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

Patients with CLL Should Be Monitored for Skin Cancer, Including Melanoma

MedicalResearch.com Interview with:

Clive S. Zent MD Professor of Medicine Director of Lymphoma/CLL Program Wilmot Cancer Institute University of Rochester Medical Center Rochester NY

Dr. Zent


Clive S. Zent MD

Professor of Medicine
Director of Lymphoma/CLL Program
Wilmot Cancer Institute
University of Rochester Medical Center
Rochester NY

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

Response: Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) have an increased risk of all skin cancers including malignant melanoma.

This study in a stable population of CLL patients managed by a regional referral center confirmed that melanoma was over 6 times more common in than in an age and sexed matched general population. Because of the proactive skin screening program at the University of Rochester Medical Center’s Wilmot Cancer Center, most melanomas (77%) were detected at earlier stages and were treated surgically with curative intent. One patient with CLL and metastatic melanoma had a sustained remission of both diseases on treatment with ibrutinib and pembrolizumab. Continue reading

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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Early Breast Cancer Screening Recommended For Survivors of Childhood Hodgkin’s Lymphoma

MedicalResearch.com Interview with:

David Hodgson, MD, MPH, FRCPC Associate Professor University of Toronto

Dr. David Hodgson

David Hodgson, MD, MPH, FRCPC
Associate Professor
University of Toronto
Toronto, ON Canada  

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

Dr. Hodgson: We know that treatment for childhood Hodgkin lymphoma can cause some side effects that arise years after treatment is  finished. In particular, radiotherapy given to the chest of adolescent females increases the risk of developing breast cancer in young adult survivors. But there are very little data about whether the early initiation of breast cancer screening will prevent breast cancer deaths in these survivors, and what kinds of screening is optimal. This is important because less than half of these young survivors are undergoing breast cancer screening, and in some jurisdictions early screening is not covered by insurance.

MedicalResearch.com: What are the main findings?

Dr. Hodgson: Because there has not been, and likely never will be, a large randomized screening trial for these patients, we used all the available information about their breast cancer risk, other health issues and the effectiveness of screening, and created a mathematical model that allows us to estimate the number of breast cancer deaths prevented by starting screening at age 25 for women who had received chest RT as teenagers. We found that one would have to invite about 260 survivors to early mammographic screening to prevent one breast cancer death, which compares favorably to other accepted reasons for breast cancer screening. Using MRI for screening, approximately 80 women would have to be invited to prevent one breast cancer death, because MRI is so much more sensitive than mammography. One of the problems with MRI, however, is that a substantial number of women will have “false positive” tests – abnormal findings that are not really cancer.

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Socioeconomic Factors Influence Survival in Youth Hodgkin Lymphoma

MedicalResearch.com Interview with:

Theresa Keegan, PhD, MS Associate Professor Division of Hematology and Oncology UC Davis Comprehensive Cancer Center Sacramento, California 95817

Dr. Theresa Keegan

Theresa Keegan, PhD, MS
Associate Professor
Division of Hematology and Oncology
UC Davis Comprehensive Cancer Center
Sacramento, California 95817

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

Dr. Keegan: This study expanded upon our earlier work examining survival among the young population diagnosed with Hodgkin lymphoma, which can be cured about 90 percent of the time with it is diagnosed at its earliest stages.  We tracked 9,353 patients ages 15-39 who were diagnosed with Hodgkin lymphoma between 1988 and 2011. Using California Cancer Registry data, we examined the impact on survival of socio-demographic characteristics such as race/ ethnicity, neighborhood socioeconomic status (SES), health insurance, the types of treatment patients received and whether they were diagnosed with subsequent cancers.

We found that insurance coverage, neighborhood socioeconomic status (SES) and the types of treatment provided patients all played a role in survival.  Young adults diagnosed with early-stage Hodgkin lymphoma were twice as likely to die if they resided in a lower SES neighborhood. They were also twice as likely to die if they had public health insurance or were uninsured, whether they were diagnosed at an early stage or late stage.

While there were improvements in survival over time, disparities in survival persisted for some racial/ethnic groups. African American patients were 68 percent more likely to die of their disease than non-Hispanic white patients, regardless of stage at diagnosis. Hispanic AYA patients diagnosed at a late stage were 58 percent more likely than non-Hispanic white patients to die of Hodgkin lymphoma; there was not a significant disparity for Hispanic patients diagnosed at an early stage.

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Childhood Cancer Survivors Need Better Long Term Care Follow up

More Cancer Research on MedicalResearch.com

Erin E. Hahn, PhD, MPH Research Scientist Southern California Permanente Medical Group Kaiser Permanente Research Department of Research & Evaluation Pasadena, CA 91101

Dr. Erin Hahn

MedicalResearch.com Interview with:
Erin E. Hahn, PhD, MPH

Research Scientist
Southern California Permanente Medical Group
Kaiser Permanente Research
Department of Research & Evaluation
Pasadena, CA 91101

Medical Research: What is the background for this study?

Dr. Hahn:  Adolescent and young adults, or AYAs, who are diagnosed and treated for Hodgkin lymphoma have very high overall survival rates. However, these patients are at high risk for short and long term health issues related to their cancer treatment, including cancer recurrence, cardiac and pulmonary problems, and developing new primary cancers. Some of these issues arise during treatment and persist over time, called long-term effects, and some develop years later, called late effects.

Evidence and consensus based guidelines are available from organizations like the National Comprehensive Cancer Network and the Children’s Oncology Group to help manage the post treatment care of  Adolescent and young adults Hodgkin lymphoma survivors. Examining adherence to guidelines is an important part of high quality care, and can help us find and address gaps in care.

Guideline recommended care for these patients includes: oncology visits, imaging and labs, preventive care, counseling and education, risk based screening for late effects. Risk-based screening is based on a patient’s treatment. The type of health screening a patient needs is determined by the treatment exposure they had, such as certain types of chemotherapy or high-dose radiation that have known late effects 

Medical Research: What are the main findings?

Dr. Hahn: For this pilot study, I was interested to see if post-treatment  Adolescent and young adults Hodgkin lymphoma patients in an integrated health care system received recommended short and long term care. The study setting is Kaiser Permanente Southern California (KPSC). KPSC provides care for almost 4 million members with 14 medical centers, and they have a long-standing electronic medical record.

For our population, we included AYA patients diagnosed with classical Hodgkin lymphoma between 15 and 39 years of age, diagnosed between 2000 and 2010. We wanted to find patients who were diagnosed, treated, and followed for at least 2 years within this single system. We have a sample of 354 patients, which is great. It has been traditionally difficult to find and follow these patients/obtain accurate medical information that isn’t only self-report data. We were able to extract chemotherapy, radiation, and other care details from the electronic medical record.

We first looked at receipt of short term recommended care, within the first year after treatment had ended. We looked specifically at oncology visits, use of recommended CT scan and lab tests, and preventive care, such as the flu vaccine. The great majority of patients had the recommended oncology visits, CT scan, and lab tests. However, receipt of the flu vaccine was lower, at 20%. When we looked at a composite measure of all 4 recommended services, only about half of the patients received all four recommended services within the first year after treatment.

We also looked at use of a longer term recommended service for cardiac issues. Cardiac screening is recommended for patients who are 10 years out from their treatment and who received high-dose anthracyclines, plus radiation to the chest. This is the highest risk group for cardiac damage. Almost everyone received annual blood pressure screening, but only about 30% received screening with an electrocardiogram, echocardiogram, or MUGA scan.

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Second Cancer Risk Remains Elevated After Treatment of Hodgkin’s Lymphoma

MedicalResearch.com Interview with:
Dr. Michael van Leeuwen PhD
Department of Epidemiology
Netherlands Cancer Institute
Amsterdam, the Netherlands

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

Response: Over the last decades cure rates for Hodgkin’s lymphoma patients have increased dramatically. Cure and long-term survival may, however, come at a price, in the form of an increased risk of second cancers and other late effects. Since the late 1980’s treatment of Hodgkin’s lymphoma has been changed towards smaller radiation target volumes and more effective, generally less toxic chemotherapy.

In a study which included 3905 Hodgkin’s lymphoma patients treated between 1965 and 2000 in the Netherlands, the impact of these treatment changes on second malignancy risk was evaluated. Hodgkin’s lymphoma patients were between the ages of 15 and 50 years and had survived at least 5 years after treatment.

During follow-up, 1055 second cancers were diagnosed in 908 survivors, corresponding to a risk of 4.6 times as high as the occurrence of cancer in the general population. Up to at least 40 years after treatment for Hodgkin’s lymphoma, survivors remained at increased risk for second cancers.

The cumulative incidence of a second cancer was 33.2% at 30 years, compared with 9.6% in the general population, and 48.5% at 40 years, compared with 19.0% in the general population.

Breast cancer was the most common second cancer reported followed by lung and gastrointestinal cancers. Thirty-year cumulative incidence was 16.6% for breast cancer, 7.1% for lower respiratory tract cancers, 7.0% for gastrointestinal cancers, and 3.7% for non-Hodgkin’s lymphomas.

The risk of solid cancer after treatment for Hodgkin’s lymphoma was not lower among more recently treated patients (patients treated between 1989 and 2000) than among those who were treated in earlier time periods, despite changes in treatment. Nonetheless, patients treated with smaller radiation fields (e.g., a supradiaphragmatic field radiotherapy not including the axilla) were at a 63% lower relative risk of breast cancer as a second malignancy than if they received complete mantle-field radiotherapy. The lack of change in the cumulative incidence of solid cancers could be due to an incomplete adoption of the more modern radiotherapy concepts but may also be explained on the basis of a change in the chemotherapy regimens used in the 1990s. Because in the 1970’s many women exposed to high doses of alkylating agents were experiencing premature menopause, doses of alkylating agents were lowered over time to preserve fertility. However, early menopause introduced with the alkylating regimens was likely responsible for decreasing the breast cancer incidence. With the lower doses of the alkylating agents, this protection was taken away.

The cumulative incidence of non-Hodgkin’s lymphoma and of leukemia (and the myelodysplastic syndrome) was, however, much lower among patients who were treated in the period from 1989 through 2000 than among those who were treated in the period from 1965 through 1976. For leukemia, the decrease in cumulative incidence is likely due to the much lower doses of alkylating agents used in Hodgkin’s lymphoma treatment in the 1990’s compared to earlier decades.

It is important to realize that current common practice in radiation oncology, including involved-node or involved-site radiotherapy, three-dimensional conformal radiation treatment planning, and radiation doses of less than 36 Gy, was not applied in our study population. It is hoped that these changes may reduce the risk of solid cancer among patients treated after 2000.

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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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Q Fever Added To List of Germs Causing Non-Hodgkin Lymphoma

C. burnetii, the Q fever-causing agent

C. burnetii, the Q fever-causing agent

MedicalResearch.com Interview with:
Matthieu Million, MD, PhD
Assistant of Professor RAOULT
French National referral center for
Q fever
Service de Maladies Infectieuses du Professeur BROUQUI
Chemin des Bourrely
Marseille

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

Dr. Million: Human lymphomas have been associated with many infectious agents including viruses (HCV, HIV) but also bacteria (Helicobacter pylori). Q fever, the infection by Coxiella burnetii, mainly acquired from domestic (cattle, sheep, goats but also dog and cats) or wild animals (deer), has been associated with many lymphoproliferative disorders (hyperlymphocytosis, mononucleosic syndrome). We observed a lymphoma developing in a patient followed up for Q fever that prompted us to investigate the association between the two diseases.

In this study, we reported 11 cases of B-cell lymphoma developing after Coxiella burnetii primary-infection, we found an increased incidence of lymphoma in Q fever patients, particularly those with persistent focalized infection, and we detected the viable bacterium within lymphoma tissues. More specifically, we found that this bacterium infect the plasmacytoid dendritic cells (pDCs) in patients with C. burnetii-related lymphoma. This is particularly important since these cells are critical modulating their immune microenvironment including the natural antitumoral activity. Moreover, we found that peripheral blood mononuclear cells of these patients overproduce interleukin-10 even in the absence of the bacterium. This suggests that a persistent reprogramming of their immune cells have been triggered by the infection. Finally, we showed that these patients have very high levels of the anti-inflammatory Interleukin-10 in their serum, suggesting a systemic immune escape favoring the development of cancer.

Coxiella burnetii is associated with an increased risk of lymphoma, its presence in the tumor microenvironment may favor lymphomagenesis. C. burnetii should be added to the list of bacteria that promote human B-cell non-Hodgkin lymphoma.

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Third Generation CAR T cells For Relapsed Lymphoma and Leukemia

Angelica Loskog, PhD Professor of Immunotherapy (adjunct) Dept of Immunology, Genetics and Pathology Uppsala University Uppsala SwedenMedicalResearch.com Interview with:
Angelica Loskog, PhD
Professor of Immunotherapy (adjunct)
Dept of Immunology, Genetics and Pathology
Uppsala University
Uppsala Sweden

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

Dr. Loskog: CAR T cells have shown remarkable effect in patients with B cell malignancy in the US using 2nd generation CAR T cells. Acute leukemia (ALL) seems easier to treat than lymphomas and one of the reasons may be difficulties for CAR T cells to penetrate a solid lesion or due to a higher local presence of immunosuppressive cells within a lesion. As one of the first centers outside US we are evaluating 3rd generation CAR T cells in both lymphoma and ALL aiming to compare the responses and investigating biological reasons for the different responses. So far we have treated 11 patients and 6 of them had initial complete responses. Unfortunately, some progressed later.

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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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Occupational Exposure To Low Dose Radiation Linked To Leukemia

MedicalResearch.com Interview with:
Dr Klervi Leuraud, Epidemiologist
Institute for Radiological Protection and Nuclear Safety
Cedex, France

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

Dr. Leuraud: INWORKS was performed to quantify the risk of cancer mortality associated to protracted low doses of ionizing radiation typical of occupational or environmental exposures, as well as of diagnostic medical exposures. While such risks are well known for acute exposures as those experienced by the Japanese survivors of the A-bombs, there is still a lack of information for exposures experienced by the workers and the public. Our study confirms the existence of an association between leukemia mortality and chronic exposure to low doses received by nuclear workers.

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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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