TML Helps Predict Time to Treatment in CLL and its Precursor, Study Shows
TML Helps Predict Time to Treatment in CLL and its Precursor, Study Shows
This article was originally published by AJMC
Tumor mutational load (TML) can be used as a prognostic indicator in patients with chronic lymphocytic leukemia (CLL) and high-count monoclonal B-cell lymphocytosis (HC MBL), according to a new study.
The findings suggest that performing a focused mutation panel on recurrently mutated CLL genes could help risk-stratify patients and more accurately predict time to treatment (TTT).
Most patients who are newly diagnosed with CLL do not require therapy for a number of years, but some patients will require therapy right away. CLL’s precursor, HC MBL, will progress to CLL at a rate of 1-5% per year, but it can be difficult to predict how soon an individual patient will progress.
In hopes of better predicting patient progression, investigators from the Mayo Clinic conducted a study to analyze the total number of recurrently mutated CLL genes (TML) and the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed patients with CLL and HC MBL.
To do so, they recruited 557 patients, 445 of whom had CLL and the remainder of whom had HC MBL, and sequenced 59 genes in the patients. Their goal was to identify links with TTT, adjusted for CLL and sex.
The authors found that TML correlated with shorter TTT. Among patients with low/intermediate risk, the link was even stronger when patients were stratified by CLL-IPI. Their results are published in the American Journal of Hematology.
Ball Score Predicts Benefit From Ibrutinib in CLL
Ball Score Predicts Benefit From Ibrutinib in CLL
This article was originally published by MedScape
The BALL score was able to identify a subset of patients with chronic lymphocytic leukemia (CLL) who particularly benefit from single-agent ibrutinib therapy, according to the results of a study of 111 patients followed from two different institutions.
The BALL model consists of four factors: serum beta₂-microglobulin at 5 mg/dL or greater, hemoglobin < 110 g/L for women or < 120 g/L for men, lactate dehydrogenase [LDH] > upper limit of normal [UNL], and time elapsed from last therapy less than 24 months. Each parameter was alloted 1 point, leading to a stratification of patients into three different prognostic groups: low risk (score 0-1), intermediate risk (2-3), and high risk (score 4), according to a report published online in Leukemia Research.
According to Stefano Molica, MD, of the Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues, the majority of patients (82%) were clinical Rai stage II-IV. The median patient age was 63 years and nearly 68% were men.
The researchers assessed four models for predicting overall survival. The modified version of CLL-International Prognostic Index (CLL-IPI) failed to provide prognostic information in relapsed/refractory (R/R) CLL (P = .77) as did the Ahn et al. model (P = .95) and a simplified BALL model (P = .09). In contrast, the full BALL score captured two groups of patients with significant differences in survival (hazard ratio, 0.240; 95 % confidence interval, 0.10-0.54; P = .0005); however, because of the low number of patients in the high-risk category, these cases were combined with the intermediate-risk group.
The BALL score identified a subset of patients, accounting for about 50% of the whole population, who particularly benefit from single-agent ibrutinib, according to Dr. Molica and his colleagues. These patients had a survival rate of 85% at 3 years.
“In contrast, the outcome of subjects with intermediate-high risk is disappointing. These patients should be considered for a combination of targeted drugs or cellular-based therapies,” the researchers concluded.
Cohen Expands on Treatment Options in Patients With Genomic Aberrations in CLL
Cohen Expands on Treatment Options in Patients With Genomic Aberrations in CLL
This article was originally published by Targeted Oncology
During a virtual Case Based Peer Perspective event, Jonathon B. Cohen, MD, MS, the codirector of the Lymphoma Program, medical director of Infusion Servies, and associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and Winship Cancer Institute, discussed a case of a 71-year-old woman diagnosed with chronic lymphocytic leukemia.
Targeted Oncology™: What are reasonable treatment options to consider in a patient with CLL?
COHEN: The National Comprehensive Cancer Network guidelines offer 6 treatment options for patients with del(17p).1 As I tell my fellows when I work with them, if you ever see a list of preferred regimens with 6 options, that likely means that nobody really knows what the best option is.
The 1 option not listed in the guideline is chemotherapy, especially in the relapsed setting for patients with del(17p). I generally would not use chemotherapy.
The only exception to that might be a situation where we have a patient who’s young and for whom we’re thinking about moving on to something like an allogeneic transplant or some other definitive therapy. We might consider using chemotherapy for a cycle or 2. But otherwise, if you’re not going in that direction, that’s the 1 thing we do feel comfortable saying—that is, that chemotherapy is probably not the right option.
FDA Clears clonoSEQ to Detect MRD in Chronic Lymphocytic Leukemia
FDA Clears clonoSEQ to Detect MRD in Chronic Lymphocytic Leukemia
This article was originally published by AJMC
Adaptive Biotechnologies received its third approval from the FDA for the use of its next-generation sequencing assay to detect minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL).
The assay, clonoSEQ, uses a proprietary immunosequencing platform to monitor for MRD, where a small number of cancer cells remain during and after treatment. It is difficult to detect without precise, sensitive tools, and can lead to a recurrence of disease.
The approval follows a decision by CMS in January to pay for cloneSEQ testing for CLL, in addition to multiple myeloma and B-cell acute lymphoblastic leukemia. Nearly 80% of US patients with CLL are age 65 or over.
Continue reading this article on AJMC
Experts Outline Best Practices in the Treatment of Chronic Lymphocytic Leukemia
Experts Outline Best Practices in the Treatment of Chronic Lymphocytic Leukemia
This article was originally published by Pharmacy Times
Chronic lymphocytic leukemia (CLL) is a cancer of the blood and bone marrow that can be treated to extend the life of some patients even by decades. Treatments and best practices are developing rapidly and health care providers need to stay up to date on all relevant information. In a Pharmacy Times Insights video series, a panel of experts discussed how to best treat and monitor patients living with CLL.
The panel included Alison Duffy, PharmD, BCOP, an associate professor and clinical pharmacy specialist in oncology at the University of Maryland School of Pharmacy and Cody Steeves, PharmD, BCOP, a clinical pharmacist for Biologics by McKesson.
Both intravenous (IV) and oral CLL medications are available, each with their own benefits and disadvantages. A combination method is also used by many patients, but that also presents a unique set of challenges.
“Some of the economic challenges we’ve seen have been the timely approval of the oral and the IV therapy together because of pharmacy benefits and medical benefits, and so that can be a challenge, especially if a patient’s disease is very aggressive. If they have progressed on ibrutinib it would be really important to start their subsequent therapy very quickly, or it can progress to Richter transformation,” Duffy said. “The economic challenges in improving can be a barrier. As pharmacists, anything we can do to facilitate the approval process, and in the clinic, I can certainly help with the prior authorization process.”
Experts Discuss Treatment Advances for Chronic Lymphocytic Leukemia
Experts Discuss Treatment Advances for Chronic Lymphocytic Leukemia
This article was originally published by Pharmacy Times
In the Pharmacy Times ® Directions in Oncology™ Insights series on chronic lymphocytic leukemia (CLL), experts Alison Duffy, PharmD, BCOP, and Cody Steeves, PharmD, BCOP, discussed current treatment recommendations and what is next for the disease state.
CLL is a rare cancer of the blood and bone marrow, and although it is difficult to treat many advances have been made in the past 6 years, said Duffy, an associate professor, clinical pharmacy specialty in oncology at the University of Maryland School of Pharmacy.
Earlier recommendations included single-agent chemotherapy or single-agent monoclonal antibodies, but Duffy explained that patients are increasingly receiving small molecule inhibitors, including Bruton tyrosine kinase (BTK) inhibitors.
Without the use of single-agent chemotherapies or single-agent monoclonal antibodies, Duffy said pharmacists can see patients with CLL in many settings.
“Using those as single agents, or more commonly in combination, that’s where the pipeline and future directions are really moving towards, with combination therapy as well as more potent, more selective, targeted therapies,” she said.
According to recommendations from the National Comprehensive Cancer Center (NCCN), Duffy said some current frontline treatment agents include ibrutinib, venetoclax plus obinutuzumab, acalabrutinib with or without obinutuzumab, and chemo-immunotherapy, when warranted.
Frontline therapies present various challenges, although Duffy said the treatment criteria has become less rigid.
“Some of the things that I would think about would be age, fitness, comorbidities such as atrial fibrillation, and renal function if I was going to give something like fludarabine within the FCR [fludarabine, cyclophosphamide, and rituximab] regimen,” Duffy said.
She added that considering patient preferences and clinical experiences is important. Some patients may not be great candidates for oral therapy due to a lack of access, finance, comfort level, or adherence challenges. Similarly, transportation might be an issue for patients receiving intravenous chemotherapy and should be considered.
“Moving forward, it’s positive to see that the outcomes, when they’re stratified by those patients with the deletions, still tend to trend in the positive direction for those patients with these newer oral therapies we’ve had over the past 5 or 6 years,” Steeves said.
The experts also turned their attention to minimum residual disease (MRD) testing and how it affects the use of limited duration therapy. MRD testing is particularly helpful for diseases that require stronger treatments, Steeves said. He explained that some data has found that obtaining a low or negative MRD corresponds with significantly increased progression-free survival compared with medium or high levels of MRD. However, patients receiving oral agents, especially single-agent BTK inhibition alone or with a CD20 inhibitor, are not expected to achieve MRD. Despite the lack of MRD, Steeves said these agents can be valuable.
“Even though we’re not seeing those deep remissions with MRD negativity, undetectable MRD, we certainly are still seeing a large benefit of using these agents without that,” Steeves said.
Steeves, clinical oncology pharmacist, Biologics by McKesson, also emphasized the importance of a patient-specific treatment plan. Some patients may want to take the drug for as short a period as possible, while others find that it does not disrupt their daily lives to a large extent because they are already receiving multiple medications.
Finally, Duffy and Steeves turned their attention to BTK inhibitor monotherapy for patients with newly diagnosed CLL. Ibrutinib, a new BTK inhibitor, was investigated in the RESONATE trial (NCT01578707), which found long-term benefit of the drug upon 6-year follow-up. The trial also established ibrutinib as the first-line choice for older patients and those without a 17P deletion, thereby demonstrating significant progression-free survival benefit among those high-risk subgroups. However, Duffy noted that ibrutinib is not for everybody.
“If you have a patient with uncontrolled atrial fibrillation, who has a high risk of bleeding that can’t be mitigated, or uncontrolled hypertension despite optimizing therapy management, ibrutinib wouldn’t be my first choice,” Duffy said.
Although the various treatments all need to be evaluated based on unique patient needs, the recent developments for the treatment of CLL are very promising and exciting, Duffy concluded.
“We’re getting to have a better understanding of CLL biology and some of the prognostic indicators,” Duffy said. “These new therapies allow for treatment without some of the traditional chemotherapy agents.”
THE PHARMACY TIMES® DIRECTIONS IN ONCOLOGY™ INSIGHTS SERIES ON CLL CAN BE VIEWED AT WWW.PHARMACYTIMES.COM/INSIGHTS.
Immunoglobulin Abnormalities Do Not Affect Overall Survival in CLL, Study Finds
Immunoglobulin Abnormalities Do Not Affect Overall Survival in CLL, Study Finds
This article was originally published by AJMC
Patients with chronic lymphocytic leukemia (CLL) who have immunoglobulin (Ig) abnormalities at diagnosis have shorter treatment-free survival (TFS) periods, but do not have shorter overall survival (OS), according to a new study.
The report, published in the British Journal of Hematology, sheds new light on the ways in which qualitative and quantitative gammaglobulin abnormalities affect—and do not affect—the prognosis of patients with MM.
A team of investigators, including corresponding author Luca Laurenti, MD, of Gemelli University Hospital, in Italy, noted that prior research has looked at the impact of hypogammaglobulinemia in patients with CLL. However, they said there is significant heterogeneity between cohorts, and much research has included both treated and untreated patients, making it difficult to examine the prognostic impact of such abnormalities.
In an effort to get a clearer picture of the impact, the investigators examined 1505 patients with CLL and split them into 4 cohorts based on the degree of Ig aberrations upon diagnosis. The vast majority (1083) had normal Ig levels, making up the largest of the 4 groups. The other 3 groups included 73 patients with IgM monoclonal gammopathy (IgM/CLL), 149 patients with IgG monoclonal gammopathy (IgG/CLL), and 200 patients with hypogammaglobulinemia (hypo-c).
“IgM paraprotein was significantly associated with a more advanced Binet/Rai stage and del(17p)/TP53 mutation, while IgG abnormalities correlated with a higher occurrence of trisomy 12,” the authors said.
Any type of Ig abnormality lowered a patient’s expected TFS, Laurenti and colleagues found, but there was not a corresponding statistically significant impact on OS.
The authors noted that hypogammaglobulinemia specifically has been linked in the past with higher infections and morbidity. Thus, Ig replacement therapy, which was not investigated in this study, is indicated by current guidelines for the management of patients with CLL.
“However, some studies suggest that hypogammaglobulinemia is not associated with a higher risk of death from infections, but rather with a shorter TFS and a higher risk of death from all causes, being primarily a marker of greater tumor burden and reflecting a more aggressive disease,” Laurenti and colleagues wrote.
This hypothesis is supported by the current study, they said.
More broadly, the authors said their 28% rate of Ig abnormalities fell somewhere in the middle of rates reported in existing research, which ranged from 7% to a high of 80%. The investigators also reported that the proportion of patients with each type of abnormality held generally steady across the 4 cancer centers in the study. However, the authors said the rates were somewhat of a surprise.
“Even though we did not perform any characterization of the heavy-chain isotype and considering that CLL cells express breakpoint cluster region proteins (BCRs) mostly of IgM and IgD isotypes, rather than the IgG class, IgM paraprotein was expected to be more frequent but instead the occurrence of IgG monoclonal component was even double than that of IgM,” the authors said.
In conclusion, the authors said while other factors such as IGHV status mutation, Binet/RAI stage, and del17p are known prognostic factors for OS, “Ig alteration does not have any impact on OS.”
CLL Advocates NZ Newsletter Issue 2
CLL Advocates NZ Newsletter Issue 2
A number of you will be familiar with and regularly reading HealthUnlocked and Patient Power, two patient support and networking services (based in the UK and US respectively) that cover CLL in detail.
For those not yet in the habit, I can recommend both websites to CLL patients, and their families and supporters. You can access both through our website on our useful links page here, or go directly to Patient Power here and HealthUnlocked here. Access is free.
HealthUnlocked is published daily, with ten articles in each edition, that are mainly personal stories and discussion among people with CLL, and also occasional reviews of CLL-related clinical studies.
One such study, in the 20 July edition was on CLL and Covid 19. It provided an analysis of the assessment of 190 patients with CLL who had proven Covid 19 infection. Most presenting for analysis (79%) were in the “severe” category (requiring ICU admission and/or oxygen). This is likely to be related to their having had contact with a hospital. One third of these patients died of Covid 19. The severe group were older than the less severe group, so increasing age is a risk. There was a reduced rate of severe disease in those patients who had had treatment recently as opposed to those who had treatment remotely, or never.
Patient Power (PP) sends email updates to subscribers, generally weekly. Their CLL articles tend to have more of a scientific and medical focus. They also regularly post videos of interviews conducted by the PP CEO, Andrew Schorr, who is a long-term CLL survivor. He interviews well known clinicians on aspects of CLL, including the latest research and developments in the understanding and treatment of CLL. His wife, Esther, also writes regularly for PP.
An interesting recent PP article discussed CAR T-cell treatment, which is being trialled for CLL in research centres globally, including the Malaghan Institute in Wellington (Dr Rob Weinkove).
As an aside on CAR T-cell therapy, I recently enjoyed a book by NZ comedian David Downs on his experience with cancer (in his case, lymphoma). The book is entitled “A Mild Touch of the Cancer”. It is humorous and insightful on living with a serious health issue, and I commend it to you.
Finally, if you haven’t already seen it, check out our message on Facebook and on our website about our first CLL education event, to be held in Auckland, on Wednesday 14 October 2020. The event will be jointly hosted with Leukaemia & Blood Cancer. For those unable to be there in person, you’ll be able to join us via Zoom, to hear talks by and discussion with three of our country’s foremost CLL clinicians. As well as providing the latest information on CLL we hope to extend our reach and ability to support people living with CLL, and I warmly encourage you to help spread the word and attend the event with your family and supporters. More detail on the event including how to register will be circulated soon.
With best wishes
Neil Graham FRACP, FRCP
Executive Director
CLL Advocates NZ
Genetic Prognostic Factors in CLL Treated With Novel Compounds
Genetic Prognostic Factors in CLL Treated With Novel Compounds
This article was originally published by Cancer Therapy Advisor
Treatment with obinutuzumab plus venetoclax (VenG) was associated with improved outcomes compared with obinutuzumab plus chlorambucil (CGlb) among patients with chronic lymphocytic leukemia (CLL) and established unfavorable genetic factors, according to a study published in Blood.1
“Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds,” the authors wrote.
Unmutated IGHV, mutated TP53, and deletion of chromosome 17p (del[17p]) that contains the TP53 locus, are associated with progression and shorter survival among patients with CLL treated with chemoimmunotherapy. Other genetic markers have been identified that are also prognostic for outcomes.
This analysis used data from the multicenter, phase 3 CLL14 trial, which randomly assigned 432 patients with CLL to receive first-line VenG or CGlb. The analysis used fluorescence in situ hybridization (FISH), DNA sequencing, and next-generation sequencing to evaluate genetic prognostic factors.
CLL Experts Favor Social Distancing, but Vary on Treatment Continuation Amid Pandemic
CLL Experts Favor Social Distancing, but Vary on Treatment Continuation Amid Pandemic
This article was originally published by AJMC
The survey is the latest attempt to figure out how best to manage patients with CLL amid the pandemic, given that patients with the cancer tend to be older in age, have comorbidities, and be immunosuppressed.
In a letter to the editor of the American Journal of Hematology, corresponding author Mazyar Shadman, MD, MPH, of the Fred Hutchinson Cancer Research Center, in Seattle, and colleagues reported on a survey sent to 62 CLL specialists in the United States, Canada, Europe, and Australia. Of those, 59 responded to at least 1 question, and 44 completed the entire survey.
When asked about social distancing recommendations for patients with CLL, 32% said they would advise patients to follow the same guidelines as the WHO and Centers for Disease Control and Prevention (CDC) recommend for the general public. Twenty-one percent said they would advise patients to follow those guidelines but also limit regular outings by asking friends to pick up groceries or medications for them. Another 35% went even further, saying patients with CLL should avoid work, even if they are essential workers. The remaining 12% said they would recommend all of the above, plus wearing N95 masks and gloves outside of the house.
In terms of testing, most experts said it was not necessary to test all patients with CLL for COVID-19. Specifically, 62% of experts said they would limit testing to patients who call to and report symptoms, and another 9.5% said tests should be limited to patients who come in for an office visit and report symptoms.
Still, while clinicians generally had a low bar for what types of symptoms warranted testing. “Most favored testing patients with any levels of reported symptoms, even with limited testing availability,” Shadman and colleagues wrote. “With unlimited access, 23% recommended universal testing.”
Though their approaches to social distancing and testing were in line with recommendations for the general public, the experts expressed caution when it came to continuation of outpatient therapy. Only 14% said CLL therapy should be continued unconditionally. Most (60.5%) favored treatment discontinuation, and 25.5% said they favored continuation only based on the specific clinical situation.
However, when it came to bruton tyrosine kinase inhibitors (BTKis), such as ibrutinib (Imbruvica) and acalabrutinib (Calquence), the proportion of experts favoring unconditional treatment continuation was much higher, at 44%.
Shadman and colleagues said the more favorable responses concerning BTKi continuation may be due to concern about disease flares if treatment were stopped.
“Also, there is a theoretical benefit of BTKi’s in blunting the hyperinflammatory stage of COVID-19 disease by targeting macrophages and/or inhibiting pro-inflammatory cytokines,” they said.
Most experts (72%) recommended against the use of intravenous immune globulin (IVIG), though the authors noted that the survey was conducted in late March and early April, “before passive antibodies in the gammaglobulin pool would be expected.”
Shadman and colleagues said additional study is warranted to better understand the optimal approach to management of patients with CLL during the pandemic.