Itacitinib

LOS ANGELES--( BUSINESS WIRE )--Researchers from City of Hope ® , one of the largest and most advanced cancer research and treatment organizations in the United States, whose Los Angeles comprehensive cancer center is ranked among the nation’s top 5 cancer centers by U.S. News & World Report, presented new study results on treatment options, side effect prevention and risk prediction for blood cancer patients at this year’s ASH conference in San Diego, California, held Dec. 7 to 10. Scientists and physicians discussed outcomes for clinical trials and studies that investigated immunotherapies, like CAR T cell therapy and monoclonal antibodies, in understudied and rare blood cancer types, graft-versus-host disease, prevention strategies for donor stem cell transplant patients, a new risk assessment model for older transplant recipients and more. “The work presented by City of Hope experts at this year’s conference showcases our commitment to comprehensive, patient-centered cancer care and research that includes rare and difficult blood cancer subtypes and other patient populations that are often overlooked in clinical trials,” said Eileen Smith , M.D., City of Hope’s Francis & Kathleen McNamara Distinguished Chair in Hematology & Hematopoietic Cell Transplantation. “Studies in supportive care and better risk prediction models add depth to our groundbreaking translational work in new treatment options.” Highlighting City of Hope’s leadership in treatment and research of blood cancers and related diseases, its experts will present or contribute to more than 104 sessions, including 35 oral sessions, 56 poster sessions, 13 scientific symposia, scientific workshops and educational programs. Highlights of their novel work include: Updating results for revumenib study in acute leukemias Roughly 10% of patients with acute leukemias have a certain mutation known as rearrangement in the lysine methyltransferase 2A (KMT2Ar) gene. This change in the gene is associated with a poor prognosis. Ibrahim Aldoss , M.D., City of Hope associate professor in the Division of Leukemia, reported on findings from a phase 2 study aimed at targeting a protein interaction with a therapy called revumenib for the treatment of patients with relapsed and therapy-resistant KMT2Ar acute leukemia. “In this updated pivotal phase 2 analysis, revumenib continues to consistently provide clinically meaningful responses in heavily pretreated patients with relapsed or refractory KMT2Ar acute leukemias, including high rates of complete remission and the ability to proceed to blood stem cell transplants,” said Dr. Aldoss. Previously reported interim data from the clinical trial, one of the most significant abstracts presented at the ASH conference in 2023, had shown that revumenib — a potent oral therapy that inhibits a scaffolding protein called menin, which plays a key role in the development of leukemia — had a tolerable safety profile and a high rate of complete remission. Dr. Aldoss’s 2024 ASH presentation included results from a longer follow-up timeline and a larger data set. The trial enrolled 116 heavily pretreated patients, representing the largest evaluation of menin inhibition in people with relapsed or resistant KMT2Ar acute leukemia, including the largest pediatric menin inhibitor cohort to date. The safety arm of the trial included all participants and showed that revumenib is manageable. For the efficacy cohort, including 97 patients, 62 (64%) responded with 22 (23%) attaining complete or complete remission with partial hematologic recovery (CR+CRh). At the time of the interim analysis, 13 patients had achieved CR+CRh, and with seven additional months of follow-up, the updated median duration of CR+CRh in these responders was 13 months. “Our study led to the recent FDA approval for patients with relapsed or refractory KMT2Ar acute leukemia,” said Dr.. Aldoss. “We are thrilled that our work means these high-risk patients now have access to an effective therapeutic option.” Early application of CAR T cell therapy as a curative treatment in older adults with B-ALL Dr. Aldoss also reported on preliminary results of a trial investigating the use of CD19 CAR T cell therapy in older patients with B cell acute lymphoblastic leukemia (B-ALL), a fast-growing and aggressive cancer. People 55 years or older who develop B-ALL often have poor outcomes due to both the disease’s propensity to come back or be therapy-resistant and limited tolerability of curative modalities, like stem cell transplants. To see if a City of Hope-developed CD19 CAR T cell therapy could offer a curative option for older B-ALL patients who had achieved a complete response to a frontline therapy but remained at-risk for relapse due to the biology of the disease, Dr. Aldoss and a study team have treated 13 patients with CD19 CAR T cells in a pilot, nonrandomized trial . They hypothesize that administering of single infusion of CAR T during remission could result in low rates of toxicity and offer potential cure without the need for additional cycles of therapy. So far, their hypothesis has held true, according to Dr. Aldoss. The therapy was shown to be tolerable and safe, and the patients have maintained their walking speed and cognitive function post-infusion, and returned back to their regular lifestyle early. CD19CAR T cells expanded adequately and persisted for up to nine months post-infusion. These preliminary results indicate a durable remission for patients after receiving an infusion. “Once our favorable results are validated in a larger confirmatory study this may change the treatment paradigm of older adults with B-ALL who otherwise do poorly with current therapeutic strategies,” said Dr. Aldoss. Evaluating CAR T cell therapy for a high-risk non-Hodgkin lymphoma Patients with transformed indolent non-Hodgkin lymphoma (tiNHL) are a high-risk patient population historically associated with poor outcomes when using conventional therapies. Now, a multicenter retrospective study led by Swetha Kambhampati Thiruvengadam , M.D, assistant professor in the Division of Lymphoma, has evaluated the real-world use of a chimeric antigen receptor (CAR) T cell therapy for this group of patients. 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, which is found on B cell lymphomas, including tiNHL. The treatment is approved for people with tiNHL, but they were underrepresented in pivotal clinical trials that established CD19 CAR T cell therapy as an effective treatment for B cell cancers. “This is the largest study to our knowledge evaluating outcomes of CD19 CAR T for transformed indolent non-Hodgkin lymphoma patients compared to de novo aggressive large B cell lymphoma in the real-world setting,” said Dr. Thiruvengadam. The multicenter, retrospective study included 1,182 patients who had received CD19 CAR T cell therapies for two types of cancer: 338 tiNHL patients and 884 patients in the de novo aggressive large B cell lymphoma (aLBCL) comparison group. The results demonstrated that patients with tiNHL have higher complete response rates and may have lower risk of death or relapse/progression than those with de novo aLBCL. Patients in the tiNHL cohort also had a more favorable toxicity profile compared to de novo aLBCL. “Our study suggests CD19 CAR T is a highly effective and safe treatment option for patients with tiNHL and may overcome the historically poor prognosis in this population,” said Dr. Thiruvengadam. “It also suggests that these patients would be good candidates for clinical trials that move CAR T cell therapy to earlier lines of therapy, both because of poor expected outcomes with chemoimmunotherapy and because of excellent outcomes with CAR T.” This study was nominated for a “Best of ASH” award, which highlights the most leading-edge science presented in oral abstracts at the conference. Finding an effective therapy for rare types of lymphoma Cytotoxic T cell lymphomas (CTL) are a group of lymphomas that are very rare and have no standard treatment of care. Due to their rarity, very few patients with cytotoxic T cell lymphomas are included in clinical trials, meaning very little data exists regarding the efficacy of known T cell lymphoma therapies for this population. But a recently launched clinical trial led by Jasmine Zain , M.D., director of the T Cell Lymphoma Program and professor of hematology and hematopoietic stem cell transplantation, puts these CTL patients — for which there are five subtypes — front and center. And results from phase 1 of the phase 1/2 study testing a novel anti-CD94 monoclonal antibody are promising. “This is a first time that there is a therapy that could be effective for these rare lymphomas and may change the treatment landscape of these diseases,” said Dr. Zain. “As investigators, we now have the space to focus on these diseases that are usually fatal for patients and for which there are currently no treatments.” CD94 is a molecule that arises from cytotoxic T cells and is expressed on rare T cell lymphomas. The clinical trial tested the safety and efficacy of a next-generation therapeutic antibody called DR-01 that targets CD94. When the antibody binds to CD94 on the cancer cells, it engages natural killer cells to destroy the lymphoma. In the safety cohort of 39 CTL patients, there were no dose-limiting toxicities, and the only significant treatment-related adverse event observed was an infusion-related reaction that was managed with supportive measures. In the efficacy group of 21 patients, the overall response rate was 33%, with three complete responses in which two of the patients went on to receive a potentially curative stem cell transplant. “These results are very promising for patients,” said Dr. Zain. “This trial is for relapsed and refractory patients, but if it is successful, then we may be able to study it either alone or in combinations in the upfront setting and move the needle towards curing these patients.” Improving outcomes for cutaneous T cell lymphomas Cutaneous T cell lymphomas (CTCL) are rare, aggressive, incurable types of cancer that cause itchy, disfiguring skin conditions impacting patients’ quality of life. Patients with therapy-resistant or advanced CTCL have poor prognoses and few treatment options. Which is why Christiane Querfeld , M.D., Ph.D., director of the Cutaneous Lymphoma Program at City of Hope’s Toni Stevenson Lymphoma Center, is searching for new ways to treat the disease. Dr. Querfeld recently led a phase 1/2 trial investigating whether adding an immune booster called lenalidomide — typically used to treat multiple myeloma — to durvalumab, an immune checkpoint inhibitor to treat relapsed and/or resistant CTCL, would improve outcomes for CTCL patients. Findings from phase 2 of the study suggest that, when combined, the two therapies harness the body’s immune system to attack cancerous cells more potently than durvalumab alone. “This combined treatment demonstrated superiority to single-agent durvalumab and showed unparalleled responses relative to FDA-approved therapies, producing the most encouraging outcomes we have seen in our long experience of treating CTCL,” said Dr. Querfeld, who is also a professor in dermatology and dermatopathology at City of Hope. “It’s particularly exciting to note that these positive results were also seen in a subset of Black patients, who have a significantly increased risk of developing CTCL with worse outcomes.” A total of 25 patients who had failed at least two prior treatments were enrolled in the trial and randomized: 12 received durvalumab and 13 received a combination of durvalumab and lenalidomide. The overall response rate was 42% in patients who just received durvalumab and 75% in those who received the combination treatment. Similarly, progression-free survival at the one-year mark was 36% for the single agent cohort and 73% in the combination cohort. Responses were durable and ongoing, and the treatment was well tolerated. “This proposed immunotherapeutic strategy could provide CTCL patients with a more effective treatment for a disease that is currently incurable and in which standard approved treatments only achieve short durations of responses,” said Dr. Querfeld. “Furthermore, the knowledge gained from this study may be used to develop novel treatments not only for those with CTCL but for many other cancers.” Developing a new transplant risk-assessment model for older adults For many patients with high-risk blood cancers, hematopoietic cell transplantation (HCT), also known as bone marrow/blood stem cell transplants, are the only treatment options for long-term disease control. The older the patient, though, the higher the risk for transplant-related death. A team of researchers have now developed a model to better predict allogenic HCT outcomes in patients 60 years or older . “CHARM is a new score based on patient health information that predicts toxicities and degree of recovery after transplantation in older patients,” said Andrew Artz , M.D., M.S., a professor in the Division of Leukemia and senior author of a study outlining the model’s capabilities that was presented at ASH. “By using CHARM to assess risk, older patients who are likely to have fewer complications and better function after transplant will be more likely to be offered a potentially curative transplant.” CHARM assigns a total score for seven health variables: increasing age, lower albumin, higher C-reactive protein, higher percent of weight loss over the preceding year, lower patient-reported performance status scores, lower cognitive score per Montreal Cognitive Assessment and higher hematopoietic cell transplantation-specific comorbidity index (HCT-CI) scores. HCT-CI summarizes comorbid conditions aside from the primary disease. Originally developed to predict risks of nonrelapse mortality, the researchers wanted to assess CHARM’s ability to predict functional trajectories and morbidity after allogenic HCT in older patients. They enrolled 1,226 HCT candidates (ages 60+) from 49 centers in the United States to take the assessment and followed up on 1,105 patients who received the transplants. Among the HCT recipients, high CHARM scores predicted worse frailty, disability, cognitive decline and serious organ toxicities, all of which are critically important to older recipients of HCT. CHARM succeeds at informing patients and clinicians of transplant morbidity risks, which are separate from risks of developing acute graft-versus-host disease, the most common complication in donor HCT recipients. According to Dr. Artz and the other researchers, the study results support adopting CHARM in practice to counsel patients, expedite HCT referrals for lower risk patients and design trials to address the needs of high-CHARM-score patients. The Aging and Blood Cancers Program facilitated the high enrollment at City of Hope as one of many initiatives to advance transplant and cellular therapy outcomes in older adults. Assessing potential for engineered T cell therapies to reduce relapse in transplant patients In preparation for a hematopoietic cell transplantation (HCT), or bone marrow transplant for blood cancers, a patient’s own bone marrow cells must be destroyed. But for many older or less healthy individuals, a treatment regimen called reduced intensity conditioning (RIC) that uses lower doses of chemotherapy or radiation to prepare a patient for a bone marrow transplant is often more appropriate. However, disease relapse affects nearly 40% of this patient population — due to residual disease that RIC doesn’t eliminate — and is the leading cause of death. To reduce relapse rates, a group of researchers led by Monzr M. Al Malki , M.D., director of the unrelated donor bone marrow transplant and haploidentical transplant programs at City of Hope, is currently testing donor-derived T cell receptor engineered T cells designed to eliminate residual disease cells after transplantation in clinical trial called ALLOHA . “Early trial results show that the treatment is safe and tolerable,” said Dr. Al Malki. “Only 8% of all participants who received the engineered T cells relapsed compared to 35% relapsing on the control arm, showing the potential of the therapy to extend lives in high-risk populations.” ALLOHA is investigating the use of TSC-100 and TSC-1001, donor-derived T cell receptor engineered T cells that target HA-1 and HA-2 antigens, respectively, which are only expressed on bone marrow stem cells of HLA-A*02:01-positive patients. By choosing donors who are negative for the same target, this therapy can eliminate residual patient stem cells post-transplant while sparing donor-derived cells, thereby preventing relapse. Developed by TScan Therapeutics, Inc., a clinical-stage biotechnology company, TSC-100 and TSC-1001 were administered to 22 patients with either acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome which are the most common indication for transplantation. A control arm of 13 patients received the standard of care RIC HCT with no follow-up treatment. No dose-limiting toxicities were reported among the group receiving treatment and side effects encountered were similar in the treatment arm and control arm indicating the safety profile. The multicenter trial is ongoing, and enrollment continues. Targeting disease-initiating cells in acute myeloid leukemia In acute myeloid leukemia (AML) cells, a protein called cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed, especially in leukemia stem cells, where it supports their growth. HyunJun Kang, Ph.D., a staff scientist in the City of Hope’s Department of Hematologic Malignancies Translational Science, and his colleagues conducted the study in their lab using the novel PCNA inhibitor AOH1996 — developed by researchers in the lab of Linda Malkas, Ph.D., the M.T. & B.A. Ahmadinia Professor in Molecular Oncology — to treat AML by reducing the energy production of leukemia stem cells, effectively slowing tumor growth and diminishing their numbers. “AOH1996, the PNCA inhibitor, represents a highly selective and innovative therapeutic approach for acute myeloid leukemia,” said Dr. Kang. “Effectively reducing leukemia stem cells can eliminate the disease and prevent reoccurrence. And, importantly, AOH1996 spares normal hematopoietic stem cells, emphasizing its safety and specificity.” The research team tested AOH1996 in animal models of AML, showing that the therapy effectively inhibits cancer cell growth and induces DNA damage in multiple cancer cells with minimal toxicity. Additionally, when combined with an existing, FDA-approved cancer medication called venetoclax, AOH1996 showed enhanced efficacy and improved survival in the animal models. While AOH1996 is in clinical trials for solid tumors, the team plans to develop a clinical trial to assess the combination of AOH1996 with venetoclax in patients with AML. “By selectively targeting leukemia stem cells while sparing normal blood stem cells, AOH1996 offers a promising therapeutic option with fewer off-target effects,” said Le Xuan (Truong) Nguyen, Ph.D., an assistant professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation and the study’s senior author. “The demonstrated efficacy in preclinical models suggest that a combination of AOH1996 and venetoclax could provide a powerful and well-tolerated strategy for patients with relapsed or refractory AML, ultimately improving survival rates and reducing the likelihood of relapse.” Preventing graft-versus-host disease in stem cell transplant patients Graft-versus-host-disease, or GVHD, is the most common complication for patients receiving stem cell transplants from a donor for blood cancers. According to results from a clinical trial led by Haris Ali , M.D. associate professor in the Division of Leukemia, adding a potent anti-inflammatory therapy to a standard GVHD prophylaxis may improve GVHD-free, relapse-free survival for transplant recipients. GVHD develops when donated cells attack a patient’s own tissues and can cause a variety of symptoms ranging from mild to life-threatening. In a phase 2a clinical trial, Dr. Ali and his colleagues tested the efficacy of a combination of the standard therapy to prevent GVHD, immunosuppression therapies tacrolimus and sirolimus, with itacitinib, a Janus kinases-1 inhibitor, which help reduce the body’s inflammatory response. (Previously reported early results of the trial had shown the combination to be safe and tolerable.) A total of 59 patients with acute leukemias, myelodysplastic syndrome or myelofibrosis who underwent hematopoietic stem cell transplants from matched donors received the combination GVHD prophylaxis. At one- and two-years post-transplant, GVHD-free, relapse-free survival was 54% and 40%, respectively. The historical rate of GVHD-free, relapse-free survival at one year is 30%. “This novel GVHD prophylaxis markedly improves GVHD-free, relapse-free survival by significantly reducing acute GVHD, a key cause of transplant related mortality and morbidity,” said Dr. Ali. “We hope to refine tapering strategies of the combination to further increase the length of GVHD-free, relapse-free survival timelines.” About City of Hope City of Hope's mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest and most advanced cancer research and treatment organizations in the U.S., and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines , as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center that is ranked top 5 in the nation for cancer care by U.S. News & World Report at its core, City of Hope’s uniquely integrated model spans cancer care, research and development, academics and training, and a broad philanthropy program that powers its work. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHope TM . For more information about City of Hope, follow us on Facebook , X , YouTube , Instagram and LinkedIn .

MONDAY, Dec. 9, 2024 -- For patients with haploidentical hematopoietic cell transplantation (haplo-HCT), the addition of itacitinib to standard graft versus host disease (GvHD) prophylaxis is well tolerated and results in low rates of cytokine release syndrome (CRS), according to a study published online Nov. 2 in Blood . Noting that posttransplant cyclophosphamide (PtCy) has improved GvHD prophylaxis in haplo-HCT, but that patients continue to experience life-threatening complications, Ramzi Abboud, M.D., from the Washington University School of Medicine in St. Louis, and colleagues examined the effect of adding the JAK-1 selective inhibitor itacitinib to PtCy-haplo-HCT in an open-label, single-arm study. Forty-two patients were treated with itacitinib 200 mg daily from day −3 to +100 or +180. The researchers found that itacitinib resulted in low CRS grades; 22, 78, and 0 percent of patients had grades 0, 1, and 2 to 5, respectively. No cases of primary graft failure were reported. At day +100, the cumulative incidence of grade 2 acute GvHD was 21.9 percent; no patients developed grade 3 to 4 acute GvHD at day +180. There was a 5 percent one-year cumulative incidence of moderate or severe chronic GvHD. At two years, the cumulative incidence of relapse was 14 percent. At one year, overall survival was 80 percent. At day 180, the cumulative incidence of nonrelapse mortality was 8 percent. "We saw no severe GvHD, and the rates of relapse were lower than expected in these high-risk patients," senior author John F. DiPersio, M.D., Ph.D., also from the Washington University School of Medicine, said in a statement. "Low GvHD rates and low relapse resulted in very encouraging survival for the patients in this study." Incyte Corporation provided the itacitinib and funding for the study.