New drug shows promise in treating indolent non-Hodgkin lymphomas

Slow-growing, or indolent, non-Hodgkin lymphomas are difficult to treat, with most patients relapsing repeatedly and the disease becoming increasingly resistant to therapy over time.

But a new drug made by Seattle-based Gilead Sciences Inc. appears to offer hope for fighting the disease, according to a study published online today in The New England Journal of Medicine in advance of its March 13 print issue.

The phase 2 study involved 125 patients aged 33 to 87 with indolent non-Hodgkin lymphoma (iNHL) who had not responded to conventional treatments or had relapsed within six months of therapy. The patients, who were from the Seattle area, around the United States and Europe, were given a twice-daily dose of idelalisib, a highly selective oral drug that inhibits phosphoinositide 3-kinase (PI3K) delta. P13K deltas are a family of enzymes seen in many types of B-cell malignancies.

Following treatment with idelalisib, tumor size shrunk by at least half in 57 percent of the patients and 6 percent had no measurable evidence of cancer.

"These are patients who had exhausted current standard therapies," said Ajay Gopal, M.D., a member of Fred Hutchinson Cancer Research Center's Clinical Research Division and the study's lead and corresponding author. "In terms of effective therapy available, there really wasn't much left."

Indolent non-Hodgkin lymphomas comprise about one-third of all cases of NHL. About 20,000 people in the United States were diagnosed with iNHL in 2012 and approximately 7,000 died of the disease. The standard treatment for iNHL is a combination of rituximab, a drug that targets the protein CD20 found on B cells, and chemotherapy.

New drug shows promise in treating indolent non-Hodgkin lymphomas -- ScienceDaily

New molecule demonstrates ability to block lymphoma growth

The prestigious scientific journal Clinical Cancer Research has published a study conducted by the research group led by Dr. Francesco Bertoni of the Institute of Oncology Research (IOR, affiliated to USI Università della Svizzera italiana), that have tested a new molecule that demonstrates its ability to inhibit lymphoma growth.

Lymphomas are tumors that originate from blood cells, more specifically from lymphatic tissue. There are numerous types of lymphomas and each have different characteristics, aggressiveness, evolution and prognosis. In most cases, the standard treatments include irradiation and chemotherapy, two therapies that can have important side effects. Innovative biological approaches and the discovery of new biological molecules are changing the therapeutic approach and increasing the chances of healing.

Cancer cells are able to elude physiological control and grow in uncontrolled manner. In fact, groups of "pro-tumor" proteins can get activated and no longer respond to the normal intracellular "anti-tumor" control mechanisms. Among the "pro-tumor" proteins, the network including the signal molecules "PI3K/AKT/mTOR" is well known to sustain the survival and proliferation of cancer cells. Importantly, the PI3K/AKT/mTOR signaling axis is active in lymphomas and blocking could represent a good strategy to fight lymphoma cells.

The IOR research group led by Dr. Francesco Bertoni (who is also Vice-president of the SSAK Swiss Group for Clinical Cancer Research Project Group Lymphoma) with in particular Chiara Tarantelli and Eugenio Gaudio, has focused on the possibility to inhibit the PI3K/AKT/mTOR signaling with PQR309 (bimiralisib) in the lymphoma cells. PQR309 is a new molecule produced by a Swiss company that directly blocks multiple proteins driving the PI3K/AKT/mTOR signaling and has shown the ability to block the growth of lymphoma cells.

A drug (idelalisib) that acts by blocking only one specific type of protein in the "PI3K" family (PI3K delta) is already approved for clinical use, but many patients do not respond to this treatment. However, in the laboratory, PQR309 shows that it has anti-tumor activity even in lymphoma models that do not respond to idelalisib. PQR309 seems to act even better when combined with other novel anti-tumoral drugs. Furthermore, the mechanism of action of the drug PQR309 has been investigated and compared to that of other signaling inhibitors, obtaining results with implications in the design of novel treatment schemes for patients with lymphoma.

The results of this study, together with the ongoing clinical studies with PQR309, can lead to better treatments for people affected with lymphoma and to better understanding of the mechanisms of action of anti-lymphoma agents. Lymphomas are among the 10 most common cancers in adults and the third most frequent neoplasia in children and adolescents. Despite the great advancements made in their treatment, European statistics show that around 5 people per 100.000 still succumb to lymphoma every year.

Ref: https://www.usi.ch/en/feeds/6604

New molecule demonstrates ability to block lymphoma growth

Ibrutinib: Indication of added benefit in one of three therapeutic indications...

In continuation of my update on Ibrutinib

Ibrutinib is a drug for the treatment of rare diseases. It has been approved for the treatment of adults with chronic lymphocytic leukemia (CLL) or with relapsed or refractory mantle cell lymphoma (MCL) since 2014, and since 2015 also for the treatment of adults with Waldenström macroglobulinaemia. Regarding the treatment of patients with CLL or MCL, the Federal Joint Committee (G-BA) already conducted a benefit assessment and made a decision in 2015.

On request of the G-BA, the drug manufacturer now submitted a new dossier because the turnover of the drug in the statutory health insurance exceeded 50 million euros in the preceding 12 months. The German Institute for Quality and Efficiency in Health Care (IQWiG) therefore examined in an early benefit assessment whether the drug offers an added benefit for patients with these diseases in comparison with the respective appropriate comparator therapies.

According to the findings, there is no hint of an added benefit in CLL and Waldenström macroglobulinaemia. In relapsed or refractory mantle cell lymphoma, there is an indication of major added benefit of ibrutinib for patients for whom temsirolimus is the individually optimized treatment option. An added benefit is not proven for patients for whom temsirolimus is no or only a secondary option.

Chronic lymphocytic leukemia

The G-BA differentiated between pretreated and treatment-naive patients within the therapeutic indication of CLL. Pretreated patients were separated into two subpopulations, resulting in three research questions.

Pretreated patients for whom chemotherapy is indicated were to be treated with individually optimized chemotherapy in the comparator arm. The manufacturer presented no relevant data for these patients in its dossier: The direct comparison and the indirect comparisons conducted by the manufacturer were unsuitable for the derivation of an added benefit of ibrutinib.

Pretreated patients for whom such chemotherapy is not an option were to be treated with idelalisib or best supportive care in the comparator arm. A non-quantifiable advantage in the outcome "mortality," but also potentially lesser benefit of ibrutinib in morbidity and health-related quality of life as well as potentially greater harm in severe and serious side effects resulted from the study data presented. In the consideration of the beneficial and harmful effects, an added benefit is therefore not proven for these patients either.

Idelalisib or best supportive care constituted the appropriate comparator therapy also for treatment-naive patients for whom chemo-immunotherapy is unsuitable due to mutations. The manufacturer presented only one study irrelevant for the research question so that an added benefit is not proven for this patient group either.

Waldenström macroglobulinaemia

Pretreated and treatment-naive patients were to be considered separately also in the therapeutic indication Waldenström macroglobulinaemia. In both cases, the appropriate comparator therapy was individually optimized treatment specified by the physician.

The manufacturer presented no data on first-line treatment so that an added benefit of ibrutinib for treatment-naive patients is not proven.

Regarding patients who have received at least one treatment, the manufacturer submitted a historical comparison based on uncontrolled studies because there were no randomized controlled trials. Due to the selective choice of data, among other reasons, this comparison was unsuitable for drawing conclusions on the added benefit. Hence there was no hint of an added benefit in this case either.

Relapsed or refractory mantle cell lymphoma

Two subpopulations have to be differentiated also in relapsed or refractory MCL: patients for whom temsirolimus is the individually optimized treatment, and patients for whom this is not the case.

Due to a lack of data, an added benefit of ibrutinib is not proven for patients for whom temsirolimus is no or only a secondary treatment Option.

For the other patient group, in contrast, the manufacturer presented data from the study MCL3001, in which ibrutinib was compared with temsirolimus. There was no statistically significant difference between the study arms regarding overall survival. Ibrutinib had positive effects in the outcomes "health status" and "side effects," which were not offset by negative effects in other outcomes. Overall, there is therefore an indication of major added benefit for patients for whom temsirolimus constitutes the individually optimized treatment.

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

Ibrutinib: Indication of added benefit in one of three therapeutic indications

Phase 3 study of idelalisibin reports positive results in CLL patients

Gilead Sciences, Inc. (Nasdaq:GILD) today announced that its Phase 3 study (Study 116) evaluating idelalisib in previously-treated chronic lymphocytic leukemia (CLL) patients who are not fit for chemotherapy will be stopped early. This DMC recommendation is based on a predefined interim analysis showing highly statistically significant efficacy for the primary endpoint of progression-free survival in patients receiving idelalisib plus rituximab (see structures I and II respectively) compared to those receiving rituximab alone. 

Phase 3 study of idelalisibin reports positive results in CLL patients

Zydelig Approved for Three Types of Blood Cancer

 Zydelig (idelalisib) has been approved by the U.S. Food and Drug Administration to treat relapsed forms of blood cancer, including chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL), the FDA said Wednesday in a news release.

The approval for the three forms of blood cancer covers instances when the cancer returns despite treatment with at least one other therapy, the agency said.

The drug's label will include a boxed warning that the medication could cause liver toxicity, diarrhea, high blood sugar, elevated liver enzymes, high blood triglycerides [a blood fat] and inflammation of the colon (colitis). Other side effects noted during clinical testing included fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills and rash.

Zydelig is marketed by Gilead Sciences, based in Foster City, Calif.

Zydelig Approved for Three Types of Blood Cancer