Combination Therapy Could Dramatically Alter CLL Treatment

MedicalResearch.com Interview with:

Dr. Danelle James,

Dr. James

Dr. Danelle James, M.D., M.A.S.
Head of Clinical Science
Pharmacyclics, an AbbVie Company

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

Response: CAPTIVATE is a Phase 2 study investigating IMBRUVICA (ibrutinib) plus VENCLEXTA (venetoclax) for the treatment of Chronic Lymphocytic Leukemia (CLL) in the first-line setting. It was designed to evaluate if remission with undetectable minimal residual disease (MRD) can provide treatment-naïve CLL/SLL patients with treatment holidays (a period of time when a patient is able to stop therapy). The study enrolled 164 patients with previously untreated CLL or SLL.

In preclinical and ongoing clinical studies, we’ve seen complementary activities with this combination. The combination has also previously shown potential for deeper remissions, as well as potential for lower risk of tumor lysis syndrome with ibrutinib as the lead-in therapy.

Early data from CAPTIVATE show promising activity for the combination in this patient population, with 77 percent of the first 30 patients achieving responses with no detectable MRD in the blood after only six cycles of the combination therapy. Approximately nine out of 10 of the first patients achieved undetectable MRD after 12 cycles of combination therapy (which were preceded by three cycles of single agent ibrutinib, for a total of 15 cycles of therapy). Specifically, 86 percent of the first 14 patients achieved undetectable MRD in the marrow and 93 percent in the peripheral blood.

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Engineered Single Cell ‘Cured’ Patient of CLL

MedicalResearch.com Interview with:

Dr. J Joseph Melenhorst, PhD Director, Product Development & Correlative Sciences laboratories (PDCS) Adjunct Associate Professor Penn Medicine Center for Cellular Immunotherapies University of Pennsylvania

Dr. Melenhorst

Dr. J Joseph Melenhorst, PhD
Director, Product Development & Correlative Sciences laboratories (PDCS)
Adjunct Associate Professor
Penn Medicine
Center for Cellular Immunotherapies
University of Pennsylvania

MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by CLL and CAR T cells? 

Response: We started treating patients with a form of blood cancer called CLL (chronic lymphocytic leukemia) using a form of gene therapy wherein we engineer the patient’s own immune cells – T cells – with a tumor targeting molecule: The CAR, which stands for chimeric antigen receptor. When we engineer the patient’s immune cells we use a vehicle, in this case virus, that inserts the payload – the CAR – into the patient’s DNA. The virus disappears, and the CAR stays. Where this CAR inserts itself is unpredictable, but we always get stably engineered cells.  Continue reading

Multiple Myeloma Cases and Deaths Increase Worldwide

MedicalResearch.com Interview with:

Andrew J. Cowan, MD Seattle Cancer Care Alliance Division of Medical Oncology University of Washington, Seattle

Dr. Cowan

Andrew J. Cowan, MD
Seattle Cancer Care Alliance
Division of Medical Oncology
University of Washington, Seattle

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

 

Response: Multiple myeloma (MM) is a plasma cell neoplasm with substantial morbidity and mortality. A comprehensive description of the global burden of multiple myeloma is needed to help direct health policy, resource allocation, research, and patient care.

Myeloma cases and deaths increased from 1990 to 2016, with middle-income countries contributing the most to this increase. Treatment availability is very limited in countries with low socioeconomic development.

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Pre-Emptive Therapy of CMV in Allogeneic Hematopoietic Cell Transplant

MedicalResearch.com Interview with:

 Dr-Roy F. Chemaly

Dr. Chemaly

Roy F. Chemaly, MD, MPH F.A.C.P., F.I.D.S.A.
Department of Infectious Diseases
Infection Control and Employee Health
Division of Internal Medicine
MD Anderson Center

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

Response: CytomegalovirusCMV infection is a common cause of morbidity and mortality in allo-HCT recipients. Evidence suggests that CMV infection has not only an enormous clinical burden, but a substantial economic burden as well.

We conducted this study at MD Anderson to determine the economic and clinical burden of preemptive therapy (PET) for CMV infection. Between 2012 and 2015, 100 consecutive patients hospitalized at our institution for allo-HCT who experienced reactivation of CMV and were treated pre-emptively, were enrolled.

The majority of patients were men (55%), who had underlying leukemia (73%), and underwent matched unrelated donor transplant (59%). At the time of hospitalization, most patients had acute GvHD (62%), and were on steroids (58%) within 30 days of CMV reactivation which occurred at a median of 32 days post-HCT (2 -174). A total of 192 episodes of PET occurred in the 100 allo-HCT recipients within 1 year post-HCT. PET consisted of ganciclovir (41%), foscarnet (40%), and valganciclovir (38%). IVIG was also used as adjunct therapy in 20% of episodes.

Progression to Cytomegalovirus disease occurred in 4 patients (4%) and mainly affected the GI tract. Mean length of stay for patients treated with ganciclovir or foscarnet was 32 days (2-141) and 41 days (1-177), respectively. The average direct cost per patient admitted for PET was $126,038 ($7,866-$641,841) and the mean cost of CMV antiviral drug per hospitalization was $6,096 for IVIG, $2,410 for foscarnet, $836 for ganciclovir, and $780 for valganciclovir.

Serious side effects from PET were observed in 35% of patients on ganciclovir and 12% of patients on foscarnet. Total direct cost per encounter was significantly higher in patients who had serious side effects from foscarnet. All-cause mortality was 59% at 1 year post-transplant.

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DARZALEX® (daratumumab) Approved for Newly Diagnosed Patients with Multiple Myeloma who are Transplant Ineligible

MedicalResearch.com Interview with:

Andrzej Jakubowiak, MD, PhD Professor of Medicine Director, Myeloma Program University of Chicago

Dr. Jakubowiak


Andrzej Jakubowiak, MD, PhD
Professor of Medicine
Director, Myeloma Program
University of Chicago

MedicalResearch.com: What is the background for this announcement? Would you briefly explain what is meant by multiple myeloma?

 

Response: DARZALEX (daratumumab) in combination with VELCADE (bortezomib), melphalan and prednisone – VMP – received U.S. FDA approval for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT). With this most recent approval, DARZALEX is now the first monoclonal antibody approved for newly diagnosed patients with this disease.

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow. Despite the introduction of new medicines over the last decade, which has led to significant improvements in outcomes for patients with multiple myeloma, multiple myeloma remains an incurable disease. In 2018, it is estimated that 30,700 people will be diagnosed and 12,770 will die from the disease in the United States.

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Letermovir (Prevymis) Prevents CMV Infection in Stem Cell Transplant

MedicalResearch.com Interview with:

Francisco M. Marty, M.D Associate Professor, Harvard Medical School Dana–Farber Cancer Institute and Brigham and Women’s Hospital

Dr. Marty

Francisco M. Marty, M.D
Associate Professor, Harvard Medical School
Dana–Farber Cancer Institute and
Brigham and Women’s Hospital

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

Response: Cytomegalovirus (CMV) is the most common infection in patients who undergo allogeneic hematopoietic-cell transplantation (bone marrow transplantation with cells from donors different than the patient). Up until now, we had no antiviral agent that could be used for prophylaxis (prevention) of CMV post-transplant because of the side effects of drugs available to date (ganciclovir, valganciclovir, foscarnet, cidofovir).

This trial confirmed that letermovir was highly effective in preventing CMV infection when used in the first 100 days after allogeneic HCT, was associated with minimal side effects of concern and was also associated with lower all-cause mortality by Week 24 post-HCT.

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Microtransplantation Can Be Safe and Effective For Older AML Patients

MedicalResearch.com Interview with:
Huisheng Ai, MD, Director

Department of Hematology and Transplantation,
Affiliated Hospital of the Academy  of Military Medical Sciences,
Beijing, China 

MedicalResearch.com: Which of these results did you find most interesting or surprising?

Response: First, we must stress that microtransplant dramatically improved the outcome of older patients with AML.

As we know, older AML patients often possess unfavorable prognostic factors, organ dysfunction, and slow post-chemotherapy hematopoietic recovery. Therefore, the general treatment outcome is unsatisfactory even though the incidence is increasing by age with low complete remission (CR) rates (34% to 65%) and poor short-term survival (Two years overall survival was about 11% to 25%).

This study involved cases from multiple centers of China, USA and Spain, and found that microtransplant could not only significantly improve complete remission rate in older AML patients among all age groups from 60 to 85, but also improve 1-year and 2-year overall survival and disease free survival especially in patients aged 60 to 75. Second, microtransplant completely overcomes the restriction of HLA typing. The donor could be the patient’s haploidentical family member, or unrelated and fully mismatched one. The incidence of graft-versus-host disease (GVHD) was only 1.1%, even if no any GVHD prevention was given. Other treatment related complications and mortality were also decreased.

These results are much better than those of traditional chemotherapy, myeloablative and non-myeloablative transplant, which provides a more safe and effective treatment choice. We are looking forward to seeing the revision of NCCN guideline for older AML to make microtransplant benefit more older patients.

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CLL: Long-term efficacy of ONO/GS-4059 is maintained without emergence of new toxicities

MedicalResearch.com Interview with:

Martin J.S. Dyer, D.Phil MA FRCP FRCPath Ernest and Helen Scott Haematological Research Institute University of Leicester, UK

Prof. Dyer

Martin J.S. Dyer, D.Phil MA FRCP FRCPath
Ernest and Helen Scott Haematological Research Institute
University of Leicester, UK

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

Response: This study follows on from a world-first clinical trial of a new drug to treat particular blood cancers. Results of that international clinical trial were published in the journal Blood in November 2015 and looked at the efficacy of a new inhibitor, ONO/GS-4059, in the treatment of CLL and Non-Hodgkin Lymphoma patients, refractory or resistant to current chemotherapies.

ONO/GS-4059 targets BTK, a protein essential for the survival and proliferation of the tumour cells.

The study opened in January 2012 and 90 patients were enrolled in different centres in the UK and in France, with 28 coming from Leicester. Patients with CLL showed the best response and most of them were still on the study after 3 years, and remarkably without notable toxicities.

In the new paper, we are reporting the long-term follow-up results. This work, published in the journal Blood, was funded by the Ernest and Helen Scott Haematological Research Institute, ONO Pharmaceuticals, Gilead Pharmaceuticals and the Cancer Research UK Leicester Experimental Cancer Medicine Centre. Local charity Hope Against Cancer fund the Clinical Trials Facility based at the Leicester Royal Infirmary.

This current paper describes the long term follow up and shows that in patients with CLL the remissions are durable and associated with no new toxicities. Furthermore, in collaboration with Sistemas Genomicos, a company in Valencia, we have shown that mutations associated with aggressive disease respond well to treatment with ONO/GS-4059.

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Intermittent Fasting Inhibits Cancer Cells in Childhood Leukemia ALL

MedicalResearch.com Interview with:

Chengcheng (Alec) Zhang, Ph.D. Associate Professor Hortense L. and Morton H. Sanger Professorship in Oncology Michael L. Rosenberg Scholar for Medical Research Department of Physiology  UT Southwestern Medical Center

Dr. Alec Zhang

Chengcheng (Alec) Zhang, Ph.D.
Associate Professor
Hortense L. and Morton H. Sanger Professorship in Oncology
Michael L. Rosenberg Scholar for Medical Research
Department of Physiology
UT Southwestern Medical Center

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

Response: New therapeutic targets and approaches are needed to effectively treat leukemia. Acute myeloid leukemia (AML) is the most common form of adult acute leukemia whereas acute lymphoblastic leukemia (ALL) is the most common form of cancer in children; ALL also occurs in adults. Although treatment of pediatric ALL is highly effective, a sizeable number of patients are non-responders who succumb to this disease. The outcome of ALL in adults is significantly worse than for pediatric ALL. Additionally, some types of ALL have a much poorer prognosis than others.

Dietary restriction, including fasting, delays aging and has prolonged effects in a wide range of organisms and has been considered for cancer prevention. In certain types of solid tumor,_ENREF_1 dietary restriction regimens are able to promote T cell-mediated tumor cytotoxicity and enhance anticancer immunosurveillance, and coordinate with chemotherapy to promote the anti-cancer effects. However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown. Furthermore, whether dietary restriction alone can inhibit cancer development is not clear.

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Novel Relapse Markers Identified in Pediatric ALL

MedicalResearch.com Interview with:
Jason Saliba PhD

Perlmutter Cancer Center
New York University Langone Medical Center
New York, NY

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

Response: The outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically over the last four decades, but the prognosis for those who relapse remains dismal, especially for those who relapse while on therapy. In fact, relapsed disease remains a leading cause of cancer related mortality in children. To date, various studies have discovered a number of somatic alterations that contribute to driving relapse and have provided profound insight into the selective forces that lead to clonal outgrowth of drug resistant populations. However, the timing of the initial emergence of the driving mutations along with the speed of clonal outgrowth is unknown.

Whole exome sequencing (WES) was run on available diagnosis, germline (remission), and relapse samples collected from thirteen pediatric ALL patients treated according to Nordic NOPHO ALL protocols. Analyses were then performed to find somatic missense mutations enriched in the relapse samples versus their patient matched diagnosis and/or germline samples. Candidate relapse driving missense mutations were identified as present at high levels (>20%) in the relapse sample, but were undetectable in germline or low to absent in the diagnosis sample. Eight of the thirteen patients contained mutations in genes previously reported to be enriched at relapse. Interestingly, a majority of the patients contained novel candidate relapse specific genes involved in a wide array of cellular processes such as cell adhesion/migration, RNA polymerase II/transcription, circadian rhythm, the unfolded protein response, RNA transport, epigenetic regulation, DNA methylation, and kinases.

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