Drug ‘cures’ 33% of patients with aggressive leukaemia in early trial

How shortage of commonly used cancer drugs compromises, complicates care, by studies

An experimental pill for leukaemia has shown promise in early clinical trials — sending a third of patients with aggressive disease into complete remission.

The drug — revumenib — was also credited with putting half of patients with acute myeloid leukaemia (AML) into partial remission during phase one clinical trials.

Dr. Scott Armstrong, a blood cancer expert at the Dana-Farber Cancer Institute in Boston, Massachusetts, who is running the trial, heralded the results as ‘very encouraging’. But he said more research was needed to prove that the drug worked.

He said if more rigorous trials are successful, his team could apply for Food and Drug Administration (FDA) approval by the end of this year. The initial trial did not include a control group, meaning the drug was not tested against current treatments.

Acute myeloid leukaemia is a type of blood cancer that affects white blood cells, causing them to start dividing uncontrollably and become abnormal — leaving them unable to fight infections.

There are about 59,000 cases diagnosed every year in the United States and 23,700 people die from the cancer.

It is notoriously hard to treat because the cells involved are diverse and can mutate rapidly, making them difficult to target with novel treatments like immunotherapy.

They also divide quickly and spread to different areas of the body, which leaves doctors struggling to eliminate them without harming healthy tissue.

In the study, published this month in the journal Nature, researchers focused on leukaemias that were triggered by mutations in the NPM1 and KMT2A genes.

This accounts for about 40 per cent of America’s leukaemia cases. Up to 80 per cent of people diagnosed with these mutations in their leukaemia die within five years.

Beth Reilly, from Wallasey in Merseyside, first became concerned about her son Bailey Kilbane, now 16 months, last October when he developed flu-like symptoms and bruises that would not heal.

In leukaemia with these mutations, a protein called menin binds to genes that trigger cancerous cells to keep growing and dividing.

To break this cycle, revumenib uses a molecule that binds to menin stopping it attaching to and, therefore, triggering the genes.

In their study, scientists administered the drug to 68 patients who had relapsed leukaemia or leukaemia that did not respond to treatment. Nearly all had leukaemia with NPM1 or KMT2A mutations and they were about 42 years old.

Patients were asked to take the drug, administered in a capsule, twice a day — with each dose 12 hours apart.

They were tracked for about a year on average.

Results showed that a total of 18 patients (30 per cent) had complete remission of the cancer during the study, meaning all signs and symptoms of cancer had disappeared.

The average time to reach complete remission was two months, the scientists said.

Another 32 patients (53 percent) were also shown to have partial remission, or a decrease in the size of tumors or the extent of cancer in the body.

They remained in partial remission for nine months.

Overall, patients survived for about seven months after the start of the study.

Nearly all patients experienced adverse effects, with the most common being an irregular heartbeat and nausea.

Seven people had to withdraw from the study because of severe reaction to the drug.

There was, however, evidence in some participants that cancerous cells had developed resistance to the drug.

Phase one trials are designed to test the safety and optimal dose of an experimental treatment.

Currently, those with NPM1-mutated leukaemia or the KMT2A mutations are offered chemotherapy to fight the disease.

Surgery is rarely used to treat acute myeloid leukaemia. Radiotherapy may be used in some cases where the cancer has spread out of the bone marrow and blood.

About two out of three of these patients will then go into remission, the American Cancer Society says.

Doctors say that those who have NPM1 leukaemia tend to have better responses to chemotherapy treatments.

What is leukaemia? Leukaemia is a cancer that starts in blood-forming tissue, usually the bone marrow. It leads to the over-production of abnormal white blood cells, which fight off infections.

But a higher number of white blood cells means there is ‘less room’ for other cells, including red blood cells – which transport oxygen around the body – and platelets – which cause blood to clot when the skin is cut.

There are many different types of leukaemia, which are defined according to the immune cells they affect and how the disease progresses.

For all types combined, 9,900 people in the UK were diagnosed with leukaemia in 2015, Cancer Research UK statistics reveal.

And in the U.S., around 60,300 people were told they had the disease last year, according to the National Cancer Institute.

Most cases have no obvious cause, with cancer not being contagious or inherited.

Leukaemia generally becomes more common with age – the exception being acute lymphoblastic leukaemia, which peaks in children.

Other risk factors include being male, being exposed to certain chemicals or radiation, and some bone-marrow disorders.

Symptoms are generally vague and get worse over time. These can include tiredness, frequent infections, sweats, bruising, heavy periods, nose bleeds or bleeding gums, palpitations, and shortness of breath.

Acute leukaemia – which progresses rapidly and aggressively – is often curable via chemo, radiotherapy or a stem cell transplant.

Chronic forms of the disease – which typically progress slowly – tend to be incurable; however, these patients can often live with the disease.

Meanwhile, several widely used branded and generic cancer drugs are in short supply, causing some people to be treated with less-effective medications or even die while waiting for the medication to become available.

Pluvicto, used to treat advanced prostate cancer, and injectable methotrexate, cisplatin, and fluorouracil — chemotherapy drugs that target many different cancers — are all becoming scarce, according to the United States Food and Drug Administration (FDA). A fifth drug, BCG, used to treat bladder cancer, is also dwindling, according to the University of Minnesota.

A delay in cancer treatment of even just a few weeks can affect a person’s survival. A study published in the November 2020 BMJ found that every month of delayed treatment was associated with a 10 percent increased risk of death.

“Drug shortages have been a major challenge for the last decade, especially in acute-care hospitals,” says Jeffrey Pilz, an assistant director of pharmacy, medication safety, and drug policy for the Ohio State University Wexner Medical Centre and the James Cancer Hospital and Solove Research Institute in Columbus.

Recent disruption in global supply chains and production issues have combined to create shortages for a greater number of drugs, longer-lasting shortages, and less product availability during a shortage, says Pilz.

“Current drug shortages also are impacting ever more important medications, not just older generics that are no longer first-line therapies. For 2023, the number of drug shortages is forecast to reach a record number,” says Pilz.

At a minimum, drug shortages are a frustrating and inconvenient experience for patients, says Pilz. “At their worst, drug shortages historically have been deadly for patients,” he says.

There are currently five drugs used in cancer treatment that are running low. Shortage severity varies by institution and region, adds Pilz.

Pluvicto (injectable lutetium vipivotide tetraxetan) is used to improve survival time in people with advanced prostate cancer. In a pivotal study announced in December 2022, men who received the drug lived a median of 15 months, which is four months longer than the median for patients who didn’t get the drug.

Pluvicto is currently made in just a single factory in Italy, notes Pilz. “Because it is a radiopharmaceutical (a drug that contains a radioactive substance), it can only be produced in small batches within a few days of when it needs to be delivered to patients. Any interruption in production or delivery may delay doses,” he says.

Although Novartis is running the factory at full capacity, the high demand for this agent and previous delivery interruptions have led to a backlog in production and the resulting shortage, says Pilz.

There is a prioritisation programme for patients who have already received at least one dose so that they can complete the course of therapy, according to the company. Long term, there are plans to increase the production of the drug with two new manufacturing sites in the United States.

Meanwhile, these delays have had tragic consequences for some cancer patients. At Dana-Farber Cancer Institute in Boston, delays to starting treatment on Pluvicto went from 41 days in May 2022 to three months by October. During that period, 127 patients were approved for the drug and 6 died waiting, according to a report from the Wall Street Journal.

Bacillus Calmette-Guerin (BCG) BCG is considered an “essential drug” in the treatment of bladder cancer, according to the University of Minnesota. The drug has been in shortage since 2019.

Because this drug, too, has only one manufacturer and is produced in only one facility, an increased global demand has led to a prolonged shortage, says Pilz. “Plans are underway to open at least one new facility, but this will take several years before authorized,” says Pilz.

In the United States alone, the shortage has caused more than 8,000 people with moderate to advanced bladder cancer to receive less-than-optimal care, according to the End Drug Shortages Alliance (EDSA).

Injectable cisplatin, methotrexate, and fluorouracil- these generic drugs are widely used to treat common cancers in adults and children.

Methotrexate treats acute lymphoblastic leukemia in children and a number of cancers in adults, including breast, head and neck, lung, bone, and uterine cancers. The drug has been scarce since March 14, according to the American Society of Health System Pharmacists (ASHP).

Supplies of cisplatin, used to treat metastatic ovarian and bladder cancer, have been tight since March 6, per ASHP.

The fluorouracil shortage was first reported on March 14, according to ASHP. The injectable drug is used to treat colon, breast, pancreas, and stomach cancer.

Unfortunately, drug shortages are not a new problem, says William Dahut, MD, the chief scientific officer at the American Cancer Society. “Shortages tend to occur with drugs that are no longer on patent and are made by only one or two manufacturers,” he says.

The factories that manufacture generic drugs are often old, and if there’s a problem at the primary site of production, the impact can be significant. “Since production sites are limited, there are no options to easily make up the deficits,” says Dahut.

From the perspective of frontline clinicians, it can be hard to determine the specific causes of individual drug shortages, says Pilz. “There is a lack of transparency with the pharmaceutical industry as to causes of drug shortages, timeline to resolution, and even where products are made. Some manufacturers may volunteer this detail when known, but it is not required outside of the mandatory reporting elements to the FDA,” he says.

Ultimately, inexpensive (less than $9 a dose) medications that are only available as generics provide little financial incentive for manufacturers to reinvest in the production line or expand production capability, says Pilz.

Even though they are commonly used, many of the traditional chemotherapy agents fall in this category, he says.

“However, shortages may still impact newer, branded medications such as Pluvicto due to production issues,” says Pilz.

Although there has been more attention focused on shortages lately, Pilz believes there needs to be significant investment by the pharmaceutical industry, significant regulatory changes, or both to find meaningful solutions to the underlying problems.

“The lack of transparency in the manufacturing and supply chain for pharmaceuticals is one area where change could be implemented relatively quickly,” he says.

If manufacturers provided information on issues with specific production sites, the amount of medication available, and a timeline for getting back up to speed after a production problem, that would allow healthcare providers to make better plans to mitigate shortages and minimize patient impact, he says.

It’s reasonable to check in with your healthcare team about possible shortages before starting treatment, says Dahut. “If this is a concern, discuss potential alternatives with them. If a shortage occurs during therapy, ask about alternative routes of administration (oral versus IV), similar drugs in the class of agents, or potentially different therapeutic strategies,” he suggests.

“If you are struggling to find an outpatient prescription product, ask your provider or pharmacist if there are other locations where the product may be available or if there is a reasonable alternative therapy,” says Pilz.