BTK inhibitors have become an important class of targeted therapies for several blood cancers, including CLL, mantle cell lymphoma, and...
BTK inhibitors have become an important class of targeted therapies for several blood cancers, including CLL, mantle cell lymphoma, and...
Dr. Davila[/caption]
MedicalResearch.com Interview with:
Marco Davila, MD, PhD
Hematologist/Oncologist,
Senior Vice President and Associate Director for Translational Research at
Roswell Park Comprehensive Cancer Center (Buffalo, NY) - study senior author
[caption id="attachment_71820" align="alignleft" width="150"]
Dr. Stone[/caption]
Co-author Meredith Stone, PhD
Assistant Director for Cell Therapy Translation
in Dr. Davila’s lab at Roswell Park - presenting author
MedicalResearch.com: What is the background for this study?
Response: While CD19-targeted CAR T cell therapy has garnered clinical success and FDA approval for the treatment of large B cell lymphoma, approximately half of patients suffer from primary resistance or relapse. Increasing evidence suggests that resistance mechanisms are supported by the tumor microenvironment (TME). Cytokines secreted by CAR T cells can remodel the TME, determining the phenotype and function of other immune cells.
Dr. Brody[/caption]
Joshua Brody MD
Director, Lymphoma Immunotherapy Program
Icahn School of Medicine at Mount Sinai
Hess Center for Science and Medicine
New York, New York 10029
MedicalResearch.com: What is the background for this study?
Priscilla White, spokesperson
Senior Manager, Corporate Relations
Genentech
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Horwitz[/caption]
Steven M. Horwitz, MD
Memorial Sloan Kettering Cancer Center
New York, NY
MedicalResearch.com: What is the background for this study?
Response: Relapsed or refractory Peripheral T-Cell Lymphoma (R/R PTCL) remains a disease of significant unmet medical need.
Duvelisib is an oral dual inhibitor of PI3K-δ and PI3K-γ approved for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies, relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies, and is being developed for the treatment of additional hematologic malignancies including R/R PTCL.
In early studies, we saw a suggestion of quite good activity of duvelisib as a single agent in a range of subtypes of T-cell lymphoma.
The PRIMO study is an ongoing, multi-center, open-label, registration-directed Phase 2 study evaluating duvelisib in patients with R/R PTCL that is expected to enroll approximately 120 patients. The study includes both a dose optimization phase and an expansion phase.
The Primo study will be sufficiently powered to give a much more precise estimate of the activity in peripheral t cell lymphomas. However, prior to initiating the main cohort we needed to first try to identify an optimal dose. That “dose optimization cohort” is the subject of our presentation here.
Prof. John Seymour, MBBS, Ph.D
Lead investigator of the MURANO Trial
Director. Department of Hematology at the Peter MacCallum Cancer Centre &
Royal Melbourne Hospital in Australia
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Davids[/caption]
Dr. Matthew S. Davids MD MSC
Associate Director of the Dana-Farber CLL Center
Attending physician
Lymphoma Program, Division of Hematologic Malignancies
Dana-Farber
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Dr. Crombie[/caption]
Dr. Jennifer Crombie MD
Instructor in Medicine
Harvard Medical School
MedicalResearch.com: What is the background for this study?
Response: New data from our investigator-sponsored Phase 1 study exploring duvelisib in combination with venetoclax will be presented at ASH on December 7. In relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), duvelisib plus venetoclax demonstrated promising clinical activity, a manageable tolerability profile, and identified a recommended Phase 2 dosing (RP2D) regimen. The preliminary results suggest that CD20-TCB monotherapy have promising clinical activity and may induce durable complete responses in patients with...
Dr. Sundaram[/caption]
Murali Sundaram, MBA, Ph.D.
Director of Real World Value and Evidence
Oncology, Janssen
MedicalResearch.com: What is the background for this study?
Response: Ibrutinib is a novel Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with newly diagnosed chronic lymphocytic leukemia (CLL).
Ibrutinib is administered orally while standard of care (CD20 monoclonal antibody-based chemoimmunotherapy [CIT]) is administered intravenously. This difference in route of administration impacts what type of benefit covers these treatments (i.e., pharmacy benefit for oral ibrutinib and medical benefit for intravenous CIT).
Previous studies evaluating the costs burden of patients treated with ibrutinib versus CIT did not include the full spectrum of real-world healthcare costs.
Dr. Humphrey[/caption]
Jeffrey S. Humphrey, MD
President of Kyowa Kirin Pharmaceutical Development, Inc
MedicalResearch.com: What is the background for this announcement? Would you briefly explain what is meant by Mycosis Fungoides and Sézary Syndrome?
Response: Kyowya Kirin has received FDA approval for Poteligeo (mogamulizumab), based on findings from the MAVORIC trial. Mogamulizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets CC chemokine receptor 4 (CCR4), for the treatment of the most common subtypes of cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF) and Sézary syndrome (SS).
MF and SS may have a profound and severe impact on quality of life, including a patient’s functional, emotional and social well-being, as symptoms may include a scaly red rash or light or dark patches in areas of the body that are not usually exposed to the sun; thin, reddened, eczema-like rash; thickened scaly, red skin (or plaques) or psoriasis-like rash; more advanced disease can include tumors (with significant thickness) on the skin, which may develop ulcers and become infected. Because CTCL manifests in skin lesions, it is often mistaken for other skin conditions (early stage MF and SS can be diagnosed as other skin conditions), which can delay conclusive diagnosis and treatment options.
MF is the most common subtype of CTCL, affecting 50-70% of individuals. In most patients diagnosed with early stage MF, the skin involvement does not progress, but in some patients, it will slowly progress. SS accounts for approximately 3% of CTCL cases and is a more aggressive, leukemic form of CTCL, affecting the blood, skin, lymph nodes and visceral organs
Dr. Mintsje de Boer, MD Resident plastic surgery
Department of Plastic, Reconstructive and Hand-Surgery
Maastricht University Medical Centre+, Maastricht the Netherland
On behalf of the Netherlands BIA-ALCL Consortium: Daphne de Jong (Hematopathologist, VU university medical Center, Amsterdam, the Netherlands), Hinne Rakhorst (Plastic Surgeon, MST/ZGT, Enschede, the Netherlands) René van der Hulst (Plastic surgeon, MUMC+ Maastricht, the Netherlands) Flora van Leeuwen (Epidemiologist, Netherlands Cancer Institute, Amsterdam, the Netherlands), Jan Paul de Boer (Hemato-oncologist, Netherlands Cancer Institute, Amsterdam, the Netherlands) Lucy Overbeek (Database expert PALGA, Houten, the Netherlands),
MedicalResearch.com: What is the background for this study?
Response: Breast implants are one of the most commonly used medical devices worldwide. Associations with breast cancer, connective tissue diseases and auto-immune diseases have never been unequivocally supported. For lymphoma risk, this is different and several reports have suggested an association between breast implants and risk of anaplastic large cell lymphoma in the breast (breast-ALCL).
Over the past few years, the number of women with breast implants reported with breast-ALCL has strongly increased. This has resulted in significant attention amongst medical professionals and women alike with publications in medical journals and lay press. In part due to the rarity of the disease and due to the lack of breast implant prevalence data in the population, the absolute risks of breast-ALCL are largely unknown, precluding evidence-based counseling about implants. In the Netherlands, we are in the unique position to be able to retrieve all diagnosed breastALCL since 1990 as well as appropriate population-based control groups from the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA). This has allowed a formal epidemiological risk assessment study based on sufficient numbers. Moreover, using combined and complementary sources of information, we have been able to determine age- and calendar year-specific implant prevalence rates to determine reliable absolute risks.
This study could be successfully performed thanks to a multidisciplinary taskforce consisting of plastic surgeons, hematopathologists, epidemiologists, hemato-oncologists and radiologists from the several large institutions in the Netherlands
Rosemary Dray-Spira, MD, PhD
Department of Epidemiology
French National Agency for Medicines and Health Products Safety (ANSM)
Saint-Denis, France
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Anti-tumor necrosis factor (anti-TNF) agents are increasingly used for the management of inflammatory bowel diseases (IBD), either alone or in combination with thiopurines. Their clinical benefits have been largely assessed, however they may expose to potentially serious adverse effects. While an increased risk of lymphoma has been established with thiopurines, up to now such a risk of lymphoma remained uncertain with anti-TNF agents.
In this study based upon a large, nationwide cohort of 189,289 patients with IBD, the use of anti-TNF agents alone was found associated with a 2 to 3 fold increase in the risk of lymphoma, similarly to thiopurines alone. In addition, the combination of these two treatments was associated with a 6 fold increase in the risk of lymphoma, ie a higher risk than with each treatment used alone. Although these differences are statistically significant, the risk of lymphoma among patients exposed to anti-TNF agents is less than 1 case per 1000 person-years.
Dr. Dirk Huebner[/caption]
Dirk Huebner, MD
Senior Medical Director
Oncology Therapeutic Area Unit
Takeda Pharmaceutical Company
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Cutaneous lymphomas are a category of non-Hodgkin lymphoma that primarily involve the skin. Cutaneous T-cell lymphoma, also known as CTCL, is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis.
ADCETRIS® (brentuximab vedotin) is an antibody-drug conjugate directed to CD30, which is expressed on skin lesions in approximately 50 percent of patients with CTCL. The Phase 3 ALCANZA trial compared the use of single-agent ADCETRIS to a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene, in 131 patients with CD30-expressing CTCL who received prior systemic or radiation therapy.
The study met its primary endpoint, demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4). The ORR4 was 56.3 percent in the ADCETRIS arm compared to 12.5 percent in the control arm.
Prof. Peter Johnson[/caption]
Peter Johnson MA, MD, FRCP
Professor of Medical Oncology
Cancer Research UK Centre
Southampton General Hospital
Southampton
MedicalResearch.com: What is the background for this study? What are the main findings?
Prof. Johnson: Based upon retrospective series looking at the ability of interim PET to predict the outcomes of treatment, we aimed to test the idea of modulating treatment in response to an early assessment of the response to ABVD: could we safely reduce the amount of treatment by omitting bleomycin in the group who had responded well? Although the risk of severe toxicity from bleomycin is generally low, for the small number of patients who experience it, it can be life-changing or even fatal. We also wanted to test whether it might be possible to reduce the use of consolidation radiotherapy by comparison to our previous trials, and this seems to have worked too: we used radiotherapy in less than 10% of patients in RATHL, as compared to around half in our previous trials. We have seen better survival figures than in our previous studies with less treatment overall, so it feels as though we are on the right track.
Dr. Catherine Diefenbach[/caption]
Dr. Catherine S. M. Diefenbach MD
Assistant Professor of Medicine
NYU Cancer Center
New York, NY 10016
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Diefenbach: It is well known that age is important prognostic factor in non-Hodgkin’s lymphoma (NHL). Multiple studies have illustrated that elderly lymphoma patients have inferior survival outcomes as compared to their younger counterpart. While the tumor biology is often different in these two groups, and may play a role in this discordancy, elderly patients are often frail or have multiple medical comorbidities. These include geriatric syndromes, such as: cognitive impairment, falls, polypharmacy, and potentially inappropriate medication (PIM) use. All of these may contribute to poor outcomes for elderly patients. In addition, elderly patients are often under-treated for their aggressive lymphoma out of concern for toxicity or side effects, even though the data clearly demonstrates that elderly patients can still benefit from curative intent chemotherapy.
Dr. Diefenbach[/caption]
MedicalResearch.com Interview with:
Dr. Catherine S. M. Diefenbach MD
Assistant Professor of Medicine
NYU Langone
Laura and Isaac Perlmutter Cancer Center
New York, NY 10016
Medical Research: What is the background for this study? What are the main findings?
Dr. Diefenbach: The background of the study is that through an understanding of the unique immunobiology of Hodgkin lymphoma we can derive rational treatment strategies which may heighten the efficacy of existing therapies, and improve the outcomes for patients with relapsed disease. In E4412 which is a national study sponsored by the Eastern Cooperative Oncology Group (ECOG-ACRIN) we explore the safety and efficacy of combination of the antibody drug conjugate brentuximab vedotin which targets CD30 on the surface of the Hodgkin lymphoma tumor cells, and immune stimulation of the T cells in the tumor microenvironment using checkpoint inhibitors. We reported the data from the first arm of the study Brentuximab Vedotin and Ipilimumab. To date 23 patients with relapsed Hodgkin lymphoma have been treated; the combination of brentuximab and ipilimumab was safe and well tolerated with primarily grade 1 and 2 toxicities. In 18 patients evaluable for response the ORR was 72% with a complete response rate of 50%.
Dr. Shah[/caption]
MedicalResearch.com Interview with:
Dr. Jatin J. Shah, MD
Associate Professor, Department of Lymphoma/Myeloma
Assistant Professor, Lymphoma/Myeloma
Division of Cancer Medicine
The University of Texas, MD Anderson Cancer Center
Houston, TX
Medical Research: What is the background for this study? What are the main findings?
Dr. Shah: The ubiquitin-proteasome system (UPS) is one of the key regulatory systems in our body’s cells. It controls the destruction of the majority of cellular proteins, which can be involved in making cells grow, expand, or die, among other functions. Defects in the UPS can result in a number of diseases, including cancer, for example by destroying too quickly the proteins that cause cells to die. The UPS has already been shown to be a rational target for cancer therapy: the approved drugs bortezomib and carfilzomib inhibit the proteasome itself, thus causing cancer cells to die. However, by completely blocking the proteasome, which is at the ‘end’ of the UPS, these drugs block the destruction of 100% of proteins, and can cause side effects. By contrast, blocking the NEDD8-activating enzyme (NAE) stops the cellular processes that are responsible for only approximately 20% of proteins being degraded by the UPS – including proteins of relevance to cancer development. Previous studies of pevonedistat in animals have shown that inhibiting NAE alters the ability of a cancer cell to repair its DNA after it is damaged; this leads to the death of cancer cells.
The man finding is this was the first reported study of pevonedistat in patients with multiple myeloma or lymphoma. It demonstrated that pevonedistat hits its target in cancer cells, exerted anticipated pharmacodynamic effects, and has modest activity as a single-agent in heavily pretreated patients with relapsed/refractory lymphoma.
MedicalResearch.com Interview with:
Jia Ruan, M.D., Ph.D.
Associate Professor of Clinical Medicine
Weill Cornell Medicine
Lymphoma Program
Division of Hematology & Medical Oncology
New York, NY 10021
Medical Research: What is the background for this study? What are the main findings?
Dr. Ruan: Mantle cell lymphoma is an uncommon subtype of non-Hodgkin lymphoma that primarily affects elderly populations. Conventional chemotherapy regimens are generally not curative, and may not be tolerated by many patients, underscoring the need for treatment alternatives. Previous experience with immunomodulatory compound lenalidomide has shown favorable activity and was well tolerated in patients with relapsedMantle cell lymphoma. We evaluated the efficacy and safety of the biologic combination with lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma (MCL).
The main findings of the study showed that the combination was effective and generally well tolerated when given as induction and maintenance treatment. The overall response rate was 92%, with complete response rate of 64% in the 36 evaluable patients. Median duration of response has not been reached at a median follow up of 30 months. Treatment was outpatient-based and quality-of-life was preserved for most patients.
Dr. Alain H. Rook[/caption]
MedicalResearch.com Interview with:
Alain H. Rook, M.D.
Professor of Dermatology
University of Pennsylvania
Philadelphia, PA 19104 and
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Dr Rachael Ann Clark[/caption]
Rachael A. Clark, M.D., Ph.D.
Department of Dermatology
Brigham and Women's Hospital
Boston, MA 02115
Researchers’ summary: In this paper, Dr. Rachael Clark and I describe a novel topical therapy for mycosis fungoides (MF), which is a skin-limited variant of cutaneous T-cell lymphomas (CTCL), a group of non-Hodgkin's lymphomas which represent cancers derived from skin-homing T cells. Although therapies exist that suppress the inflammatory skin lesions of MF, there are no curative therapies for this otherwise lifelong disease except for stem cell transplantation, which is only carried out in patients with aggressive and progressive disease.
This manuscript describes a phase I trial of a novel immunomodulatory compound called resiquimod. This molecule stimulates two key receptors TLR7 and TLR8. Unlike imiquimod, a similar compound that is FDA approved for the treatment of local skin cancers, resiquimod actually stimulates inflammatory cytokine release from the dendritic cells that populate both healthy and inflamed human skin. As a result, this drug can enhance antigen presentation and immune responses.
This study demonstrated that topical resiquimod was remarkably effective in that 90% of patients experienced a decrease in the percentage of the malignant T cell clone in skin lesions, and two patients had complete clearance of all disease, including both the treated skin lesions and the untreated lesions. To our knowledge, this is the first demonstration of regression of untreated skin lesions using a topical medication. This suggests that systemic antitumor immunity develops in these patients. Translational studies on the skin before and after treatment showed that the malignant T cell clone declined and inflammatory cytokine production by benign T cells increased after therapy suggesting the medication enhanced antitumor responses.
In summary, this manuscript describes a small phase I trial that showed that topical resiquimod is safe, effective therapy for mycosis fungoides and can cause regression of both treated and untreated skin lesions, and may therefore represent a long-term potential cure for this otherwise lifelong disease.
MedicalResearch.com Interview with:
Mara Meyer Epstein, ScD
Assistant Professor
Meyers Primary Care Institute
University of Massachusetts Medical School
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Epstein: Hodgkin lymphoma is a relatively rare cancer, with about 9,000 new cases diagnosed in the US each year. Hodgkin lymphoma is most commonly diagnosed in earlier (aged 15-34 years) or later adulthood (aged ≥50 years). The causes of the disease are not well understood, and most identified risk factors are not modifiable (for example, age, sex, family history, and infection with Epstein-Barr virus [EBV]). Previous studies have suggested that chronic inflammation may play a role in the development of Hodgkin lymphoma. Therefore, it is possible that a factor that can influence inflammation, such as diet, may be associated with risk of Hodgkin lymphoma. Discovering modifiable risk factors for Hodgkin lymphoma could offer a means for preventing this disease. The few existing studies of diet and Hodgkin lymphoma risk have focused on individual nutrients or foods; this is the first study to examine dietary pattern and risk of Hodgkin lymphoma. By examining dietary patterns instead of individual foods, we sought to assess Hodgkin lymphoma risk from the food combinations that may more closely reflect typical dietary habits.
The current study includes 435 cases of Hodgkin lymphoma and 563 controls with no history of cancer from Massachusetts and Connecticut who were enrolled in the study between 1997 and 2000. Cases and controls provided information about their average intake of 61 food and beverage items over the year prior to the study. By evaluating foods commonly consumed by the study participants, we identified four major dietary patterns; high vegetable intake, high meat intake, high intake of fruit and low-fat dairy, and high intake of desserts and sweets. We looked for associations between each dietary pattern and risk of Hodgkin lymphoma overall, and also separately by age group (<50 years or ≥50 years old), tumor EBV status (positive or negative), and by tumor cell pattern (nodular sclerosis or mixed cellularity). The dietary pattern characterized by high intake of desserts and sweets was associated with a statistically significant increased risk of Hodgkin lymphoma among younger adults, and in particular, a 2-fold increased risk among younger adults with EBV-negative tumors. The dietary pattern featuring high meat intake was associated with a 3-fold increased risk of Hodgkin lymphoma among older adults, and again, we saw a stronger association among older adults with EBV-negative tumors, although the number of such cases in this group was small. We did not observe a clear association between the high vegetable dietary pattern, or the dietary pattern high in fruit and low-fat dairy intake, with Hodgkin lymphoma risk, and we also did not find any clear associations with EBV-positive tumors, which were relatively infrequent in the study population. The findings described above were obtained from statistical calculations that also took into account known Hodgkin lymphoma risk factors, other lifestyle factors, total caloric intake, and body mass index.
esearch.com Interview with:
Dr Yeow Tee Goh MBBS
Department of Haematology
Singapore General Hospital
Republic of Singapore
Medical Research: What is the background for this study? What are the main findings?
Dr. Goh: Relapsed or refractory peripheral T-cell lymphoma after conventional chemotherapy is associated with a very poor prognosis and there is currently no recommendation on the standard approach to helping these patients. Novel targeted treatments for relapsed or refractory peripheral T-cell lymphoma such as romidepsin, pralatrexate, belinostat, and brentuximab vedotin has been approved by the US Food and Drug Administration (FDA) based on the results of their Phase II studies. With the exception of the remarkable efficacy of brentuximab vedotin in systemic anaplastic large cell lymphoma (86% of patients responding to treatment), the efficacy of romidepsin, pralatrexate, and belinostat in relapsed or refractory peripheral T-cell lymphoma is only modest with objective response rates between 25% and 29%. To our knowledge, no other clinical study has reported on the use of novel combination of targeted agents in in relapsed or refractory peripheral T-cell lymphoma. In our study, Of 23 patients assessable for responses, 10 (43%, 95% CI 23–63) patients had an objective response, of which 5 were complete responses. The combined proteasome and histone deacetylase inhibitor treatment shows promising activity for patients with peripheral T-cell lymphoma.
MedicalResearch.com Interview with: Olivier Elemento, PhD Associate Professor Head, Laboratory of Cancer Systems Biology Department of Physiology and Biophysics Institute for Computational Biomedicine Weill Cornell Medical...
MedicalResearch.com Interview with:
Judith Trotman MBChB, FRACP, FRCPA
Associate Professor Concord Hospital
University of Sydney, Australia
Medical Research: What are the main findings of the study?
Dr. Trotman: That PET-CT (applying the cut-off of ≥4 on the now internationally recommended 5 Point Scale) is a more powerful predictor of both Progression Free and Overall Survival than conventional CT in patients responding to first line immunochemotherapy for advanced follicular lymphoma. It is also a much stronger predictor than the pre-treatment prognostic indices FLIPI and FLIP2. Patients who achieve PET-negative status have a median PFS over 6 years compared to only 17 months in those who remain PET-positive.
MedicalResearch.com Interview with
Kieron M. Dunleavy, M.D.
Metabolism Branch
Lymphoma Therapeutics Section
Center for Cancer Research
National Cancer Institute, Bethesda, MD 20892
MedicalResearch.com: What are the main findings of the study?
Dr. Dunleavy: We found that low-intensity therapy was highly effective in Burkitt's lymphoma and cured over 95% of patients with the disease.