was effectively controlled across the as-treated patient set during bridging therapy.2

At 12 months following infusion, the PFS rate was 85 percent, and the overall survival (OS) rate was 92 percent. Median PFS had not been reached. The overall response rate (ORR) was 99 percent and 86 percent of patients achieved complete response or better (>CR). Of the minimum residual disease- (MRD) evaluable patients (n=144), 77 percent achieved both MRD negativity and >CR.2

The most common CAR-T cell-related toxicity was Cytokine Release Syndrome (CRS) at 76 percent (1 percent grade 3), the neurotoxicity rate was 21 percent (3 percent grade 3/4), and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurred in 5 percent of patients (no grade 3/4). Other neurotoxicities occurred in 17 percent of patients (2 percent grade 3/4). By the clinical cut-off, CRS and ICANS had resolved in all patients.2

Data from CARTITUDE-2 Cohorts A and B Demonstrated Deep and Durable Responses

During a second oral presentation, longer term efficacy and safety data from CARTITUDE-2 cohorts A and B were also presented at the ASH (Free ASH Whitepaper) Annual Meeting (Abstract #1021). At a median follow-up of approximately 29 months, patients with lenalidomide-refractory MM after one to three lines of therapy (Cohort A) and those with early relapse (Cohort B) that were treated with CARVYKTI in earlier lines of therapy experienced deep and durable responses .3

In both Cohort A (n=20) and Cohort B (n=19), treatment with CARVYKTI led to overall response rates of 95 percent (≥CR, 90 percent) and 100 percent (≥CR, 90 percent), respectively. In Cohort A, the 24-month PFS rate was 75 percent, and the 24-month OS rate was 75 percent. As for cohort B, the 24-month PFS and OS rates were 73 percent and 84 percent, respectively. There were no new CAR-T-related safety signals for Cohorts A and B, however one additional CAR-T related cell neurotoxicity (grade 2) was reported in cohort B.3

"We believe the safety and efficacy data presented from the CARTITUDE Clinical Development program at the 2023 ASH (Free ASH Whitepaper) Annual Meeting support our continuous efforts to bring CARVYKTI to myeloma patients in various stages of disease progression," said Ying Huang, Ph.D., Chief Executive Officer of Legend Biotech. "Part of our mission is to improve the lives of patients worldwide, and we are excited that the CARTITUDE-4 PRO analyses indicate that patients may experience a higher health-related quality of life following a single CARVYKTI infusion."

Disclosure: Dr. Mina has provided consulting, advisory, and speaking services to Legend Biotech

CARVYKTI Important Safety Information

CARVYKTI INDICATIONS AND USAGE

CARVYKTI (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

CARVYKTI IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, and PROLONGED and RECURRENT CYTOPENIA

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed.

Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities.

Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI.

CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.

WARNINGS AND PRECAUTIONS

CYTOKINE RELEASE SYNDROME (CRS) including fatal or life-threatening reactions, occurred following treatment with CARVYKTI in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade) occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 112 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (ALT) (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received only tocilizumab, of whom 33 (34%) received a single dose and 11 (11%) received more than one dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

NEUROLOGIC TOXICITIES, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Overall, one or more subtypes of neurologic toxicity described below occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in two ongoing studies.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Patients may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). All 22 patients with ICANS had CRS. The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Parkinsonism: Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs. The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion of ciltacabtagene autoleucel.

Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré Syndrome: A fatal outcome following Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.

Peripheral Neuropathy: Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor, or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range 4-136 days), median duration of peripheral neuropathies was 256 days (range 2-465 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel.

Cranial Nerve Palsies: Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)/MACROPHAGE ACTIVATION SYNDROME (MAS): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The HLH event was preceded by prolonged CRS lasting 97 days. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction. HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS.

Further information is available at View Source or 1-844-672-0067.

PROLONGED AND RECURRENT CYTOPENIAS: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia, and anemia were seen in 63% (61/97), 18% (17/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following infusion. After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Eighty-seven percent (84/97) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Six and 11 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

INFECTIONS: CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening or fatal infections occurred in patients after CARVYKTI infusion.

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 23% (22/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 17%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, four patients had Grade 5 infections: lung abscess (n=1), sepsis (n=2) and pneumonia (n=1).

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care, as medically indicated.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

HYPOGAMMAGLOBULINEMIA was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.

HYPERSENSITIVITY REACTIONS have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage appropriately according to the severity of the hypersensitivity reaction.

SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy of T cell origin.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia.

Please read full Prescribing Information including Boxed Warning for CARVYKTI.

ABOUT CARVYKTI (CILTACABTAGENE AUTOLEUCEL; CILTA-CEL)

Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells. The cilta-cel CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.4

In December 2017, Legend Biotech entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel.

ABOUT CARTITUDE-4

CARTITUDE-4 (NCT04181827) is an ongoing, international, randomized, open-label Phase 3 study evaluating the efficacy and safety of cilta-cel versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy, including a PI and an IMiD. The primary endpoint of the study was progression-free survival.5

ABOUT CARTITUDE-2

CARTITUDE-2 (NCT04133636) is an ongoing Phase 2 multicohort study evaluating the safety and efficacy of cilta-cel in various clinical settings (Cohorts A, B, C, D, E, F, G, H). The primary study objective is to measure the percentage of patients with negative minimal residual disease (MRD).6

ABOUT MULTIPLE MYELOMA

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.7 In 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.8 While some patients with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.

On December 11, 2023 Cimeio Therapeutics, the leading biotechnology company in the field of epitope shielding, reported data for its CD45 and CD33 programs during this weekend’s American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in San Diego (Press release, Cimeio Therapeutics, DEC 11, 2023, View Source [SID1234638466]). The two studies provide further evidence that epitope editing allows for the development of powerful immunotherapies that would not be safe to administer without first protecting healthy cells.

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The first abstract, titled "Hematopoietic Stem Cells Expressing Engineered CD45 Enable a Near Universal Targeted Therapy for Hematologic Diseases," demonstrated the efficacy of Cimeio’s proprietary CD45 targeting ADC (CIM053-ADC) at depleting an aggressive AML cancer cell line in vivo, while the CD45 engineered HSCs were fully protected, engrafted and reconstituted the hematopoietic system in humanized mice. After just two doses of CIM053-ADC, all mice were cancer-free while the healthy hematopoietic cells were unaffected. This study demonstrates the potential of CD45-targeted ADC therapy for patients with hematologic malignancies.

The second abstract, titled "Base Edited HSPCs Are Shielded From CD33 Therapy but Preserve CD33 Expression," showed how Cimeio’s CD33 shielding variant effectively protected cells from a CD33 antibody, while maintaining CD33 expression. CD33 is a useful target for AML and other diseases of HSCs.

Collectively, these studies further underscore the potential for Cimeio’s therapies, when coupled with its shielding technology, to transform the treatment of hematologic malignancies, genetic, and autoimmune diseases.

"AML patients who have residual disease at the time of a bone marrow transplant have a high risk for relapse," said Corey Cutler, M.D., M.P.H., Medical Director of the Stem Cell Transplantation Program at the Dana Farber Cancer Institute and Professor of Medicine at Harvard Medical School. "An effective therapy that could be given post-transplant to treat residual disease and prevent relapse, but would not affect the newly transplanted cells, would be a real advancement in the way we treat AML. Bone marrow transplant has the potential to cure patients of their leukemia, and improving upon this approach through epitope shielding and novel post-transplant therapies is an exciting possibility."

On December 11, 2023 Bristol Myers Squibb (NYSE: BMY) reported the results of two early studies evaluating combinations of potential first-in-class CELMoD agent golcadomide in non-Hodgkin lymphomas (Press release, Bristol-Myers Squibb, DEC 11, 2023, View Source [SID1234638465]). These data are being presented in separate posters (#4459, #4496, #1631) at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from December 9-12.

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"Golcadomide is a novel, oral CELMoD agent representing one of several compelling assets generated from our differentiated targeted protein degradation research platform," said Michael Pourdehnad, M.D., senior vice president, Head of Early Clinical Development, Hematology, Oncology and Cell Therapy Development, Bristol Myers Squibb. "In the studies being presented at ASH (Free ASH Whitepaper) 2023, golcadomide has shown potential warranting further evaluation in patients with first-line and previously treated large B-cell lymphomas. We are encouraged by the growing body of evidence for this purposefully designed lymphoma agent as we continue toward a registrational program."

CC-220-DLBCL-001

In the dose expansion phase of this Phase 1b study, patients were randomized 1:1 to golcadomide at one of two recommended Phase 2 dose levels (DL) (DL-1: 0.2 mg day 1-7, n=35; DL1: 0.4 mg day 1-7, n=37) plus R-CHOP-21 for a fixed duration of 6 cycles. A total of 65 (83.3%) patients completed 6 cycles of the combination with 13 discontinuing treatment.

There were 71 patients evaluable for efficacy, and results showed:

Overall response rate (ORR) at end of treatment rate was 84.5% in patients overall, with 87.9% of patients in the DL1 arm achieving a complete metabolic response (CMR) compared to 63.6% in the DL-1 arm.
Minimal residual disease negativity at the end of treatment was achieved in 93% (14/15) of patients treated with 0.4 mg of golcadomide plus R-CHOP compared to 70% (7/10) treated with 0.2 mg of golcadomide plus R-CHOP.
At both DL1 and DL-1, steady-state levels of golcadomide reduced Ikaros over 80%, to levels predicted to optimize tumor cell killing and to stimulate T and NK cells.
In the safety population (n=78), the majority of patients (98.7%) experienced at least one treatment-emergent adverse event (TEAE). Grade 3/4 TEAEs were primarily hematologic with neutropenia (89.7%), thrombocytopenia (42.3%) and anemia (32.1%) being the most common. Any grade febrile neutropenia was reported in 21.8% of patients. Median relative dose intensity of key R-CHOP components was maintained at >90%.

CC-99282-NHL-001

A separate poster detailed the efficacy and safety results from the dose expansion segment of a Phase 1/2 open-label study of two doses of golcadomide (0.2 mg, 0.4 mg) plus rituximab in relapsed/refractory patients with non-Hodgkin lymphoma. Patients were heavily pre-treated with a median number of 4 prior therapies (range 1-11), including 61% who had prior CAR T.

In patients evaluable for efficacy (n=26), the ORR was 42% (11/26) with 19% (5/26) achieving a complete response (CR). The median duration of response was 7.5 months (1.8-14.5). The ORR and CR rate was greater for patients in the 0.4 mg arm compared to the 0.2 arm (55% vs. 33% and 27% vs. 13%, respectively).

In the study, neutropenia was the most common TEAE of any grade, occurring in 50% of patients (22/44). Febrile neutropenia was observed in 2 patients, with 1 patient at each dose level. A total of 6 patients had serious adverse events with only pneumonia and pyrexia occurring in more than 1 patient (2 each). There were 4 deaths on treatment during the study with one considered related to the study treatment.

About Non-Hodgkin Lymphoma and Large B-Cell Lymphoma

Non-Hodgkin lymphoma (NHL) is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system.1 Diffuse large B-cell lymphoma (DLBCL) is a rapidly growing, aggressive disease and the most common form of non-Hodgkin lymphoma (NHL), accounting for one out of every three cases diagnosed.2 More than two-thirds of patients with DLBCL will not respond to or will relapse following second-line treatment. For patients who relapse or do not respond to initial therapies, conventional treatment options that provide durable remission are limited and median life expectancy is about six months, leaving a critical need for new therapies.

On December 11, 2023 Laekna (2105.HK), a clinical-stage biotechnology company, reported the results of a phase Ib study to evaluate the efficacy and safety of afuresertib plus fulvestrant in patients with locally advanced or metastatic HR+/HER2- breast cancer who failed standard of care therapies at the 2023 San Antonio Breast Cancer Symposium (SABCS) on December 8 (Press release, Laekna Therapeutics, DEC 11, 2023, View Source;laekna-reports-afuresertib-phase-ib-breast-cancer-study-results-302011286.html [SID1234638464]).

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From May 2022 to April 2023, 20 patients (19 female and 1 male) with locally advanced or metastatic HR+/HER2- breast cancer who had failed 1-2 lines of endocrine therapy were enrolled in the Phase Ib study. The median duration of follow-up was 11 months.

As of October 16, 2023, the main study results are as follows:

– 70% of the patients were previously treated with CDK4/6 inhibitors.

– Among the total patient population, the confirmed ORR was 30% (95% CI, 11.9, 54.3), the median PFS was 7.3 months (95% CI, 3.7, NE). The disease control rate (DCR) was 80%.

– Among the 11 patients with specific biomarker alterations (PIK3CA/AKT1/PTEN), the confirmed objective response rate was 45.4% (95% CI, 16.7, 76.6), the disease control rate was 82%, and the median PFS was 7.3 months (95% CI, 3.6, 8.2).

– Among the 17 Chinese patients, the confirmed ORR was 29.4% (95% CI, 10.3, 60.0), the disease control rate was 82.4%, and the median PFS was 7.3 months (95% CI, 3.6, 8.2).

– The results demonstrated a well-tolerated safety profile of afuresertib plus fulvestrant. No dose modification was required during the safety run-in period. No patient discontinued treatment due to TEAE. No serious adverse event (SAE) was reported.

Investigators concluded that the combination therapy of afuresertib and fulvestrant has shown promising efficacy with a well-tolerated safety profile, supporting further evaluation in the upcoming Phase III part of the study.

Academician Binghe Xu, the lead investigator of the study, said: "While therapies for breast cancer are increasing, the treatment of drug resistance remains one of the clinical challenges. With the approval of the world’s first AKT inhibitor last month, patients with locally advanced or metastatic HR+/HER2- breast cancer now have new hope. The Phase Ib data of the combination therapy of afuresertib and fulvestrant are promising. I look forward to the next Phase III study of afuresertib in breast cancer."

"Biomarkers of response and/or resistance to endocrine-based therapies has become a prominent topic in the field of breast cancer treatment. It is also the central theme of the ‘Poster Spotlight Session’ in which our study was presented," said Dr. Yong Yue, Chief Medical Officer of Laekna. "Compared with the PFS data of 3-4 months for fulvestrant monotherapy[1], the median PFS of afuresertib plus fulvestrant is significantly increased to 7.3 months, with a favorable safety profile."

Lakena has initiated the Phase III pivotal trial of afuresertib plus fulvestrant in the treatment of HR+/HER2- breast cancer. The company strives to bring new hope to patients.

Notes

Breast cancer

The latest data released by the International Agency for Research on Cancer (IARC) of the World Health Organization show that the number of new cases of breast cancer in 2020 reached 2.26 million worldwide, surpassing lung cancer for the first time and becoming the world’s most prevalent cancer with 685,000 deaths. The latest epidemic data of malignant tumors in China also show that breast cancer has ranked first among women, with about 420,000 new cases each year[2].

Approximately 69% of breast cancer patients in the United States are considered HR+/HER2[3], and the proportion of this subtype among Chinese patients is 62%[4]. Although most patients with this type of breast cancer initially benefit from first/second-line endocrine ± CDK4/6 inhibitors and/or chemotherapy, most may develop drug resistance after a period, leading to treatment failure.

With further research on AKT, it has been demonstrated that factors such as PTEN loss and AKT/PIK3CA mutation can lead to excessive activation of the AKT signaling pathway, resulting in the occurrence, development, and drug resistance of tumors, especially prevalent in HR+ breast cancer. AKT has consequently emerged as a popular target for treating tumors.

Afuresertib

Afuresertib (LAE002) is an AKT inhibitor developed by Laekna. Laekna has initiated multiple clinical studies of combination therapies with Afuresertib in patients with PROC, HR+/HER2− breast cancer, mCRPC, TNBC, PD-1-resistant cervical cancer, and endometrial cancer.