1. Neff Newitt, Valerie

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Zaid Abdel-Rahman, MD, might have called 2020 a stellar year, had it not been for the loss of too many patients to COVID-19.

ALL. ALL... - Click to enlarge in new windowALL. ALL

"Patients with cancer, specifically bone marrow transplant recipients, do worse than others when they contract COVID-19. These patients are profoundly immunosuppressed; they're getting therapies that prevent their immune systems from fighting the virus," he lamented. "I primarily treat hematologic malignancies which, themselves, also render patients immunosuppressed. We saw evidence of this early in the pandemic, but we didn't have data to back it up. Now, however, several studies prove it."


The doctor admitted, "It is hard to say it was a great year." Yet, during that time, the Stem Cell Transplantation and Cellular Therapy fellow at The University of Texas MD Anderson Cancer Center was then knee-deep in research at his former place of employment, the Mayo Clinic Florida. The work was an impressive examination of outcomes related to a somewhat new subtype of acute lymphoblastic leukemia (ALL) called Philadelphia-like. The effort earned him a prestigious 2020 Young Investigator Award from ASCO's Conquer Cancer Foundation that was funded by the Florida Society of Clinical Oncology.

Zaid Abdel-Rahman, M... - Click to enlarge in new windowZaid Abdel-Rahman, MD. Zaid Abdel-Rahman, MD

A Contrast of Cultures

A native of Amman, Jordan, Abdel-Rahman found his oncology roots in his home country after graduating from Hashemite University and beginning his career at King Hussein Cancer Center, one of the largest cancer centers in the Middle East. "It's a great medical facility and a remarkable place to work," he told Oncology Times.


"Jordan is not a rich country. But cancer is an equalizer for patients there, because the government covers the expenses and King Hussein Cancer Foundation also provides a nonprofit cancer insurance policy to cover treatment at the center," the physician said proudly. "It doesn't matter if you can't afford the treatment; if you have cancer, your outcome will be as good as is clinically possible. Socioeconomic status does not impact survival. Clinicians there never deal with insurance companies, never even think about how expensive a drug is or isn't. Everybody is given the best treatment possible. If a patient lives far away, the cancer center provides transportation and accommodations for the patient and their family until treatment is finished. The only thing patients have to focus on is getting better."


As a new doctor, Abdel-Rahman's very first patient had Hodgkin's lymphoma. "She relapsed despite being treated with several lines of chemotherapy and having gone through an autologous stem cell transplantation. Unfortunately, she died from complications related to her disease. I still remember every detail of her case to this day," said the physician scientist. "Some things just never leave you. I became very interested in hematologic malignancies after that. And then, when I started delving deeper into it, I really loved the science and I just got attached to it. So that first patient had an enormous impact on my life and the direction I would take."


When he arrived at the Henry Ford Hospital, Detroit, in 2015 to complete his residency in internal medicine, Abdel-Rahman experienced quite a change in the way cancer and its treatments are handled financially in the U.S.


"It is something that was hard for me to get over," he admitted. "When I started seeing patients who could not afford treatment, I was completely shocked; it was disheartening. And in Detroit, the disparities are everywhere. I went to a city that was struggling. Even though I came from a country with limited resources, I saw how disparities could be eliminated and how much of a difference it makes to patient outcomes.


"We can all understand why novel drugs may be expensive. I now prescribe medications that cost $10,000 to $20,000 a month. But even things outside of novel treatments and new drugs are extremely expensive here. A bone marrow transplant in Jordan costs just a fraction of what it costs in the United States. There are no new drugs or novel therapies used in bone marrow transplants, yet treatment still costs a lot. It's a problem with the health care system overall, and I'm hopeful it will be addressed in the future. I feel it is not sustainable."


Abdel-Rahman is also quick to express gratitude for what this country has given him-stellar medical training, expanded research opportunities, and personal financial independence.


A Look at the Research

As a prelude to describing his research, Abdel-Rahman explained a new subtype of ALL was discovered in 2009. It was called Philadelphia-like because it behaved in the same manner as a known type called Philadelphia-positive, which harbors the Philadelphia chromosome. Though Philadelphia-like ALL has the same gene expression profile as Philadelphia-positive, it lacks the Philadelphia chromosome and the classic translocation seen in patients with Philadelphia-positive ALL.


"It was like a black box," said Abdel-Rahman. "We didn't have any way of identifying it in clinical practice. So when patients had it, we didn't know about it. We couldn't identify it in real time in order to make changes to the treatment algorithm of these patients. And these patients were doing really poorly compared to those with other types of ALL."


The subtype was first described in children with ALL. "We didn't have any insight on the outcomes of adults with this ALL subtype until a few years ago. Even in pediatrics where ALL is one of the best success stories in oncology, this subgroup's survival rate is between 40-50 percent. And for pediatrics that number is just terrible."


In adults, ALL has been an ongoing challenge, in part because it is relatively rare. "And it usually occurs in older adults," added Abdel-Rahman. "These patients do not tolerate the same intense treatment that children can tolerate and have a higher-risk disease, therefore, our 5-year overall survival for older patients with ALL has been in the 40-50 percent range. But this Philadelphia-like subgroup is doing even worse than everybody else with 5-year overall survival as low as 20-30 percent."


The statistics bring into a sharp focus the need for this area of research. "Our biggest problem was we couldn't identify who these patients were. There are several tests we do to ALL patients that help us classify them into subgroups and then tailor treatment based on their risk status. We knew this subgroup was high risk, but we just didn't have a way of identifying these patients in clinical practice," detailed Abdel-Rahman.


While several gene expression profiling tests existed, it was only practical for use in research because of extremes in expense, time factor, and the level of expertise required for administering and interpreting the test.


A Turning Point

All of that changed when a FISH assay developed by the Mayo Clinic Genomics Laboratory went live in 2017, just about the time Abdel-Rahman arrived on the scene.


"This platform is now widely available and can be performed in any cytogenetics lab," he explained. "It's very sophisticated and detects most of the clinically actionable translocations or genetic alterations in Philadelphia-like ALL, but at the same time can be interpreted with ease. All of a sudden, this entity can now be recognized in real time, in real practice, in pretty much every single hospital with a cytogenetics lab in the country. It has revolutionized the way we look at this disease. Suddenly we don't have to send patients to one of the few academic centers in the country previously able to detect this subtype."


In its infancy, the test necessarily prompted a deeper dive into its utility with Philadelphia-like ALL. "That's where my role came into play," said Abdel-Rahman. "We had to test it against specimens that were in existence and see if it actually worked and detected this entity. We took advantage of annotated datasets from former patients with ALL treated at Mayo Clinic between 2008 and 2019. That's 12 years of patient data-one of the biggest ALL datasets in literature-derived from 365 patients. Now, this may not seem like a big number to someone unfamiliar with the disease, but for those who are, this is a huge number."


The doctor went on to explain that he and his team built a highly annotated database with over 200 variables per patient. "We went back to the date when they were diagnosed, looked in the freezers in the cytogenetics lab, and pulled all those diagnostic leukemia specimens. And then we applied the FISH panels to those stored specimens and we started identifying cases.


"At the time when these cases were first diagnosed, they clearly were not known to be Philadelphia-like because we didn't have any means of diagnosing it," he reminded. "But now we were identifying these cases in retrospect to gain some clarity on how adult patients with this entity do. After identifying the cases, we described the outcomes of these patients compared to other cytogenic groups and we had some really interesting findings."


With the gradual unraveling of a medical mystery, Abdel-Rahman continued the tale of his research, which also was presented at ASCO. "Allogeneic bone marrow transplantation is a very important treatment modality in adults. A cornerstone of treatment in ALL, it is one of the few treatments offering long-term disease control and cure for adults, specifically for those with high-risk disease," he explained.


The researchers did not know if transplant alters or impacts the outcomes of patients with Philadelphia-like ALL at all because there was no data, "... no systematic study of the outcomes of patients with this ALL subtype who underwent allogeneic transplantation," noted Abdel-Rahman. "So we identified 33 patients and compared the outcomes of those with Philadelphia-like ALL to the outcomes of those with Philadelphia-positive and Philadelphia-negative ALL. The majority of patients (over 200) in our dataset had undergone an allogeneic transplantation. We described outcomes through the entire cohort and then we looked specifically at a sub-cohort of patients who underwent a transplant."


Unexpected Findings

The findings were a surprise to Abdel-Rahman. "In the overall cohort, patients with Philadelphia-like ALL were less likely to achieve a complete remission after induction chemotherapy, more likely to have measurable residual disease, more likely to relapse, and less likely to be alive in 5 years. They had worse outcomes in every single outcome factor that we looked at."


However, when the researchers compared outcome factors of Philadelphia-like, Philadelphia-positive, and Philadelphia-negative patients who went to transplant, "all of these statistically significant findings that were present in the overall cohort disappeared in the transplant cohort," said Abdel-Rahman. Their relapse risk after transplant was similar to other subgroups and their overall survival was also very similar.


"To be honest, I did not expect this when I started working on this. I was expecting the poor outcomes in the overall cohort. I wasn't sure if transplant was going to be the answer to this high-risk group," he noted. "But transplant, at least partially, seems to offset the poor prognosis that is associated with this high-risk cohort."


Further detailing the research, Abdel-Rahman said when he looked at detailed cytogenetic groups, patients with Philadelphia-like ALL did as poorly as the highest-risk groups known in ALL.


"These are complex karyotype, KMT2A rearrangements and hypodiploidy/near-triploidy. Anybody familiar with the terminology knows these are the most feared things that you can possibly see because, regardless of what you do, these patients will not do very well. But with transplant, their outcomes can significantly improve." In fact the 5-year survival rate for Mayo Clinic cohort patients with Philadelphia-like ALL who underwent transplant went up to 49 percent.


"Cohort patients who did not go to transplant had 5-year survival percentages in the 30s. Although this needs to be confirmed in a prospective fashion to avoid statistical biases, we're talking about a 15-20 percent difference in overall survival at 5 years," said Abdel-Rahman. The work is now serving as the basis for a future clinical trial that is set to examine the role of allogeneic transplantation and the role of targeted therapies.


"In our research, we identified targets for some novel treatments, and there are drugs that we currently use for other leukemia subtypes that can be repurposed and used for this leukemia subtype. In order to do that, we need to identify the patient, and also identify the genetic alteration that they have," he noted. "I always say Philadelphia-like ALL today is similar to Philadelphia-positive ALL in the 1990s before the first targeted therapy (imatinib) was discovered and approved by the FDA in 2001. It dramatically changed the outcomes for patients with chronic myelogenous leukemia and ALL with a Philadelphia chromosome. And now, Philadelphia-like ALL is in a similar place. We just need to identify these targetable alterations and then use the right drugs to try and improve the outcomes for this subgroup."


What Spare Time?

Does someone so immersed in research, clinical work, and a young family have time for any unrelated interests? Despite being self-described as someone who is "no good at sports," Abdel-Rahman has joined a rigorous workout agenda at Orange Theory, ("...I'm not sure why I do's painful...") and remains an avid reader. Although one might make the argument that reading is an extension of work. "You want to know the last book I read?" he asked eagerly. "It's called Nine Pints by Rose George. Nine pints is the amount of blood you have in your body. It's really fascinating and tells everything you need to know about blood..."


The physician scientist's thirst for reading serves to confirm his conviction that doctors must stay curious and always keep an open mind to learning something new. "Our research project offered some hope for better outcomes for patients with an adverse entity," he said, thoughtfully. "We hope to adjust treatments and/or use a targetable, novel treatment in the future to offset a poor prognosis. There are a lot of puzzling things in medicine that we just don't have an explanation for. So it's extremely important to be open to new ideas and new concepts, because we still have a long way to go and a lot to achieve."


Valerie Neff Newitt is a contributing writer.


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