Acute Myeloid Leukemia: LSD1 Inhibition In Combination With Azacitidine in the Elderly

MedicalResearch.com Interview with:

Dr Carlos Buesa

Dr Buesa

Dr. Carlos Buesa PhD
Chief Executive Officer
Oryzon Genomics 

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

Response: Lysine specific demethylase 1 (LSD1, also known as KDM1A) is a histone modifying enzyme that removes methyl groups, thereby regulates the expression of many genes important in cancer progression and cell proliferation.

Aberrant expression of LSD1 has been shown in many types of cancers. In particular, LSD1 expression is upregulated in bladder, small cell lung (SCLC), and colorectal clinical cancer tissues when compared with the corresponding nonneoplastic tissues. LSD1 has also been shown to be overexpressed in some breast cancers and may function as a biomarker of the aggressiveness of the disease.

However, the function of LSD1 is most understood in acute leukemia, particularly Acute Myeloid Leukemia and Acute Lymphoblastic leukemia. LSD1 is crucial for the function and maintenance of the leukemic stem cells, a subset of malignant cells that is believed to be the ultimate reason for relapse in these patients. LSD1 inhibition might be a therapeutic solution to avoid those relapses.

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Children with High Risk AML: Intensification of Induction II Chemotherapy and Liberalization of Stem Cell Donor Source does not Improve Outcomes

MedicalResearch.com Interview with:
Joseph Germino, M.D., PhD
Vice President US Medical Affairs Oncology
Bayer Healthcare Pharmaceuticals
Whippany, N.J. 07981

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

Response: Sorafenib (Nexavar®) is an oral anticancer therapy approved in more than 100 countries worldwide. It is approved for the treatment of patients with advanced hepatocellular carcinoma (HCC); advanced renal cell carcinoma (RCC) who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy; progressive, locally advanced or metastatic differentiated thyroid carcinoma (papillary/follicular/Hürthle cell), that is refractory to radioactive iodine (RAI).

The AAML 1031 is a recently completed Phase III clinical trial evaluating the use of bortezomib and sorafenib in patients 30 years or younger with newly diagnosed acute myeloid leukemia (AML).

At the 2019 ASCO Annual meeting, results of a report from the AAML1031 trial, which assessed whether intensification of Induction II chemotherapy (ADE or AraC/ Mitoxantrone) and liberalized stem cell transplant (SCT) donor source criteria improved clinical outcomes in patients with residual AML.  Continue reading

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

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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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Novel Strategy May Lead To Elimination Of AML Stem Cells

Dr. Alec (Chengcheng) Zhang Michael L. Rosenberg Scholar in Medical Research Associate Professor of Physiology and Developmental Biology Member of the Harold C. Simmons Comprehensive Cancer Center UT Southwestern Medical CenterMedicalResearch.com Interview with:
Dr. Alec (Chengcheng) Zhang
Michael L. Rosenberg Scholar in Medical Research
Associate Professor of Physiology and Developmental Biology, Member of the Harold C. Simmons Comprehensive Cancer Center
UT Southwestern Medical Center

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

Response: Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. Treatments for AML yield poor outcomes, especially for the typical senior patients. The medical need for new therapies for AML is underscored by the fact that no new therapies for AML have been approved in over 30 years. There are over 50 experimental agents in clinical trials for the treatment of AML today, although only a few agents have promising data to date. New molecular targets and therapeutic strategies are needed for AML treatment.

In 2012, we published a paper showing that we cloned the human leukocyte immunoglobulin-like receptor B2 (LILRB2) as a receptor for several angiopoietin-like proteins (Angptls) (Zheng et al 2012 Nature 485:656-660). The LILRB family receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and are classified as inhibitory receptors because ITIM motifs can recruit phosphatases SHP-1, SHP-2, or SHIP to negatively regulate immune cell activation. Surprisingly, in that work, we showed that PirB, the mouse ortholog of LILRB2, is expressed by AML stem cells (AML-SCs) and supports AML development. Although counterintuitive, this result is consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system.

In the current paper, we continued the research and report that a number of receptors containing the ITIMs are crucial for the development of AML. We mainly focus on studying the function and downstream signaling of LAIR1 as a representative ITIM-containing receptor. We found that the deletion of LAIR1 does not affect normal hematopoiesis but abolishes leukemia development in several different mouse leukemia models. We also identified a mechanism by which LAIR1 supports AML development, showing that the LAIR1/SHP-1/CAMK1/CREB pathway sustains the survival and self-renewal of AML cells. Importantly, our findings are well supported by bioinformatics analysis of AML patient databases and experimental results of human leukemia cells. Since certain ITIM-containing receptors are essential for AML cells but not critical for normal hematopoiesis, and blocking their signaling can boost immunity, these ITIM-containing receptors including LAIR1 represent ideal targets for treating AML.

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