Tag: non-Hodgkin's lymphoma

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New Drug Effective for 3 of 4 Trial Patients with Relapsed Blood Cancer

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Photo by National Cancer Institute on Unsplash

A new targeted drug, may offer a new treatment option for patients with blood cancers, including chronic lymphocytic leukaemia (CLL) and Non-Hodgkin lymphoma (NHL) whose disease has stopped responding to standard treatments.

In the first clinical trial of this drug in humans, nemtabrutinib was effective in three-fourths of cancer patients tested, without severe side effects. The results of the trial were published in the journal Cancer Discovery.

Haematologist and study lead investigator Jennifer Woyach, MD, notes that about half a dozen drugs are available to treat these B-cell cancers. Although most patients respond to these drugs initially, over time, many patients experience disease progression. The study was done by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

“Blood cancers that have relapsed after initial treatments can be difficult to treat, and even with our effective medications, some patients run out of standard treatment options.  In this trial, nemtabrutinib looks very promising for patients whose cancer has progressive after other treatments.” said Woyach, who is co-leader of the Leukemia Research Program at the OSUCCC – James.

How this drug therapy works

When an antigen, such as a virus or bacteria, enters the bloodstream, it triggers a set of signals in B-cells to produce antibodies. In some people, said Woyach, this process goes haywire. Instead of fighting infections, the B-cells begin to divide uncontrollably, resulting in cancer. Drugs against B-cell cancers work by binding to a key enzyme, called Bruton’s tyrosine kinase (BTK). This enzyme is involved in the signaling process. The drugs block the action of the enzyme, and as a result, the abnormal B-cells die.

In many patients, this effect is temporary with available drugs. Over time, the BTK enzyme to which the drugs bind mutates so they can no longer stop its action. Soon, the cancer returns. Nemtabrutinib was designed to bind to BTK even in the presence of common mutations that make other BTK inhibitors stop working. It also binds to a number of proteins besides BTK that are important in B cell cancers. These two properties made this drug very appealing to study in this patient population.

Study methods and results

The researchers tested the new drug on 47 patients who have had at least two prior therapies for their blood cancer. Over half of these patients had relapsed CLL, while the others had NHL. The researchers gave these patients one pill of nemtabrutinib every day, with different doses along the trial. They observed the patients’ response to the drug over time and monitored them for side effects.

The study found more than 75% of the patients with relapsed CLL responded to the drug, at an optimal dose of 65mg. These included patients who had mutations in BTK. Most patients remained cancer free for at least 16 months during the trial. While all patients experienced some side effects – which is common with chemotherapeutic drugs – many of these were minor and manageable, proving that the drug was also very safe.

“The drug is being moved to larger and more definitive trials, where it will be compared against other standard-of-care drugs, and in combination with other active medications,” said Woyach.

The blood cancers investigated in this trial affect B lymphocytes, which is a cell that is responsible for producing antibodies and fighting infections. CLL is the most common leukaemia making up a quarter of leukaemia cases among adults, and NHL accounts for 4% of all cancers in the United States.

Source: Ohio State University

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Higher Risk of Lymphoma in Patients Suffering from IBD

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Karolinska Institutet researchers have found that the risk of developing lymphoma is slightly elevated in inflammatory bowel disease (IBD) and, in recent years has been on the rise in patients with Crohn’s disease. Publishing in Clinical Gastroenterology and Hepatology, the researchers also observed a risk increase in patients taking modern IBD drugs, which was less strong for those not taking them. Thus, the lymphoma risk could be affected by both the medication and the disease activity itself.

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a chronic intestinal inflammation that can increase the risk of developing lymph node cancer (lymphoma), a disease that affects the immune system.  

“Previous studies of the lymphoma risk of IBD have been too small to draw reliable conclusions,” says the study’s first author Ola Olén, consultant and docent at the Department of Medicine (Solna), Karolinska Institutet. “The studies have not taken into account of important systematic errors or been representative of today’s IBD patients.”  

The present study included almost 170 000 IBD patients identified in Swedish and Danish national registries between 1969 and 2019. Compared to patients with a matched population without IBD, patients with both Crohn’s disease and ulcerative colitis had a higher risk of lymphoma. The highest risk was in patients with Crohn’s disease, the increase being driven mainly by T-cell lymphoma and aggressive B-cell lymphoma.

“We found an elevated relative risk of different types of lymphoma in both Crohn’s disease and ulcerative colitis, but we need to point out that the absolute risk is very low,” says the study’s last author Jonas F Ludvigsson, consultant and professor at Karolinska Institutet.

“The increase in risk equates to only one extra case of lymphoma in 1000 people with IBD, who were followed for ten years.”

“Both inflammation and treatment play a part”

The risk of lymphoma has increased in patients with Crohn’s disease over the past two decades, which coincides with the increasing use of immunomodulating drugs for IBD. While the highest risk of developing the cancer was observed in patients who had received these drugs, the researchers found that patients who were not on such medication were also at a higher risk of lymphoma. 

“This finding indicates that both the inflammation in itself and its treatment play a part,” says Dr Olén. “Since there’s a lot of talk about the lymphoma risk associated with immunomodulating drugs, it’s important to make it clear that also the disease and the inflammation per se seem to drive the development of lymphoma. One has to take account of this and discuss it when prescribing modern treatments where there might be a concern that they will increase the risk of lymphoma.” 

Dr Olén says the teamaims to use more detailed data to determine whether the disease itself or its treatment is more important in terms of lymphoma risk.

Source: Karolinska Institutet

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For Women, Lymphoma Chemotherapy more Effective in Afternoon

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Photo by Malvestida on Unsplash

While chemotherapy is highly effective at killing cancer cells, it also kills healthy cells, something which medical research is trying minimise. Recently, ‘chronochemotherapy’ has garnered growing attention in the research community. As the name suggests, the aim is timing the delivery of the drug when the body is least vulnerable to the harmful effects of the drug, while the cancer cells are at their most vulnerable.

Chronochemotherapy exploits the fact that human physiological processes, including cell proliferation and differentiation, are regulated by the circadian clock. However, it is not yet widely exploited in real-world clinical settings because there at present is no systematic method to find the optimal chemotherapy delivery time.

This problem was tackled by an interdisciplinary team of researchers from the Institute for Basic Science (IBS), South Korea. They were led by the principal investigators, mathematician Kim Jae Kyoung at IBS and oncologist Koh Youngil at Seoul National University Hospital. The researchers studied a group of patients suffering from diffuse large B-cell lymphoma (DLBCL), which accounts for about 30 to 40% of non-Hodgkin’s lymphoma. Their findings are published in the journal JCI Insights.

The research team noticed that DLBCL patients at Seoul National University Hospital received chemotherapy at two different schedules, with some patients receiving morning treatment (8:30), while others taking the drugs in the afternoon (14:30). All patients received R-CHOP, which is a combination of targeted therapy and chemotherapy, 4 to 6 times in the morning or afternoon at intervals of about 3 weeks.

Figure 1. Chemotherapy in the afternoon can improve treatment outcomes
The daily fluctuation of proliferative activity of bone marrow is larger in females than in males, and it becomes higher in the morning (left). Thus, chemotherapy in the morning strongly inhibits proliferative activity in female lymphoma patients, resulting in a higher incidence of adverse events such as neutropenia and infections. This forces the clinicians to reduce the dose intensity (center). Consequently, female patients undergoing the morning treatment show a lower survival probability than those undergoing the afternoon treatment (right). Specifically, only ~13% of female patients treated in the afternoon had a worse outcome and ~2% of them died while ~37% of female patients treated in the morning had a worse outcome and ~25% of them died. Male patients did not show any difference in treatment outcomes depending on the chemotherapy delivery time.

They analysed 210 patients to investigate differences between morning and afternoon treatment. They found that female patients who received afternoon treatment had 12.5 times reduced mortality rate (25% to 2%), while the cancer recurrence after 60 months was decreased by 2.8 times (37% to 13%). In addition, chemotherapy side effects such as neutropenia were more common in female patients who received morning treatment.

Surprisingly, there was no difference in treatment efficiency depending on the treatment schedule in the case of male patients.

To understand the cause of gender differences, the research team analysed ~14 000 blood samples from the Seoul National University Hospital Health Examination Center. It was found that in females, white blood cell count tends to decrease in the morning and increase in the afternoon. This indicates that the bone marrow proliferation rate is higher in the morning than in the afternoon because there is a ~12hr delay between the bone marrow proliferation and blood cell production.

This means that if a female patient receives chemotherapy in the morning when bone marrow is actively producing blood cells, the possibility of adverse side effects becomes greater. These results are consistent with the findings from recent randomised clinical trials that showed female colorectal cancer patients treated with irinotecan in the morning suffered from higher drug toxicities.

One confounding variable was the drug dose. Since the morning female patients suffered from greater adverse side effects, oftentimes the dose had to be reduced in these patients. On average, the drug dose was reduced by ~10% compared to the dose intensity given to female patients receiving the afternoon treatment.

Unlike female patients, it was found that male patients did not show a significant difference in white blood cell count and bone marrow cell proliferation activity throughout the day, which is the reason why the timing of the treatment had no impact.

Professor Koh Young-il said, “We plan to verify the conclusions of this study again with a large-scale follow-up study that completely controls confounding variables, and to confirm whether chemotherapy has similar effects in other cancers.”

Ci Kim Jae Kyung said, “Because the time of the internal circadian clock can vary greatly depending on the individual’s sleep-wake patterns, we are currently developing a technology to estimate the time of the circadian clock from the patient’s sleep pattern. We hope that it can be used to develop an individualised anti-cancer chronotherapy.”

Source: Institute for Basic Science