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Tuesday, September 18, 2018

Q&A With Clive Zent, MD, on Chronic Lymphocytic Leukemia

​Clive Zent, MD, from Wilmot Cancer Institute offers a closer look at his recent research, "Management of melanoma in patients with chronic lymphocytic leukemia," which was featured in HemOnc Times' Research Minute. Learn more about the study and its potential clinical implications.

What prompted this research?

Skin cancers including malignant melanoma are known to be significantly more common in patients with chronic lymphocytic leukemia (CLL). We wanted to 1) determine the incidence and prevalence of melanoma in a stable regional CLL population and 2) assess the effectiveness of our policy of routine surveillance for skin cancers designed for early detection of melanomas to increase the rate of curative surgical treatment.

Can you describe the methodology?

This was an observational study using an established CLL database with 470 patients with CLL seen at the Wilmot Cancer Institute contributing 2,849 person-years of data.

What are the key findings?

Eighteen (3.8%) patients had 22 melanomas. Fourteen (3%) patients had invasive melanoma ( stage I)with a standardized incidence ratio of 6.3 (95% confidence interval 3.5-10.6) compared to an age and sex matched non-CLL SEER control population.

Most patients (n=14) were diagnosed with non-advanced stage melanoma and treated surgically. Four patients had advanced stage melanoma and one of these patients with progressive high-risk CLL (deletion of 17p13) had a sustained response (ongoing at 29 months from diagnosis of melanoma) on treatment with ibrutinib and pembrolizumab.

What (if any) are the limitations of this study?

  • This observational study included some retrospectively collected data that can be incomplete and less accurate.
  • The small number of patients with melanoma precludes more detailed analysis of the relationship between CLL and melanoma.
  • Doing the research at a referral center could have biased the results.

What are the implications of this research?

CLL patients are at significantly increased risk of malignant melanoma which can occur at any time during the course of their disease. Early detection of melanoma improves outcome. Regular skin evaluations by a dermatologist can lead to curative surgical therapy of non-advanced stage melanoma. Combination targeted therapy for patients with both CLL and advanced stage melanoma can be effective.

CLL patients need to be educated early and often about the increased risk of melanoma. Patients and their families need to learn how to decrease the risk of melanoma by avoiding excessive UV light exposure and active monitoring by a dermatologist supplemented by frequent self-examinations. ​

Tuesday, September 18, 2018

Discussion on the Role of Immunotherapy in ALL

There has been significant success in the treatment of pediatric acute lymphoblastic leukemia (ALL) patients, however the same cannot be said about the adult population. Why is this case? Reasons include chemotherapy-related toxicities in adult patients as well as biological difference in pediatric disease.

Andrew Pham, MD, a hematology/oncology expert at Scripps Clinic in San Diego discusses the state of immunotherapy in ALL. Check out his insights below and read, "The Bold World of Immunotherapy for Acute Lymphoblastic Leukemia" in the September 20 issue of HemOnc Times to learn more!

"Current immunotherapies are extremely effective in terms of efficacy when compared to prior chemotherapies," Pham explained. "Generally, this is best demonstrated in the second-line setting once patients have relapsed; under these situations, chemotherapy has generally failed to produce a significant response.

"For these patients, immune therapies have shown to still be extremely effective," he explained, "specifically, CAR T-cell therapy has been shown to have remission rates of up to 80 percent, which is unprecedented, especially in the relapsed and refractory setting. However, these results come with a different slew of [adverse events], notably CRS and neurotoxicity, which have been well-documented."

Most Commonly Employed Immunotherapies Utilized in ALL

"In terms of practicality, currently, antibody-drug conjugate or BiTE therapy are most widely used for ALL in the relapse/refractory setting," Pham said. Regarding these therapies' shortcomings, he noted, "Significant toxicities are associated with these drugs, sometimes limiting their use. Notably, veno-occlusive disorder is widely associated with the use of inotuzumab ozogamicin and blinatumomab."

Recent Developments in CAR-T Therapy

"Much of the advances in CAR T-cell therapy thus far have been to combat the severe adverse effects; knowledge and management regarding CRS has grown substantially," Pham noted.

There are areas for further development for CAR-T therapy. "An aspect of which we have to further improve includes targeting mechanisms of resistance that have developed. A known mechanism of resistance has been the loss of CD19 or a truncated CD19 receptor, which renders CAR T cells ineffective," according to Pham. "The introduction of a CD22 CAR T-cell therapy may be the solution to this. In addition, current checkpoint inhibitors are now being incorporated to overcome checkpoint blockade that develops as another mechanism of resistance."

Recent Immunotherapy-Based Studies for ALL

"There are numerous clinical trials underway to look at the combination of different immunotherapies with upfront standard chemotherapy, including the use of inotuzumab ozogamicin and blinatumomab, usually in a sequential fashion with first-line therapy," Pham explained.

"In addition, these therapies are being evaluated in the consolidative setting as well," he continued. "CAR T-cell therapy, given its known toxicity and adverse side effects, is generally reserved for the relapsed/refractory disease setting and clinical trials are also available, further evaluating its usage."

Don't miss more insights from Dr. Pham. Read HemOnc Times now!

Thursday, August 30, 2018

Research May Lead to New Treatment Approaches for Early, Smoldering Myeloma

​For many people diagnosed with smoldering multiple myeloma – a condition that is often a precursor to myeloma – the shock of the diagnosis can be compounded by the distress of learning they won't receive treatment until physical symptoms of myeloma develop.

Now, Dana-Farber Cancer Institute scientists and an international team of researchers have tracked the genomic changes that occur as smoldering multiple myeloma (SMM) advances to myeloma (Nat Commun 2018; doi:10.1038/s41467-018-05058-y). Their findings lay the groundwork for tests that can identify patients whose SMM is likely to progress rapidly to myeloma, and who could benefit from prompt treatment. Patients with SMM that has a longer lead time to myeloma could be candidates for preventive treatments.

The research showed that SMM can progress by two distinct patterns: one in which the genetic makeup of SMM tissue doesn't change much in becoming myeloma; and one in which the transition to myeloma is marked by the appearance of new, genetically distinct groups of myeloma cells. The first type, dubbed the static progression model, tends to progress fairly quickly to myeloma. The second, called the spontaneous evolution model, usually takes longer.

The findings have implications not only for how patients with SMM are treated but for how multiple myeloma is defined, noted the senior author of the study, Nikhil Munshi, MD, of Dana-Farber. "Traditionally, a diagnosis of myeloma requires not only the presence of myeloma cells but also the development of symptoms such as anemia, bone disease, too much calcium in the blood, and kidney malfunction. Treatment generally doesn't begin until symptoms appear," he explained. "Our study shows, however, when the disease follows the static progression model, SMM is, from a genomic standpoint, myeloma. The advance of the disease is solely a matter of an accumulation of diseased tissue. For such patients, it may make sense to begin treatment soon.

"In the spontaneous evolution model, by contrast, SMM is genomically distinct from myeloma," Munshi continued. "It advances toward myeloma only when genetic mutations create new subsets of SMM cells that develop into myeloma. Treatment for such patients might involve agents that prevent such subsets from arising."

Currently, there is no way of determining whether a patient's SMM is likely to follow the static progression or spontaneous evolution model, according to Munshi, but he and his associates are conducting research in that area. Making such distinctions would be crucial to selecting the appropriate treatment for individual patients.​

Before & After Analysis

The study began with blood samples from 11 patients with SMM, all of whom went on to develop multiple myeloma over the next 3-plus years. Researchers took one set of samples when patients had SMM and a second set when they were diagnosed with myeloma, and analyzed the complete genome of the myeloma cells, looking for differences between those in the myeloma set and those in the SMM set.

They found that the genomic composition of cells at the smoldering stage is very similar to that of myeloma cells, and that the course of the disease follows either the static progression or spontaneous evolution model.

The investigators also uncovered some of the processes that foul the genome of myeloma cells at key points in the development of the disease. Myeloma originates in plasma cells, which are white blood cells responsible for producing disease-fighting antibodies. As genetic mutations and other molecular derangements accumulate in the cells, they begin to grow out of control and crowd out normal, healthy cells, eventually producing the symptoms associated with myeloma.

Munshi and his colleagues found that an enzyme called activation-induced cytidine deaminase (AID), which plays a role in the development of plasma cells, is overactive early in the myeloma process, producing some of the first mutations plasma cells experience. The researchers also found that enzymes known as APOBEC cytidine deaminases become overactive at a later stage – triggering genetic changes as the disease progresses to myeloma.

"Our findings have provided important insights into the patterns of myeloma progression and into some of the mechanisms responsible for the genomic changes that occur as the disease advances," Munshi remarked. "These results suggest that multiple myeloma needs to be redefined to include some patients with smoldering myeloma, and points the way to new treatment approaches geared to the course of disease development in each patient."

Thursday, August 23, 2018

Research Points to Potential Treatment Targets for Aggressive Leukemia

​When a dangerous defect on chromosome 11q23 disrupts the genetic programming of blood cells, it causes acute myeloid leukemia (AML). With a dismal survival rate of 20-40 percent and desperate need for better treatments, scientists at Cincinnati Children's report finding a potential therapeutic target for AML in preclinical laboratory tests on donated human cells and mice (J Exp Med 2018; doi:10.1084/jem.20171312).

When scientists blocked the target molecule on human AML cells in combination with other known AML treatments, the cancerous blood cells died and were replaced by regenerating, healthy white blood cells, according to principal investigator H. Leighton Grimes, PhD, and study first author Sara Meyer, PhD, a former member of the Grimes laboratory.

The target molecule is F-box protein S-phase kinase-associated protein 2 (Skp2). Skp2 degrades another protein called p27Kip1 that is important to the formation of healthy blood cells.

While the study's findings are not ready for clinical application, according to Grimes, they do suggest the possible development of effective targeted therapies for AML.

"Our work provides a complete mechanistic look into the function of genetic and molecular programs driving this leukemia, and it exploits these processes to identify actionable therapeutic targets,'' said Grimes, Director of the Cancer Pathology Program at Cincinnati Children's. "We still have extensive additional testing to conduct in laboratory animal models of AML before knowing if this approach will translate to patient care."

Dangerous Pairs

Abnormalities on 11q23 cause the fusion of harmful genes in aggressive AML -- the Mixed-Lineage Leukemia (MLL) gene and a multitude of other genetic partners. In this study the investigators closely analyzed MLL-AF9, which includes the AF9 gene, a frequent partner in AML.

One reason AML is so hard to treat is it aggressively re-emerges after initial therapy, which appears at first to diminish the disease in blood cells. But AML is refueled by so-called leukemia stem cells (LSCs) -- precancerous blood cells that wait in the wings to evade treatment before launching a full-blown recurrence of disease.

Researchers report they were able to identify and disable the genetic and molecular programming that transform LSCs into AML. But getting to this point required extensive molecular detective work.

Clues in Patient Cells

Extensive biochemical analysis of AML cells donated by patients gave the researchers comprehensive information about the targets and functions of the miR-196 molecular signaling pathway in AML, which the authors said had largely been unknown. The miR-196 microRNA includes a family of microRNAs that help regulate other molecular targets in the cell nucleus. Those other targets depend on the type of cell in which the microRNA is functioning, according to Grimes.

The researchers inserted mimics of the microRNA miR-196 into MLL-AF9 leukemia cells to incorporate them into the cellular machinery. Mimics are strands RNA molecules designed to imitate natural miRNA molecules. Researchers then lysed the cells for analyses, which identified molecular targets of miR-196 in the leukemia cells.

After identifying miR-196 targets, the researchers genetically screened for miR-196 targets in AML cells in mice. These experiments concluded that certain microRNA targets are more important than others in the maintenance and spread of the LSCs that transform into malignant disease.

Additional testing on the cells included computer-assisted analysis of the Molecular Signature Database (a shared multi-institutional research resource). This allowed the researchers to identify sets of genes that show up in high numbers in MLL-AF9 leukemia. This was followed up by additional biochemical testing on the cells. The tests revealed that miR-196 directly targets and inhibits a gene called Cdkn1b/p27Kip1 (cyclin-Dependent Kinase Inhibitor), which controls molecular programming in leukemia stem cell that allows them to maintain aggressive MLL-AF9 leukemia.

Grimes explained that normal hematopoietic stem cells are not able to withstand extensive cell division. The researchers discovered that when miR-196 targets Cdkn1b/p27Kip1, it accelerates MLL-AF9 progression by abnormally linking stem cell activity with the growth of leukemia cells.​

Killing MLL-AF9 AML Cells

With the data suggesting elevation of p27Kip1 protein levels may be therapeutic to AML patients, researchers investigated a related molecular pathway in the cells that also regulates p27Kip1. This pathway yielded the eventual treatment target Skp2, which degrades the p27 protein and lowers its expression.

When the scientists used an experimental small molecule called SLZ P1041 that inhibits Skp2 on different human AML cell lines, it killed AML depending on the dosage used. Researchers write in their study that the approach "represents a new opportunity for AML therapeutics."

The researchers also tested SLZ P1041 in combination treatment with other molecule inhibitors (IBET-151, palbociclib and MI-1) to see if they could get a synergistic therapeutic effect on the AML cell lines. The preclinical data conclude the most consistent synergies were with the combination of SLZ P1041 and an inhibitor of the interaction between Menin and MLL (Menin-MLL) named MI-1.

Thursday, August 16, 2018

Comprehensive CAR T-Cell Therapy Pediatric Guidelines Developed

​Almost 1 year after the FDA approval of CAR T-cell therapy for children with acute lymphoblastic leukemia (ALL), researchers at The University of Texas MD Anderson Cancer Center and the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) recently published treatment guidelines for managing the treatment (Nat Rev Clin Oncol 2018; doi:10.1038/s41571-018-0075-2).

These guidelines outline lessons learned by leading experts in various fields to identify early signs and symptoms of treatment-related toxicity and detail ways in which to manage it. The FDA approved the first CAR T-cell therapy for children and young adults with ALL last year. Ongoing research aims to expand its use for other cancers.

"CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL, yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration," said Kris Mahadeo, MD, Associate Professor of Pediatrics and Chief of Stem Cell Transplant and Cellular Therapy at MD Anderson. "This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes."

As CAR T-cell therapy becomes more widely used, treatment guidelines, comprehensive training of multi-disciplinary staff, and other measures should facilitate the appropriate management of toxicities that may occur following this new treatment, added Mahadeo.

MD Anderson's CAR T-cell-therapy-associated Toxicity (CARTOX) program collaborated with PALISI and its Hematopoietic Stem Cell Transplantation (HSCT) sub-group in creating the comprehensive guidelines for treating children with cancer receiving CAR T-cell therapy. By bringing together experts from many areas, including pediatric intensivists, pharmacy, neurology, and translational immunotherapy research, the guidelines offer key learnings to providers and aim to help improve the patient experience and outcome.

"CARTOX, which oversees care for MD Anderson CAR T-cell therapy patients, is the first stand-alone immune effector cellular therapy program to earn accreditation from the Foundation for the Accreditation of Cellular Therapy (FACT)," said Elizabeth Shpall, MD, Professor of Stem Cell Transplantation and Cellular Therapy and one of the senior authors on the recent paper. "The program provides oversight for more than 20 active immune effector cell research protocols and two approved standard of care therapies at MD Anderson, and it is clear these new guidelines will serve as an important new model for care of CAR T-cell patients."

In 2017, MD Anderson's CARTOX Program published guidelines in Nature Reviews Clinical Oncology on management of adult patients receiving CAR T-cell therapy. However, early signs and symptoms of toxicity in children brought attention to pediatric-specific monitoring including escalation of care based on parent and caregiver concerns.

Some examples of the recommendations include:

  • Monitoring for cytokine release syndrome (CRS) using pediatric normal ranges for organ function.
  • Promptly addressing parent and/or caregiver concerns as early signs or symptoms of CRS can be subtle and best recognized by those who know the child best.