CLL: Overall Treatment Savings With Ibrutinib (Imbruvica) Despite Higher Prescription Costs

MedicalResearch.com Interview with:

Dr. Sundaram

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.

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Liquid Biopsy Using Circulating Tumor DNA Can Predict Treatment Response in Large B-Cell Lymphoma

MedicalResearch.com Interview with:
Dr. David Kurtz, MD/PhD, Instructor and
Dr. Ash Alizadeh MD/PhD, Associate Professor
Division of Oncology, Department of Medicine
Stanford University Medical Center 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: This work investigates the utility of circulating tumor DNA – a type of liquid biopsy – in diffuse large B-cell lymphoma, the most common blood cancer in adults.

Liquid biopsies are an emerging technology to track cancers from a simple blood draw. Here, using a cohort of over 200 patients from 6 centers across North America and Europe, we asked if circulating tumor DNA could be used to detect lymphoma in patients, and more importantly, could it be used to identify responders and non-responders.  Continue reading

FDA Approves Poteligeo® (mogamulizumab-kpkc) for T-Cell Lymphoma of the Skin

MedicalResearch.com Interview with:

Jeffrey S. Humphrey, MD President of Kyowa Kirin Pharmaceutical Development, Inc

Dr. Humphrey

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

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Relative Risk of Breast-Anaplastic Large Cell Lymphoma With Implants is Low But Still Elevated

MedicalResearch.com Interview with:

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  Continue reading

Anti-TNF Agents In Inflammatory Bowel Disease Linked to Small Increased Risk of Lymphoma

MedicalResearch.com Interview with:
ANSM
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.

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Lymphoma Drug Shows Promising Results in Phase 3 Trial

MedicalResearch.com Interview with:

Dirk Huebner, MD Senior Medical Director Oncology Therapeutic Area Unit Takeda Pharmaceutical Company

Dr. Dirk Huebner

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.

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Genetic Locus of Natural Killer T-cell Lymphoma Risk Identified

MedicalResearch.com Interview with:
Jin-Xin BEI, Ph.D.
Principal Investigator
State Key Laboratory of Oncology in South China
Sun Yat-sen University Cancer Center
Guangzhou China

MedicalResearch.com: What is the background for this study?

Response: Natural killer T-cell lymphoma (NKTCL) is a rare and aggressive malignancy with remarkable prevalence in Asian and Latin populations, suggesting that the heritable components contribute to the disease risk. Epstein-Barr virus (EBV) infection has been thought to be major factor associated with NKTCL, and EBV DNA load in plasma has been applied in clinical managements, including diagnosis, treatment response and prognosis. However, the genetic component leading to NKTCL predisposition has not been identified.

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PET-CT Scan Can Guide Treatment in Advanced Hodgkin’s Lymphoma

MedicalResearch.com Interview with:

Peter Johnson MA, MD, FRCP Professor of Medical Oncology Cancer Research UK Centre Southampton General Hospital Southampton

Prof. Peter Johnson

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.

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Potentially Inappropriate Medications Linked to Decreased Survival in Elderly Lymphoma Patients

MedicalResearch.com Interview with:

Dr. Catherine S. M. Diefenbach MD Assistant Professor of Medicine NYU Cancer Center New York, NY 10016

Dr. Catherine Diefenbach

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.

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Hodgkin Lymphoma: Combining Targeted Drug with Immunotherapy Shows Promise

Dr. Catherine S. M. Diefenbach MD Assistant Professor of Medicine NYU Cancer Center New York, NY 10016

Dr. Diefenbach

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%.

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New Enzyme Inhibitor Shows Modest Effect Against Relapsed Lymphoma

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

Dr. Shah

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.

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Combination Therapy Effective Against Mantle Cell Lymphoma

Jia Ruan, M.D., Ph.D. Associate Professor of Clinical Medicine Weill Cornell Medicine Lymphoma Program Division of Hematology & Medical Oncology New York, NY 10021MedicalResearch.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.

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Treated and Untreated CTCL Lesions Resolved With Topical Resiquimod

Alain H. Rook, M.D. Professor of Dermatology University of Pennsylvania Philadelphia, PA 19104

Dr. Alain H. Rook

MedicalResearch.com Interview with:
Alain H. Rook, M.D.
Professor of Dermatology
University of Pennsylvania
Philadelphia, PA 19104 and

Rachael A. Clark, M.D., Ph.D. Department of Dermatology Brigham and Women's Hospital Boston, MA 02115

Dr Rachael Ann Clark

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.

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Dietary Patterns May Play A Role In Risk Of Hodgkin Lymphoma

Mara Meyer Epstein, ScD Assistant Professor Meyers Primary Care Institute University of Massachusetts Medical SchoolMedicalResearch.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.

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Combination Targeted Therapy Promising For Difficult Peripheral T-Cell Lymphoma

MedicalRDr Yeow Tee Goh Department of Haematology Singapore General Hospital Republic of Singaporeesearch.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.

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Vigorous Physical Activity May Lower Risk of Non-Hodgkin Lymphoma

MedicalResearch.com Interview with:
Terry Boyle, PhD
CIHR Fellow, MSFHR Trainee, Honorary UBC Killam Fellow
Cancer Control Research, BC Cancer Agency
School of Population and Public Health, The University of British Columbia
Australian NHMRC Early Career Fellow
The University of Western Australia
Cancer Control Research, BC Cancer Agency
Vancouver BC Canada

Medical Research: What is the background for this study? What are the main findings?

Dr. Boyle : Little is known about what causes non-Hodgkin lymphoma (NHL), so trying to identify risk factors is particularly important for the prevention and control of this cancer. There is really good evidence that people who are physically active have a lower risk of some cancers (such as colon and breast cancers), but not many studies have investigated whether being physical active is associated with the risk of non-Hodgkin lymphoma.

The key finding of this case-control study was that study participants who were in the higher (second, third, and fourth) quartiles of vigorously intense physical activity performance in their lifetimes had about 25 percent to 30 percent lower risk for NHL, compared with those who were in the lowest (first) quartile of vigorously intense physical activity.

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Epigenetic Changes May Account For How Some Lymphoma Tumors Change Over Time

Olivier Elemento 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 College New York, NY, 10021

Medical Research: What is the background for this study? What are the main findings?

Dr. Elemento: In many cancer patients, initial treatment with chemotherapy or targeted therapy shrinks the tumor or makes it disappear; however the tumor eventually comes back in a form that is frequently resistant to treatment. This process is called relapse. In diffuse large B-cell lymphomas (an aggressive type of blood cancer), approximately 40% of patients eventually relapse. How relapse occurs and how these tumors adapt and become resistant to treatment is not well understood. Why 60% of patients do not relapse and are essentially cured of their disease while 40% relapse is not known. Many think the relapse process involves tumor cells acquiring DNA alterations that make them resistant to therapy. We have indeed previously identified such DNA mutations in diffuse large B-cell lymphomas (http://genomebiology.com/2014/15/8/432/abstract).

However it became apparent to us and others that DNA mutations do not explain fully why these tumors become treatment-resistant and come back, sometimes years after initial diagnosis and therapy. We therefore turned to the epigenome to look for possible reasons. Specifically, we studied chemical modifications of DNA called DNA methylation. DNA methylation is transmitted faithfully from one cancer cell division to the next but can also be modified by specific enzymes. DNA methylation is thought to impact the way genes are expressed in tumors by modulating accessibility of DNA to proteins that regulate gene expression.  DNA methylation is known to be altered in tumors. Could DNA methylation alterations also be at least partially responsible for relapse and resistance to treatment ?

To address this question, we used a high-throughput DNA methylation profiling method to capture the DNA methylation landscape genome-wide. That is, we queried DNA methylation status at millions of locations in the tumor genome. We profiled B cell lymphoma biopsies from patients treated at Cornell and Torino. Since we were interested in how tumors change upon treatment, we profiled the initial tumor biopsy obtained at time of diagnosis (pre-treatment) then profiled the biopsy obtained at time of relapse in the same patients. The profiling produces enormous amounts of epigenomic data and we therefore had to use customized Big Data analytical algorithms together with supercomputers to interpret the methylation patterns.

Our main findings are as follows:

1) We found extensive changes in DNA methylation between diagnosis and relapse – many more epigenomic changes than DNA changes. The changes are partially random – every patient’s tumor changed in different ways. However, we observed many convergent changes. That is, near some genes, all or many patients undergo the same changes. Some of the genes are known to impact tumor biology, for example genes in the TGFbeta pathway. We also found significant epigenomic changes at genetic switches – the regions in the genome that control which genes are expressed. We think that DNA methylation changes occurring at relapse interfere with the function of these switches, and perturb expression of genes controlled by these switches.

2) Perhaps most interestingly, we found that the cell-to-cell methylation heterogeneity within tumors at time of diagnosis is highly predictive of relapse. Tumors with elevated cell-to-cell methylation heterogeneity, that is, tumors where every cell has a different methylation landscape, are more likely to relapse. The higher cell-to-cell methylation heterogeneity is, the faster tumors relapse.

These are exciting findings that for the first time indicate a major role of the epigenome in supporting the evolution and adaptation of tumors in response to treatment.

Medical Research: What should clinicians and patients take away from your report?

Dr. Elemento:

1) It is important to understand how tumors change in time, especially after treatment. This applies to all tumors, not only B cell lymphomas. A tumor found at relapse is not the same as the tumor found at initial diagnosis. Relapse tumors have evolved at the genomic level and even more so at the epigenomic level as our study shows. We cannot treat a relapse tumor as if it was the same tumor as the diagnosis one. The tumor changed – we need to understand what changed in order to tailor the treatment to the new tumor. This is important because for many patients, no biopsy is performed at time of relapse. This has to change.

2) The epigenome has potential clinical relevance. In our study we found that intra-tumor methylation heterogeneity early at diagnosis can predict which patients will eventually relapse and how fast they will relapse. The precise predictive power of the epigenome needs to be studied further but one may envision that eventually patients with elevated intra-tumor methylation heterogeneity will be monitored more aggressively for signs of relapse and/or given more aggressive treatment regimens since they may be at higher risk of relapse.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Elemento: We need to better understand the role that the epigenome plays in tumor progression. What genes are affected and how? How does the tumor genome cooperate with the tumor epigenome ? Once we understand how the epigenome contributes to tumor progression, we may be able to find new ways to block or slow down such progression, maybe by modifying the epigenome. There are already FDA-approved drugs that can interfere with DNA methylation and other epigenetic mechanisms. Maybe such drugs will be used one day to limit the ability of tumors to evolve and adapt.

At a time where precision medicine programs are put in place in hospitals across the country, we think it will be important to not only sequence the genome of patients but also characterize their epigenome. The epigenome may help understand the blueprint and alterations that led to disease (not only cancer) and provide a rich source of clinically actionable information.

Citation:

Olivier Elemento et al. Epigenomic evolution in diffuse large B-cell lymphomas. Nature Communications, April 2015 DOI: 10.1038/ncomms7921

 

MedicalResearch.com Interview with: Olivier Elemento, PhD (2015). Epigenetic Changes May Account For How Some Lymphoma Tumors Change Over Time 

Tumor DNA Blood Test May Detect Lymphoma Relapse Before CT Scan

MedicalResearch.com Interview with:
Dr. Mark Roschewski, MD
and Dr Wyndham H Wilson MD-PhD
Lymphoma Therapeutics Section
Lymphoid Malignancies Branch, Center for Cancer Research
National Cancer Institute, National Institutes of Health
Bethesda, MD 20892

Medical Research: What is the background for this study? What are the main findings?

Response: Monitoring patients with diffuse large B-cell lymphoma (DLBCL) has relied on computed tomography (CT) scans which are imprecise, expensive and include radiation. We investigated the ability of a blood-based assay to monitor patients with DLBCL during and after their initial therapy. The assay we studied amplifies and quantifies small amounts of circulating tumor DNA from the patient’s blood. We showed that this assay effectively predicts which patients will relapse and identifies recurrence 3.5 months before CT scans.
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Follicular Lymphoma: PET-CT Surpasses CT For Response Assessment

Judith Trotman MBChB, FRACP, FRCPA Associate Professor Concord Hospital University of Sydney, AustraliaMedicalResearch.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.
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Burkitt’s Lymphoma: Effectivenss of Low-Intensity Therapy

Kieron M. Dunleavy, M.D. Metabolism Branch Lymphoma Therapeutics Section Staff Clinician Center for Cancer Research National Cancer Institute Bethesda, MD 20892MedicalResearch.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.
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HIV-Lymphoma Survival – Not Improving in Anti-Retroviral Therapy Era

MedicalResearch.com Interview with: Satish Gopal, MD, MPH
Program in Global Oncology, Lineberger Comprehensive Cancer Center
UNC Project-Malawi, Tidziwe Center, Private Bag A-104, Lilongwe, Malawi

MedicalResearch.com: What is the primary message our physician readers should take away from the piece?”

Answer: Lymphoma is one of the leading causes of HIV-associated death in the modern ART era. In our analyses of a large multicenter US cohort, survival for HIV-associated lymphoma patients receiving routine care has not clearly improved since the modern ART era began, and remains significantly worse than SEER outcomes for the same lymphoma subtypes in the general population. This was somewhat surprising in an era of normalizing life expectancy for HIV-infected patients on ART, and quite different from the outstanding results achieved for this population in recent clinical trials conducted by AMC and NCI.
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