Novel Subtypes in B Progenitor Acute Lymphoblastic Leukemia

MedicalResearch.comInterview with:

Zhaohui Gu, PhD
Postdoctoral Research Associate
 St. Jude Children’s Research Hospital, TN

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

Response:B-progenitor acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy and the leading cause of childhood cancer death. B-ALL includes multiple subtypes that are defined by distinct genetic alterations and that play an important role in diagnosis, prognosis and therapy of patients.  Advances in transcriptome sequencing (RNA-seq)have helped researchers discover additional subtypes and driver mutations inB-ALL and identify possible new therapeutic targets.  Still, up to 30% of B-ALL cases do not fit into established subtypes. These patients lack targeted therapeutic approaches and commonly relapse.

Fort his study, we used integrated genomic analysis of 1,988 childhood and adult cases to revise the classification system of B-ALL. The system includes eight new subtypes and a total of 23 B-ALL subtypes. The subtypes are defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations. Many show a marked variation in prevalence according to age.

The newly identified subtypes included one (n=18) defined by rearrangements of gene BCL2, MYC and/or BCL6 anda distinctive gene expression profile (GEP). Patients in this subtype were mostly adults (n=16) with very poor outcomes.

Another novel subtype was defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to disrupt IKZF1 function, with distinct nuclear mis-localization and induction of aberrant intercellular adhesion. There were eight cases in this subtype that shared highly similar GEPs.

We also identified two subtypes with distinct GEP and characterized by PAX5 alterations. One, PAX5 altered (PAX5alt), included 148 cases. PAX5alt was characterized by diverse PAX5 alterations including rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic amplifications (n=8). These PAX5 alterations were found in 73.6% of PAX5alt cases. The second distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. Bi-allelic PAX5 alterations were commonly seen in this subtype in the form of PAX5 P80R coupled with a second sequence mutation or deletion of the wild-type PAX5 allele.

Adult PAX5 P80R cases showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). In addition, Pax5 P80R heterozygous and homozygous mice developed B lineage leukemia with a median latency of 166 and 87 days, respectively.  The heterozygous mice acquired alterations on the second allele, which faithfully recapitulated the condition of the patient leukemia.

MedicalResearch.com: What should readers take away from your report?

Response: Identification of subtypes accurately is very important for diagnosis, intensity-tailored therapy, and to identify targetable lesions. In this large scale genomic study, we demonstrated the power of using RNA-seq to classifying B-ALL and established a revised B-ALL taxonomy with 23 distinct subtypes. We identified 8 novel subtypes, including two defined by PAX5 alterations. Through in vitro and in vivo experiments, we demonstrated that PAX5 P80R could impair B cell differentiation and initiate leukemia.

Together with the subtype defined by IKZF1 N159Y mutation, we showed for the first time that transcription factor missense mutations could be a subtype defining genetic lesions.

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Phase I Study T-cell Bispecific Antibody For Aggressive Non-Hodgkin’s Lymphoma

MedicalResearch.com Interview with:

Dr-Nancy Valente

Nancy Valente, M.D.,
Vice President, Global Hematology Development
Genentech

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

Response: Despite advances in treatments for people with relapsed or refractory (R/R) NHL, a substantial number of patients do not sustain a response to standard-of-care treatment, meaning new options are needed. For example, as many as 40 percent of people with diffuse largeB-cell lymphoma (DLBCL), an aggressive form of NHL, eventually relapse after initial treatment. Different mechanisms of action and different therapy combinations may help improve clinical outcomes in patients with R/R NHL.

At ASH, we presented initial safety and efficacy results from a Phase I study of our T-cell bispecific antibody, CD20-TCB, as a monotherapy in patients with R/RNHL.

MedicalResearch.com: What are the main findings?

Response: The preliminary results suggest thatCD20-TCB monotherapy have promising clinical activity and may induce durable complete responses in patients with late-line R/R aggressive NHL. In patients with aggressive NHL who received the highest tested dose roughly half (53 percent) of patients responded (objective response rate)to treatment and nearly a third (27 percent) saw the disappearance of all signs of cancer (complete response). Importantly, all complete responses have been sustained so far, with a median follow up of roughly three months (94 days). These responses are particularly encouraging since aggressive forms of NHL become harder to treat with each relapse.

Patient sin the study had previously received a median of three lines of therapy, with a range of 1-13 lines. Most were refractory to their most recent therapy (72percent) and refractory to prior treatment with an anti-CD20 antibody (74percent).

MedicalResearch.com: What should readers take away from your report?

Response: CD20-TCB is one of two bispecific antibodies we are developing that are designed to target CD20 and CD3. At ASH, we also presented data for mosunetuzumab. The results from the first clinical trials of these bispecific antibodies showed promising clinical activity and durable complete responses inpatients with R/R NHL. We are excited by the potential to harness the dual-targeting ability of CD20-CD3 bispecific antibodies to treat blood cancers and encouraged by these early results. We continue to study CD20-TCB and mosunetuzumab as potential new treatment options for patients with R/R NHL, an area of high unmet need.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Bispecific antibodies can recognize and bind to two different targets simultaneously, and in doing so, combine the binding specificity of two antibodies in one molecule. In the treatment of cancer, bispecific antibodies are designed to physically link a cancer cell to an immune cell which leads to the destruction of the cancer cell by the patient’s immune system, representing a novel approach for the treatment of cancers.

Citation:
CD20-Tcb (RG6026), a Novel “2:1” FormatT-Cell-Engaging Bispecific Antibody, Induces Complete Remissions inRelapsed/Refractory B-Cell Non-Hodgkin’s Lymphoma: Preliminary Results from aPhase I First in Human Trial

ASH 2018, December 1, 2018: 4:45 PM

MartinHutchings, MD, PhD1*,Gloria Iacoboni, MD2*, Franck Morschhauser,MD3*, Fritz Offner, MD4, AnnaSureda, MD5*, Gilles Andre Salles, MD, PhD6,Carmelo Carlo-Stella, MD7,Joaquin Martinez Lopez, MD8*,Denise Thomas, BS9*, Peter N Morcos, PhD10*, BetsyQuackenbush, MD9*, Cristiano Ferlini, MD11*,Marina Bacac, PhD12*, Ann-Marie E. Broeske,PhD13*, Natalie Dimier, PhD14*, TomMoore, MD11*, Martin Weisser, MD15* andMichael Dickinson, MBBS, FRACP, FRCPA16

https://ash.confex.com/ash/2018/webprogram/Paper110207.html

Dec 11, 2018 @ 11:08 pm

The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.

Data Support Venclexta Combinations As New Treatment Option for AML

MedicalResearch.com Interview with:

Nancy Valente, M.D.,
Vice President, Global Hematology Development
Genentech

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

Response: Acute myeloid leukemia, or AML, is a particularly aggressive blood cancer with the lowest survival rate for all types of leukemia.

Many people with this disease are unable to tolerate intensive induction chemotherapy, so additional treatment options are needed and welcomed in this patient population.

At ASH, we presented updated data from two Phase Ib/II studies with longer follow up for Venclexta combinations. These data supported the recent accelerated approval of Venclexta by the FDA for people newly-diagnosed with AML who are unable to tolerate aggressive therapies.

These updated results showed that Venclexta demonstrated complete remission rates (with at least partial blood count recovery, CR+CRh) of 67 percent and 71percent when used in combination with azacitidine or decitabine, respectively ,and 54 percent when used in combination with low-dose cytarabine (LDAC). These responses were durable with a median duration of response of 16 months for patients treated with Venclexta plus azacitadine and 8 months for those treated with Venclexta plus LDAC.

AML is a difficult-to-treat disease and these Venclexta combinations represent an important new treatment option for patients. Venclexta has been granted four breakthrough therapy designations by the FDA, two in AML and two in chronic lymphocytic leukemia (CLL).

MedicalResearch.com: What should readers take away from your report?

Response: These results further support Venclexta combinations as a new treatment option for people with AML. Venclexta is the first and only FDA-approved medicine designed to selectively bind and inhibit the BCL-2 protein, which helps trigger a natural process that helps cells self-destruct. It represents a new way to help people who have not received treatment for this aggressive type of blood cancer and are unable to tolerate intensive induction chemotherapy.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: A robust clinical development program for Venclexta in AML is ongoing, including two ongoing Phase III studies (Viale-A,Viale-C) evaluating Venclexta in combination with azacitidine or with LDAC for people with previously untreated AML who are ineligible for intensive chemotherapy. This is part of a larger development program for Venclexta in multiple blood cancers including CLL, multiple myeloma and non-Hodgkin’s lymphoma (NHL).The benefit of Venclexta has already been demonstrated in adults with previously treated CLL, with or without 17p deletion, with its approval in the U.S. and EU.

Citation:

Venetoclaxin Combination with Hypomethylating Agents Induces Rapid, Deep, and DurableResponses in Patients with AML Ineligible for Intensive Therapy

ASH 2018 Sunday, December 2, 2018: 8:00 AM

https://ash.confex.com/ash/2018/webprogram/Paper117179.html

Dec 11, 2018 @ 10:46 pm

The information onMedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.

XARELTO® Associated With a Decreased Risk of Recurrent VTE

MedicalResearch.com Interview with:

Paul Burton MD, PhD, FACC Vice President, Medical Affairs Internal Medicine Janssen Scientific Affairs, LLC.

Dr. Burton

Paul Burton MD, PhD, FACC
Vice President, Medical Affairs
Internal Medicine
Janssen Scientific Affairs, LLC.

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

Response: More than 900,000 Americans experience a venous thromboembolism (VTE) each year, with about one-third of these occurrences being fatal. Once a person experiences a VTE, they are at increased risk of a repeat occurrence. Guidelines currently recommend standard anticoagulant therapy with a Factor Xa inhibitor, like XARELTO® (rivaroxaban), for three months or longer. For those people who have had a VTE and stop anticoagulant therapy, as many as 10 percent of them will experience another VTE within one year and 20 percent within three years.

This study examined extended use of XARELTO® after the recommended three-month treatment period in patients who experienced an initial VTE, showing XARELTO® was associated with a decreased risk of recurrent VTE with no increase in major bleeding during this time period.  Continue reading

ASH18: RNA Sequencing Identifies More Subtypes of Childhood Leukemia

MedicalResearch.com Interview with:

Charles G. Mullighan, MBBS (Hons), MSc, MD Member, St. Jude Faculty Co-Leader, Hematological Malignancies Program Medical Director, St. Jude Biorepository William E. Evans Endowed Chair St. Judes Children’s Research Hospital Memphis, TN

Dr. Mullighan

Charles G. Mullighan, MBBS (Hons), MSc, MD
Member, St. Jude Faculty
Co-Leader, Hematological Malignancies Program
Medical Director, St. Jude Biorepository
William E. Evans Endowed Chair
St. Judes Children’s Research Hospital
Memphis, TN

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

 

Response: B-lineage acute lymphoblastic leukemia (B-ALL) is the commonest form of ALL, and the commonest childhood tumor. It is a leading cause of childhood cancer death. It consists of multiple subtypes defined by genetic alterations. These are often chromosomal translocations that deregulate oncogenes or form fusion proteins. These alterations are disease initiating events and are associated with distinct patterns of leukemic cell gene expression. Most subtypes also have additional mutations that are important for cells to become fully leukemic.

Identifying these initiating genetic changes is very important to identify patients that are likely to respond or do poorly with conventional therapy (multiagent chemotherapy). Also, some identify new opportunities for targeted therapy. However, using standard genetic testing approaches such as chromosomal cytogenetics, about 30% of B-ALL patients don’t have a subtype classifying alteration.

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Healthcare Costs in Patients with Cancer Rise with Increasing Risk of Venous Thromboembolism

MedicalResearch.com Interview with:

Paul Burton MD, PhD, FACC Vice President, Medical Affairs Internal Medicine Janssen Scientific Affairs, LLC.

Dr. Burton

Paul Burton MD, PhD, FACC
Vice President, Medical Affairs
Internal Medicine
Janssen Scientific Affairs, LLC.

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

Response: Despite being largely preventable, venous thromboembolism (VTE) is the second leading cause of death in people with cancer. The risk of VTE is five times greater in people with cancer than those without cancer, and that risk is magnified in those receiving certain types of chemotherapy, in the newly diagnosed and in those with more advanced, metastatic disease. This 6,194-patient study examined economic burden associated with VTE, and found patients newly diagnosed with cancer who are at a higher risk of a VTE had significantly higher all-cause and VTE-related health care costs compared to patients with a lower risk of VTE. Continue reading

Lower Overall Costs with Rivaroxaban (XARELTO® ) vs Warfarin Among Morbidly Obese Patients with Venous Thromboembolism

MedicalResearch.com Interview with:

Paul Burton MD, PhD, FACC Vice President, Medical Affairs Internal Medicine Janssen Scientific Affairs, LLC.

Dr. Burton

Paul Burton MD, PhD, FACC
Vice President, Medical Affairs
Internal Medicine
Janssen Scientific Affairs, LLC.

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

Response: Treatment of venous thromboembolism (VTE) is complicated among morbidly obese patients. Current guidelines do not recommend use of Factor Xa inhibitors in these patients due to limited clinical data available. That’s why Janssen undertook this study to examine XARELTO® (rivaroxaban) in these patients. In this 5,780-patient retrospective study, results found patients treated with XARELTO® had a similar risk of recurrent VTE and major bleeding compared to those taking warfarin.

However, treatment with XARELTO® was associated with less all-cause health care resource utilization (HCRU) (e.g., inpatient hospitalizations and outpatient visits) and reduced total medical costs compared to warfarin. Of note, patients taking XARELTO® had an average $2,829 lower total medical costs per patient per year (PPPY) than those taking warfarin, which was mainly driven by lower hospitalization costs. Continue reading

How Do Patients With Multiple Myeloma Weight Treatment Options?

MedicalResearch.com Interview with:

Caroline McKay, PhD Real World Value & Evidence, Oncology Janssen Scientific Affairs

Dr. McKay

Caroline McKay, PhD
Real World Value & Evidence, Oncology
Janssen Scientific Affairs

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

Response: Considering patient preferences in treatment decision-making in oncology is growing in importance. While recent introduction of new treatments for multiple myeloma have improved survival and the possibility of sustaining longer remission periods, regimen options still vary with respect to efficacy, safety, and dosing.

Therefore, patients and providers must consider tradeoffs inherent in making treatment decisions that are growing in complexity. Despite this, there is a lack of research describing patient preferences within the context of currently available treatment regimens. To address this gap, this study examined how multiple myeloma patients evaluate, or weigh, treatment options. Key findings from the research are that treatment preferences do not appear to be static, but instead suggest that the relative importance of treatment attributes may change over time and treatment history.

Further, patients place higher importance on overall survival and progression-free survival than other treatment attributes, and may be willing to accept an increase in the risk of serious side effects and reduced convenience in exchange for greater efficacy; however, when efficacy is comparable, patients appear to place greater weight on dosing frequency than on the duration of treatment administration, i.e., more frequent dosing appears to be less preferable to patients than longer administration/infusion time.  Continue reading

The Medalist Trial: Luspatercept Reduced Transfusion Need in Some Myelodysplastic Syndromes

MedicalResearch.com Interview with:

Dr. Alan List MD President and Chief Executive Officer Moffitt Cancer Center Tampa, FL

Dr. List

Dr. Alan List MD
President and Chief Executive Officer
Moffitt Cancer Center
Tampa, FL

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

Response: In patients with lower risk Myelodysplastic Syndromes (MDS), which accounts for the vast majority of patients with MDS overall, the most common symptomatic cytopenia is anemia. These patients, overtime, become dependent upon red blood cell transfusions and with that, they face a risk of iron loading as well as complications that occur with it. The standard first line therapy that we consider for these patients is erythropoietin-stimulating agents (ESAs). Patients who are transfusion dependent have a low response rate to ESAs, and responses are of short duration. There limited effective limited treatment options for those patients unresponsive or lose response to ESAs.

For years, we’ve known that the transforming growth factor (TGF)-β pathway play an important pathogenetic role in suppressing red cell maturation and cell survival.

Luspatercept is an agent that acts as an erythroid maturation agent by inhibiting the TGF-β signaling pathway by neutralizing a select group of TGF-β superfamily ligands.  Continue reading

Alcyone Trial: DaraVMP New Standard for Transplant-Ineligible Newly Diagnosed Multiple Myeloma

MedicalResearch.com Interview with:

Maria-Victoria Mateos, MD, PhD Associate Professor of Medicine  University of Salamanca Salamanca, Spain

Dr. Mateos

Maria-Victoria Mateos, MD, PhD
Associate Professor of Medicine
University of Salamanca
Salamanca, Spain

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

Response: Alcyone trial is a phase 3 trial in which Daratumumab, the CD38 mAb has been added to a standard of care for elderly newly diagnosed myeloma patients, VMP, and compared with VMP. The main finding is that the addition of dara to VMP resulted into a significant benefit in PFS with a 57% reduction in the risk of progression and/or death. In addition, the benefit was also reported in terms of ORR and CR rate and 45% of patients receiving Dara VMP achieved CR. Minimal residual disease was evaluated and was undetectable in 27% of the patients what it is relevant because a 5% increase was observed in comparison with the publication one year ago. This means that Daratumumab as maintenance after the first 9 cycles daraVMP was able to upgrade the quality of response. Toxicity profile was acceptable and no new safety signals were reported. Continue reading

Experimental Luspatercept Reduced Need For Transfusions in Beta Thalassemia

MedicalResearch.com Interview with:

Maria Domenica Cappellini, M.D. Principal Investigator, BELIEVE Clinical Trial Fondazione IRCCS Ca’ Granda Policlinico Hospital University of Milan, Milan, Italy

Dr. Cappellini

Maria Domenica Cappellini, M.D.
Principal Investigator, BELIEVE Clinical Trial
Fondazione IRCCS Ca’ Granda Policlinico Hospital
University of Milan, Milan, Italy

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

Response: Beta thalassemia is a severe, inherited hemoglobinophathy due to a reduced production of hemoglobin. Standard of care is blood transfusion and iron chelation to remove the accumulated iron by transfusion. This is a very demanding treatment.

Therefore, there is the need to find new approaches for treating these patients. The BELIEVE study showed that the experimental drug luspatercept significantly reduced the need for blood transfusions in patients with beta thalassemia. More than 70 percent of patients who received luspatercept were able to cut blood transfusions by at least one-third over any consecutive 12-week period Continue reading

ASH18: CENTAURUS Study Evaluates Dosing Schedule of DARZALEX® (daratumumab) for High Risk Smoldering Multiple Myeloma

MedicalResearch.com Interview with:

Peter Voorhees, MD Plasma Cell Disorders Program Department of Hematologic Oncology and Blood Disorders Levine Cancer Institute Atrium Health

Dr. Vorhees

Peter Voorhees, MD
Plasma Cell Disorders Program
Department of Hematologic Oncology and Blood Disorders
Levine Cancer Institute
Atrium Health

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

Response: All multiple myeloma arises from its precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Although the rate of progression to multiple myeloma for patients with MGUS is low (~5% over 5 years), patients with SMM have a ~50% likelihood of requiring therapy for their multiple myeloma within the first 5 years of diagnosis. For those at intermediate to high risk of disease progression, early intervention to delay progression of disease, thereby averting disease-related morbidities related and potentially changing the natural course of the disease, is highly desirable.

On the other hand, given the fact that these patients are by definition asymptomatic and would otherwise be monitored off treatment, it is critical that any intervention applied in this group of patients is well tolerated. Daratumumab is a highly attractive candidate in this particular space, because it has single agent activity in heavily-pretreated relapsed/refractory multiple myeloma and a favorable side effect profile relative to many other myeloma therapeutics. Additionally, given the importance of impaired immune surveillance in multiple myeloma, the immuno-stimulatory effects of daratumumab in the bone marrow microenvironment could potentially reawaken robust T cell responses to the disease.

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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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