Chemotherapy-Free Regimen Consisting of 3 Novel Agents for Previously Untreated, Poor Prognosis CLL

Chemotherapy-Free Regimen Consisting of 3 Novel Agents for Previously Untreated, Poor Prognosis CLL

Nearly 60% of evaluable patients with previously untreated, chronic lymphocytic leukemia (CLL) characterized by chromosomal deletion of 17p (del[17p]) and/or a deleterious TP53 mutation treated with obinutuzumab, ibrutinib, and venetoclax triplet therapy achieved either complete remission (CR) or a CR with incomplete recovery of the bone marrow, according to results of a single-arm, phase 2 study presented during the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress.

While less than 10% of patients diagnosed with CLL have disease characterized by del(17p), this biomarker is present in up to half of patients with refractory disease.2 Hence, there is an unmet need for efficacious and safe treatment regimens for this subgroup of patients. Furthermore, compounding this need is the finding that TP53 mutations, another biomarker of poor prognosis, have been reported to be present in approximately 90% of patients with disease characterized by del(17p) although only about 40% of those with TP53-mutant CLL also have del(17p).An unmutated IGHV gene is another risk factor for poor prognosis in the setting of CLL.2

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Dr. Flinn on the Role of BTK Inhibitors in CLL

Dr. Flinn on the Role of BTK Inhibitors in CLL

This story was originally published on OneLive

Ian W. Flinn, MD, PhD, discusses the role of BTK inhibitors in chronic lymphocytic leukemia.

 

Ian W. Flinn, MD, PhD, director of the Blood Cancer Research Program, Sarah Cannon Research Institute, discusses the role of BTK inhibitors in chronic lymphocytic leukemia (CLL).

BTK inhibitors such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) have been transformative in the treatment of patients with B-cell malignancies such as CLL, mantle cell lymphoma, marginal zone lymphoma, and Waldenström’s macroglobulinemia, says Flinn.

In CLL specifically, BTK inhibitors have become a prominent frontline standard of care, adds Flinn.

Though, it is important to acknowledge that the toxicities that are associated with ibrutinib, including arthralgias, atrial fibrillation, and, though rare, significant bleeding, often lead to treatment discontinuation in patients with CLL.


'CLL flares’ reported after stopping ibrutinib

'CLL flares’ reported after stopping ibrutinib

Patients with ibrutinib-resistant CLL should remain on the BTK inhibitor until immediately before starting their next therapy, Australian haematologists have advised. In a Commentary article in Leukemia & Lymphoma, Dr Chloe Tang and Associate Professor Constantine Tam wrote that ‘CLL flares’ – accelerated CLL progression after ceasing ibrutinib – can be difficult to distinguish from …

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Durable disease control achieved with BTKi salvage therapy in patients with CLL

Durable disease control achieved with BTKi salvage therapy in patients with CLL

Patients with chronic lymphocytic leukaemia (CLL) who progress on venetoclax can achieve durable disease control with Bruton tyrosine kinase inhibitor (BTKi) salvage therapy, new Australian research reveals. The study included 23 patients with refractory/relapsed CLL who received a BTKi (ibrutinib [n=21], zanubrutinib [n=2]) after ceasing the BCL2 inhibitor venetoclax due to progressive disease. After initiating …

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Gillian Corbett

A current overview of medications in the treatment of CLL in New Zealand

A current overview of medications in the treatment of CLL in New Zealand

A talk presented to the CLL Advocates NZ Board of Trustees on 7 May 2020 by Dr Gillian Corbett MBChB, FRACPath, MRCP, FRACP, Trustee, CLL Advocates NZ  https://clladvocates.nz/about-us/trustees/

Not all CLL patients need treatment. Treatment is offered for progressive disease, increasing lymphadenopathy, anaemia, and/or low platelets, as well as rapidly increasing lymphocyte count.

Patients with mutated heavy genes (about 55%) generally carry a better prognosis than those with unmutated heavy genes. This testing is unfortunately unavailable in NZ.

First line treatment

In New Zealand, FCR (fludarabine, cyclophosphamide, rituximab) is standard treatment for younger patients with CLL, up to around 70-75 years. Fludarabine and cyclophosphamide are generally given orally, once per month for up to 6 courses, and rituximab is given as an intravenous infusion once a month. This treatment is very successful for patients with mutated heavy chain genes, and some may potentially be cured. However those with unmutated heavy chain genes do not respond so well and frequently relapse early. A study has shown that such patients respond well to ibrutinib with a better outcome than FCR. However ibrutinib is not funded to treat CLL in New Zealand.

For older patients (70-85 years) the funded first line treatment is bendamustine and rituximab. Each is given by infusion once per month for up to 6 months. This treatment has been shown to be not so effective for younger patients, for whom FCR is preferred, but is better tolerated by older patients

For older patients or those unfit for bendamustine and rituximab, chlorambucil and obinutuzumab is the funded treatment. Obinutuzumab is a more potent antibody than rituximab and has been shown to be more effective in combination with chlorambucil in these patients.

Venetoclax is funded as first line treatment for patients with del17p chromosomal change. These patients do not generally respond well to the other funded treatments. It targets BCL2 which results in an increased rate of CLL cell death. It is given orally and is generally well tolerated but in some patients with bulky disease it may cause tumour cell lysis which can result in kidney damage. Such patients may require hospitalisation for intravenous fluid and supportive care.

Second line treatment

Patients who relapse within 3 years of previous treatment are eligible for venetoclax and rituximab. The venetoclax is to be used for up to 24 months. It is given orally.

Research

There are studies overseas of combining ibrutinib and venetoclax treatment with a view to achieving negative minimal residual disease and possibly cure of CLL. The results of these studies are awaited.

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor which interferes with CLL cell growth. It is effective in the majority of de novo and relapsed patients with CLL. It is not known to cure CLL. It is generally well tolerated. Other BTK inhibitors that are more targeted are being trialled eg acalabrutinib and zanubrutinib. Tauranga and Waikato Hospitals are part of an international clinical trial comparing ibrutinib to zanubrutinib in relapsed CLL.

Other areas of research are in the development of immune therapies eg CAR-T cells to target CLL cells.


Study Findings Support Long-Term Efficacy and Safety of Acalabrutinib in R/R CLL

Study Findings Support Long-Term Efficacy and Safety of Acalabrutinib in R/R CLL

Long-term follow-up of a phase 1/2 study demonstrated durable efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), according to results published in Blood.1

Acalabrutinib, an oral selective Bruton tyrosine kinase (BTK) inhibitor, was approved in November 2019 by the US Food and Drug Administration (FDA) at a dose of 100 mg twice daily for the treatment of adult patients with CLL/SLL.2

This analysis included updated results from the initial phase 1/2 study of acalabrutinib in an expanded cohort of 134 adult patients with relapsed/refractory CLL/SLL with a median age of 66 years (ClinicalTrial.gov Identifier: NCT02029443) followed for a median of 41 months. While patients initially received acalabrutinib at a dose of either 200 mg once daily or 100 mg twice daily, only the latter dose of acalabrutinib was administered following a study amendment in May 2015 based on results of pharmacodynamics studies.

At data cutoff, more than half of study patients were still receiving acalabrutinib, with 21% of patients discontinuing acalabrutinib therapy due to progressive disease.

Overall response rate (ORR), including patients achieving a complete response, a partial response. or a partial response with lymphocytosis (PRL) was 94%, with PRL as best response in 6% of patients. Of note, ORR was 90% or higher in the subgroups of patients with disease characterized by del(17)(p13.1), 
del(11)(q22.3), unmutated immunoglobulin heavy variable (IGHV) genes, and complex karyotype characterized by 3 or more abnormalities. In addition, median duration of response (DOR) was not reached, with 45-month DOR estimated at 63% for those with PRL or better.

Median progression-free survival (PFS) for the overall study population was not reached at the time of the analysis, with 45-month PFS estimated at 62%. In the subgroups of patients with disease characterized by del(17)(p13.1), unmutated/mutated IGHV, complex karyotype, and del(11)(q22.3), median PFS was 36 months, not reached, 33 months, and not reached, respectively.

Regarding safety, grade 3 or higher adverse events occurred in 66% of patients, including neutropenia, pneumonia, hypertension, anemia, and diarrhea in 14%, 11%, 7%, 7%, and 5% of patients, respectively.

Eleven percent of patients discontinued acalabrutinib as a result of one or more adverse events. Adverse event-related death was reported in 7.5% of patients, with half of these attributed to pneumonia.

Atrial fibrillation of any grade occurred in 7% patients, with approximately 3% experiencing atrial fibrillation of at least grade 3. Major bleeding classified as grade 3 or higher, serious, or involving the CNS, was reported in 5% percent of patients.

“Notably, acalabrutinib with follow-up beyond 4 years has shown a decreased frequency of [adverse events] over time and no long-term safety issues to date,” the study authors noted.

In their concluding remarks, they further commented that “this updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL.”

References

  1. Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 resultsBlood. 2020;135:1204-1213.
  2. Acalabrutinib (Calquence®) [package insert]. 2019. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

Originally published on Cancer Therapy Advisor


Coronavirus: Separating Fact From Fiction for CLL Patients

Coronavirus: Separating Fact From Fiction for CLL Patients

“We’re learning every day, and we’re modifying and adjusting based on what we learn,” says Dr. William Wierda, from The University of Houston MD Anderson Cancer Center, as new information continues to come to light on the novel coronavirus.

Can cancer medicines be used to treat COVID-19? Does the effect of the virus vary by CLL subtype? Is ibrutinib (Imbruvica) being mixed with Coca-Cola? Watch to hear expert perspectives on questions like these and more.

With much misinformation circulating online, Dr. Wierda and Dr. Kerry Rogers, from The James Comprehensive Cancer Center at OSU, joined Patient Power to help chronic lymphocytic leukemia patients separate fact from fiction and explain how care is being modified during the pandemic.

This program is sponsored by Pharmacyclics and Janssen. These organizations have no editorial control, and Patient Power is solely responsible for program content.

Click the image to view this video.

Originally published on Patient Power


COVID-19's Impact on How Patients with CLL, Myeloma Have Received Treatment

COVID-19's Impact on How Patients with CLL, Myeloma Have Received Treatment

CURE® recently invited patients, survivors, caregivers, advocates and health care professionals to attend its first-ever live webinar, “Hear from the Experts: COVID-19 & Cancer Care for Patients.”

Sponsored by Janssen and Pharmacyclics, the webinar was designed to provide those affected by chronic lymphocytic leukemia (CLL) and myeloma with information and updates as it pertained to the current landscape of cancer care during the uncertain times of the new coronavirus (COVID-19).

Dr. Saad Usmani, chief of the Plasma Disorders Program and director of clinical research in hematologic malignancies at the Levine Cancer Institute served as the moderator for the webinar. Panelists included:

  • Dr. Zainab Shahid, medical director of bone marrow transplant infectious diseases at the Levine Cancer Institute
  • Dr. Farukh Awan, director of the Lymphoid Malignancies Program at the Harold C.  Simmons Comprehensive Cancer Center at UT-Southwest
  • Dr. Ian Flinn, director of the Lymphoma Research Program at Sarah Cannon Research Institute
  • Dr. Lee Greenberger, chief scientific officer at the Leukemia and Lymphoma Society

In the first part of this series, Dr. Farukh Awan addresses how the pandemic has affected his practice, as well as how it has impacted how patients with CLL and myeloma have received care.

Awan: We’re all learning. This is something that none of us have experienced before, so we’re learning more and more about the virus with every passing day. There’s more data coming out. There’s a lot of new clinical trials happening, so everything is happening at the same time we are all trying to do the best we can to decrease the spread of this so we can better manage our patients who do get infected and that would not overwhelm the system.

In line with that, every institution has instituted a policy that suits their needs. Fortunately, in Dallas we started with social distancing early and I think we were able to keep the numbers fairly manageable.  And yet, we still had to make a lot of changes to the way we practice.

In terms of outpatient management, we have limited the number of visitors that come in with the patient. We try to keep them outside of the clinic area. We also have tried to make the most of our electronic visits so that the least number of patients get exposed to the staff, and vice versa. We have also started utilizing local labs, which are a lot of times not as busy as the oncology clinics and cancer centers. Those labs then give us the results from the blood work that we need. I think we’ve utilized all of these approaches on the outpatient side. We’ve also been fortunate that we have a service for drive-through testing for patients who have active symptoms. We are trying to get them through the drive-through testing and if they are positive, then they’re asked to quarantine at home.

For those who do get really sick and need to go to the hospital, the ER has a system where everybody gets quarantined on arrival. They get tested in a timely manner with a rapid test for their COVID-19 and if they are positive, they are then sent to a specific isolation floor meant for those patients. There are mechanisms in place, both on the outpatient and inpatient side, which have tried to minimize exposure to patients, family members, and staff at the same time.

As far as for patients with chronic lymphocytic leukemia (CLL) who are concerned, a lot of our patients can afford to wait a little bit to start their new treatment. For patients who are not actively getting treated, we do plan on delaying their treatment until at least we have some idea of better treatment modalities and if their symptoms can be managed by other approaches. For those who are on active treatment, we are trying to continue those treatments while trying to minimize their return visits and we’re trying to do that electronically as much as possible, either via telephone calls or through a video visit. Either option is being utilized so that patients can limit their back and forth to the clinic.

We know that our patients with CLL are especially at a high risk of getting infections. Infection-related complications are one of the leading problems in our patients. We expect that our patients would be at an extremely higher risk and that’s why we are also advising that they socially distance themselves from any known patient or persons who might have the virus. We are now also learning that there is a fairly large group of patients, or people in the community, who would have asymptomatic disease and they can potentially spread the disease to a lot of other people without even knowing that they have the virus, and I think that’s very scary for our patients since they are immunocompromised at baseline, even without treatment.

It’s a unique challenge. We are recommending that all our patients with CLL practice social distancing, minimize exposure, and even if they don’t have to go out for groceries they shouldn’t. I think if we can do that over the next few months, hopefully, we can right this and hopefully we will get our patients through it without having any serious complications.

On the other hand, some patients with lymphoma can wait to start treatment, some of them cannot. In some aggressive lymphomas, the treatments need to be started right away. For those patients who need to start treatment right away we are following them very closely for any symptoms. If they exhibit any symptoms, like fevers or a cough or any upper or lower respiratory tract symptoms, we are testing them before we give them any chemotherapy.  If somebody is positive for the virus, we are not using chemotherapy for those patients and we are trying to delay chemotherapy as much as possible.

For patients already on treatment and need to be admitted to the hospital we are screening them with a test 48 to 72 hours prior to their admission to the hospital, and once they’re negative, they can then start their treatments. We’re trying to use all these resources that are available to us to try to minimize the risk, again, to the staff and to patients and to prevent any complications that might happen in the future.

Finally, I’d like to make a point regarding stem cell transplants and CAR T. These can be potentially curative options for our patients. We also realize that a lot of our patients will get extremely sick during that process. So, we have multiple challenges with regards specifically to stem cell transplants and CAR T.  We’ve also learned that the Red Cross and blood banks are being stretched and that their resources are limited. The number of donors is limited. Since there aren’t a lot of donors like we normally would have, getting access to blood products can be a challenge for our transplant patients, especially if they need blood transfusions and platelets.

We’re trying to very specifically look at all the factors for every patient who is undergoing an autologous transplant, or a CAR T cell treatment and we are trying to select the patient who absolutely needs to proceed with it. We are taking that patient to transplant and are employing a multitude of tests at various time points and making sure there are no visitors during their hospital stay, and as much as possible we are ideally using electronic visits for follow-up to minimize exposure.

Have we done transplants in the last few months? Absolutely. We’ve also done CAR Ts and we have successfully and safely gotten patients through it, but it’s challenging.  It can be done but we have to be extremely careful that we minimize exposure to our patients and hopefully we can all get through this.

Originally published on Cure


How COVID-19 Has Impacted Clinical Trials for Chronic Lymphocytic Leukemia

How COVID-19 Has Impacted Clinical Trials for Chronic Lymphocytic Leukemia

Many patients with chronic lymphocytic leukemia (CLL) rely on the outcomes of clinical trials that examine new ways to treat the disease. But with the new coronavirus (COVID-19) pandemic changing the way health care is provided around the country, so too is participation in these trials, according to Dr. Brian Koffman, the co-founder, executive vice president and chief medical officer of the CLL Society.

CURE® recently spoke with Koffman about how clinical trial participation has become more flexible over the course of the pandemic in an effort to keep immunocompromised individuals like those with CLL safe, by utilizing things like telemedicine and localized care to avoid exposure to the virus.

Watch here

Originally published on Cure


New Research Shows Real-World Track Record of Common CLL Therapies

New Research Shows Real-World Track Record of Common CLL Therapies

A new study offers real-world insights into the results of several common and emerging therapies for chronic lymphocytic leukemia (CLL), and suggests differences in how the drugs perform in community settings versus clinical trial settings.

The study, based on the Connect CLL registry, was published this month in Blood AdvancesThe registry enrolled 1494 patients with CLL who sought treatment at 199 healthcare centers in the US between the years 2010 and 2014. Most of the centers were community-based. Patients were grouped by line of therapy upon enrollment in the study, and the median follow-up was 46.6 months.

The most common treatments in the study were bendamustine and rituximab (BR), with just over one-third of patients receiving that therapy. Next was fludarabine, cyclophosphamide, and rituximab (FCR), which was given to 21.4% of patients. Rituximab monotherapy was prescribed in 18.5% of cases.

Median overall survival (OS) was not achieved in the first line of therapy; median OS was 63 months in the second line of therapy, and 38 months in the third or higher line of therapy.

In the first line of therapy, median event-free survival (EFS) was 59 months for patients on BR and 55 months in FCR. In a multivariate analysis, BR or FCR in the first line of therapy outperformed the other therapies in both OS and EFS. Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center, and colleagues noted that ibrutinib also had a positive impact, according to the data.

“As expected, EFS and OS became shorter and response rates decreased as LOT increased,” Mato and colleagues wrote. “In addition, ibrutinib therapy improved OS in all R/R [relapsed or refractory] patients regardless of the LOT in which it was received (LOT2, LOT3, or LOT≥4), even though it was approved by the FDA after the start of the Registry.”

The timing of the study period also meant that no patients in the study received ibrutinib in a frontline setting.

Pneumonia (11.6%) and febrile neutropenia (6.2%) were the most common adverse events.

The investigators used the data to identify a new category of patients at particularly high risk of death within 2 years of enrollment. The group was defined by a number of characteristics, including site of enrollment, race, age, insurance coverage, income, enrollment regimen, Charlson Comorbidity Index score, Eastern Cooperative Oncology Group Performance Status score at enrollment.

The analysis differed from some clinical trials in that it did not show a significant advantage for FCR over BR. The findings suggest that FCR’s advantages may not translate into community practice, Mato and colleagues said, adding that it might be due to less-rigorous use of the therapy in a real-world setting.

Though the treatment landscape evolved over the course of the study (and continues to evolve), the authors say the study has meaningful insights for clinicians as they make treatment recommendations.

“Receiving novel agents in LOT2 improved outcomes in patients who received previous CIT [chemoimmunotherapy], supporting the inclusion of ibrutinib, idelalisib, duvelisib, and venetoclax in the treatment paradigm for patients with R/R CLL,” they wrote. “However, additional randomized clinical trials and real-world data are needed to establish the role of non-CIT regimens in the treatment of patients with R/R CLL.”

Originally published on AJMC