Jared Kaltwasser

A new multi-analyte prognostic assay has demonstrated the potential to risk-stratifying patients with mantle cell lymphoma (MCL) based on the particular molecular signature of an individual patient’s cancer, according to a new study.

The findings could eventually help improve care for patients by MCL by allowing clinicians to more accurately tailor care to patients. The study was published in the 

MCL therapy has significantly improved in recent years with the approval of novel agents, but corresponding author Lisa M. Rimsza, MD, of the Mayo Clinic, and colleagues, noted that the response to these new therapies is widely variable from patient to patient. That is in large part because most treatment plans are arrived at by taking into account broad measures like a patient’s general health, age, and perceived ability to tolerate regimens.

That status quo changed to some extent with the 2008 introduction of the MCL International Prognostic Index (MIPI), which uses a mix of clinical factors and lab results to stratify patients. A variation of that index, the biologic MIPI (MIPI-b) uses immunohistochemical staining for the antigen Ki-67, a marker for cell proliferation that Rimsza and colleagues said can add value to the MIPI. Still, the investigators said such tools still have significant room for variance.

“[M]ethods using clinical data, tumor morphology, and/or immunohistochemistry are highly subject to inter-observer and inter-laboratory variability,” they said.

However, Rimsza and colleagues have developed what they believe is another, more precise method of risk-stratifying patients. The Lymphoma/Leukemia Molecular Profiling Project research consortium was able to identify a proliferation signature using targeted “LymphoChip” microassays that was later enhanced and developed into a clinically compatible assay known as MCL35. The tool includes 17 informative genes and 18 house-keeping genes. The 17 informative genes include 13 that correspond positively with proliferation and thus with poor survival outcomes; the other 4 correspond negatively with proliferation and suggest better survival outcomes.

Having developed the tool, Rimsza and colleagues sought to evaluate its suitability in a clinical laboratory and its effectiveness compared to the Ki-67 proliferation marker.

Working with the Molecular Diagnostics-Arizona Laboratory, the assay was assessed for accuracy, sensitivity, specificity, use in acid-decalcified bone marrow core biopsies, fixatives, lower limit of RNA input, quality metrics, and other laboratory parameters.

The investigators found that the MCL35 assay is a “robust technique with outstanding reproducibility.”

“The MCL35 assay demonstrated excellent concordance with the gold standard signature defined by Affymetrix gene expression profiling, thereby validating the accuracy of the assay,” Rimsza and colleagues wrote in the published report.

They said samples run multiple times by different users yielded similar results with only small standard errors. The assay was found to be capable of robustly assigning risk category even with inputs as low as 50 ng of formalin-fixed paraffin-embedded (FFPE) sample–derived RNA.

On the other hand, Rimsza and colleagues could not verify the accuracy of the assay when analyzing acid-decalcified core biopsies. The investigators said only 4 of 10 biopsy attempts resulted in successful analysis, and all 4 of those successful biopsies led to high-risk MCL35 scores.

“Caution is therefore advised in the use of bone marrow core biopsies for the MCL35 assay, since the proliferation of the background hematopoietic cells is so high that it may dominate the results,” they said.

The authors said they were unable to assess MCL35 in other types of non-nodal samples because they lacked clinical annotation, though they said a previous publication suggested the assay is accurate and correlated with overall survival.

In the current study, the investigators compared their risk-stratification results using the MCL35 assay with Ki-67 assays. Overall, the agreement between the 2 tools was just 37%. Further analysis suggested the Ki-67 tool errs on the side of a higher risk category, whereas the MCL35 tool tended to identify more patients as lower risk.

“Since the MCL35 assay is a multiplexed assay based on the weighted expression of 17 proliferation genes rather than a single marker, it may provide a more accurate reflection of the complex multifaceted/multifactorial nature of tumor biology, and, as shown in prior publications, is highly reproducible as compared with other methods,” they wrote.

The investigators concluded by stating that existing data support molecular signatures assessed by digital gene expression profiling as an “excellent choice for use in clinical trials wherein the relationships between biomarkers and patient outcome may lead to clinical practice changes.”

The study authors said the MCL35 tool has been launched as a laboratory-developed test and can be used in retrospective analysis of clinical trials and potentially in prospective trials as well; the assay has already been used in one such trial, and others are underway.

Ramsower CA, Maguire A, Robetorye RS, et al. Clinical laboratory validation of the MCL35 assay for molecular risk stratification of mantle cell lymphoma. 

. 2020;13(4):231-238. doi:10.1007/s12308-020-00418-4

Articles

A new multi-analyte prognostic assay has demonstrated the potential to risk-stratifying patients with mantle cell lymphoma based on the particular molecular signature of an individual patient’s cancer, according to a new study.

MCL35 Assay Stratifies Risk in Patients With Mantle Cell Lymphoma

Patients with myelofibrosis (MF) who receive ruxolitinib (Jakafi) appear to face a higher risk of second primary malignancy (SPM); these risks are suggested to be even higher in men and patients with a history of arterial thrombosis and prolonged hydroxycarbamide (hydroxyurea; Hydrea) exposure, a new real-world study shows. As such, the authors of the report, published in the 

 said active skin surveillance is recommended for patients with MF treated with ruxolitinib.

Patients with MF, like patients with all types of myeloproliferative neoplasms (MPNs), face a higher-than-average risk of SPM, and existing research shows SPM is a major cause of morbidity and mortality in patients with MF.

Ruxolitinib is a selective Janus kinase 1 and 2 (JAK1/2) inhibitor used to treat MF-related splenomegaly and symptoms. The drug is effective in the majority of cases, but it has been linked with an increased risk of non-melanoma skin cancers (NMSCs).

Corresponding author Nicola Polverelli, MD, PhD, of the University of Brescia, in Italy, and colleagues collected real-world data on the incidence, type, and timing of SPMs in patients with MF who received ruxolitinib therapy in order to better understand risk factors and survival rates.

The investigators pulled data retrospectively from a database of patients with chronic-phase MF who were treated with ruxolitinib between 2011 and January 2020 at one of 20 European hematology centers.

Polverelli and colleagues pulled a range of clinical data for patients and contacted participating cancer centers to find out information about all malignancies occurring before or after ruxolitinib therapy. Myelodysplasia and acute leukemia were excluded from the analysis, since they are possible natural evolutions of MF.

A total of 700 patients were identified, all of whom had MF and were treated with ruxolitinib. The median follow-up post-initiation of ruxolitinib therapy was 2.9 years (range, 0.1-8.4).

Among the 700 patients, 80 (11.4%) went on to develop a total of 87 SPMs following initiation of ruxolitinib. SPMs were developed a median of 2.8 years after the start of ruxolitinib therapy (range, 0.3-32.2); the incidence rates also tended to increase over time. NMSCs were the most common malignancy, representing just over half (50.6%) of the SPMs. No aggressive lymphomas were reported.

The investigators then conducted a multivariate analysis to determine risk factors for SPMs. They found that men had a higher risk of SPM (hazard ratio [HR], 2.37; 95% CI, 1.22-4.60; 

 = .01). Patients with thrombocytosis >400 x 109/L at the start of ruxolitinib therapy also had heightened risk (HR, 1.98; 95% CI, 1.10-4.60; 

For NMSC specifically, male sex and a duration of hydroxyurea and ruxolitinib therapy exceeding 5 years were risk factors, with HRs of 3.14, 3.20, and 2.93, respectively.

In other types of SPMs, risk factors for SPMs were male sex (HR, 2.41; 95% CI, 1.11-5.25; 

 = .03), platelet counts above 400 x 109/L (HR, 3.30; 95% CI, 1.67-6.50; 

 = .001), and previous arterial thromboses (HR, 3.47; 95% CI, 1.48-8.14; 

The authors reported that 7.5% of patients died due to a second cancer, a figure somewhat higher than data reported prior to the approval of ruxolitinib, although the authors admitted that this is challenged by the risk status of patients included in the analysis.

In discussing their findings, Polverelli and colleagues noted that men have already been found to be at higher risk for most neoplasia, including NMSC.

Similarly, they said the risk of SPM has long been shown to be higher in patients with thrombocytosis and previous arterial thrombosis. The authors wrote that both conditions are characterized by inflammation, and in the study data, both were present long before the start of ruxolitinib in most patients. “Therefore, the underlying inflammatory process causing thrombocytosis and arterial events has persisted over time, creating the substrate favorable to the accumulation of genetic damages, from which second cancers may result,” they wrote.

In terms of clinical practice, the authors said careful skin surveillance is essential for all patients with MF who undergo ruxolitinib therapy, and especially for those who also are exposed to hydroxyurea for long periods of time. Patients with a history of arterial thrombosis should be screened for second cancers, and clinicians should consider the patient’s gender when assessing risk.

“Further collection of data on [ruxolitinib] therapy in patients stratified by sex will probably contribute to the development of personalized strategies for the management of therapy- and disease-related complications,” they concluded.

Polverelli N, Elli EM, Abruzzese E, et al. Second primary malignancy in myelofibrosis patients treated with ruxolitinib. 

. Published online November 21, 2020. doi:10.1111/bjh.17192

Patients with myelofibrosis who receive ruxolitinib appear to face a higher risk of second primary malignancy; these risks are suggested to be even higher in men and patients with a history of arterial thrombosis and prolonged hydroxycarbamide exposure.

Surveillance for Second Primary Malignancy Recommended in Select Patients With Myelofibrosis Treated With Ruxolitinib

New data show patients with mantle cell lymphoma (MCL) who were treated with ibrutinib (Imbruvica) in a community setting had similar outcomes to patients given the Bruton’s tyrosine kinase (BTK) inhibitor in a clinical trial setting, a retrospective study showed.

offers confirmation of the drug’s efficacy in this patient group, though it also highlights the limitations of the current therapeutic landscape.

MCL represents somewhere between 3% and 6% of all non-Hodgkin lymphoma cases diagnosed in the United States each year. The median age at diagnosis is in the mid-60s, and overall survival (OS) is roughly 4 to 5 years, with a 5-year survival rate around 60%.

Patients are typically treated with combination chemotherapy regimens. Some patients receive chemoimmunotherapy as induction therapy and stem cell transplantation, if eligible. Rituximab (Rituxan) has shown efficacy as post-transplantation maintenance therapy in patients treated up-front with R-DHAP (rituximab plus dexamethasone, cytarabine, and cisplatin).

The BTK inhibitor ibrutinib, meanwhile, was approved in the United States to treat patients with relapsed or refractory MCL in 2013. Phase 2 trial data showed a strong overall response rate (ORR) of 68%, including a 21% complete response (CR) rate.

 Patients had a median duration of response of 17.5 months after a median follow-up rate of 15.3 months. Adverse events in the trial were 11%.

However, lead author Jeff Sharman, MD, director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, noted that it was important to understand how the drug performs in the real-world setting, given that patients in trials are often healthier than those in non-trial settings, in part because of strict inclusion criteria.

“Real world data can be useful because it can highlight differences or similarities between trial populations and what we see in general practice,” he told 

in an interview. “In places where there are differences between the two, it provides an opportunity to clarify why trial results may not be generalized to other populations.”

If results are similar, he said, that’s a good sign that clinicians can be confident prescribing the drug.

In order to evaluate ibrutinib, Sharman and colleagues retrospectively identified 1914 patients from the US Oncology Network’s iKnowMed records database who had been diagnosed with MCL between November 2013 and October 2016. Of those, 159 had been treated with ibrutinib.

The median age in the study population was 71 years, and 76% of patients were male.

Median duration of treatment was 7.8 months (range, 2.6-23.1), OS was 25.82 months (95% CI, 19.9 – not reached), and the median progression-free survival (PFS) was 19.55 months (95% CI, 16.5-24.3). A 4% added risk of death was observed for each year of increase in a patient’s age (HR, 1.041; 

The discontinuation rate was 83.6%, with progression (35%) and toxicities (25.6%) listed as the most common reasons for discontinuation. Therapy was temporarily reduced in 16.4% of cases and held in 30.2% of cases, mostly due to toxicity (66.7%).

Multivariate modeling showed older patients had lower rates of survival. “These results are similar to other reports within the literature that have characterized the efficacy of ibrutinib in different populations of patients with R/R MCL,” the authors wrote.

For instance, a follow-up of the phase 2 study showed patients treated with single-agent ibrutinib at 560 mg daily doses had a median age of 68 years, duration of therapy of 8.3 months, and median OS of 22.5 months.

In the current study, patients treated in the third-line setting or beyond had the highest duration of response at 25.8 months versus 22.3 months in those treated in the second line, “potentially reflecting a population with more indolent disease suitable for third or greater line of salvage therapy.”

However, this patient group also had more holds and dose changes, which Sharman and colleagues said may also explain the longer duration of therapy.

Still, despite some variance in OS and PFS among the different line of therapy groups, the authors said the differences were not statistically significant (

One area of notable difference in the new study versus the trial setting is the high rate of discontinuation (83.6%). For instance, the rate of discontinuation due to toxicity in the community-setting study was 25.6%, whereas in the phase 2 trial it was just 7%. Sharman and colleagues said that could have to do with different baseline health statuses.

 that while the community data affirm positive news about ibrutinib, they also show that it’s not a panacea.

“I think it is important to recognize that patients with relapsed mantle cell lymphoma do well on BTK inhibitors but the length of time patients stay on the drug is shorter than many might expect and overall survival is still only about two years,” he said. “Effective new treatment options remain needed.”

1. Sharman J, Kabadi SM, Clark J, Andorsky D. Treatment patterns and outcomes among mantle cell lymphoma patients treated with ibrutinib in the United States: a retrospective electronic medical record database and chart review study. 

. Published online October 23, 2020. doi:10.1111/bjh.16922

2. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. 

. 2013;369(6):507-516. doi:10.1056/NEJMoa1306220

New data show patients with mantle cell lymphoma who were treated with ibrutinib in a community setting had similar outcomes to patients given the Bruton’s tyrosine kinase inhibitor in a clinical trial setting, a retrospective study showed.

New Community-Setting Data Affirm Ibrutinib’s Efficacy in R/R MCL

Active surveillance (AS) can be a safe and appropriate management strategy for patients with T1aN0M0 low-risk papillary thyroid microcarcinoma (PTMC), though the decision to use the strategy requires multidisciplinary teams and patient input, according to a new report.

Thyroid cancer has become more and more common in the world, driven largely by better detection of small papillary thyroid cancers (PTCs). Tools such as ultrasonography (US) and US-guided fine-needle aspiration cytology have made it possible to detect cancers that otherwise might never be detected or might only be detected in an autopsy. Although better detection is a positive step, it also raises the specter of overdiagnosis and overtreatment.

AS has been gaining consideration as an acceptable management strategy for low-risk PTMC although various concerns still exist. Thus, a task force of the Japan Association of Endocrine Surgery was created to make a set of recommendations on the indications and strategies for implementing AS for adult patients with low-risk PTMC. The study authors, led by Iwao Sugitani, MD, PhD, of the Nippon Medical School Graduate School of Medicine, in Japan, outlined some of the key considerations when evaluating patients with PTMC to determine the appropriateness of AS.

The task force noted that the development of routine AS in these patients can be traced back to 2 Japanese hospitals, Kuma Hospital and the Cancer Institute Hospital, which in the mid-1990s began prospective clinical studies of AS in PTMC. Outcomes were favorable: few patients experienced cancer growth or lymph node metastases, and no patients developed distant metastases or died of thyroid cancer.

Those data led to changes in Japanese clinical guidelines in 2010, and AS was added as an alternative management strategy by the American Thyroid Association in 2015.

Yet, not every physician or patient has been comfortable with the strategy. Sugitani said the idea of AS can be anxiety inducing for patients and physicians alike.

“Less experienced physicians and surgeons tend to feel anxious about the validity of AS and recommend immediate surgery even for very low risk patients,” he told 

Sugitani said surgery might seem like the easier and quicker option, though he said it should not be seen as eliminating the need for active follow-up.

“In theory, even patients who underwent surgery need long-term postoperative follow-up,” he said; “however, in reality, many physicians terminate it several years after surgery when lobectomy is performed and thyroid hormone supplementation is not necessary.”

In the consensus statements, the task force explained that AS requires considerable manpower and engagement from a multidisciplinary team.

Extrathyroidal extension (ETE) and lymph node metastases (LMN) should be evaluated using US. Chest x-ray CT is not necessary at the start of AS, the authors said, though it may be necessary if the disease progresses.

One important factor in determining the appropriateness of AS is the age of the patient. Sugitani and colleagues wrote that older patients are ideal candidates for AS, since it is less likely they will live long enough for the slow-developing cancer to progress. However, they said young patients should not necessarily be ruled out for AS, since, even among patients diagnosed in their 20s, the rate of lifetime progression is less than 50%.

In general, Sugitani said their analysis suggests “lax” inclusion criteria for AS. “For example, many physicians usually hesitate to recommend AS for patients with multiple PTMCs, young age, tumor simply close to the dorsal side of the thyroid, rich vascularity or slightly bigger than 1 cm,” he said. “Our paper showed evidence that those patients could still be candidates for AS.”

Sugitani and colleagues wrote that US evaluations should take place every 6 months for the first 1 to 2 years, followed by annual check-ups. They said there are no data to suggest a limit to the duration of AS; it could therefore be considered a lifetime strategy if nothing in the patient’s case changes.

As physicians evaluate patients over time, Sugitani and colleagues said maximal tumor diameter is the optimal method of growth evaluation. “Enlargement” should be defined as an increase of 3 mm or more, though they said enlargement does not always warrant surgery.

The authors said evidence is lacking for a number of common strategies. For example, suppression of tumor stimulating hormone (TSH) has been proposed as a strategy for limiting tumor enlargement; however, Sugitani said there are insufficient data to say that the strategy works. If used, Sugitani and colleagues said it may be best to keep TSH levels at the low to normal range.

Going forward, the task force highlighted 2 key areas where additional research is particularly needed. One is molecular markers, which, if identified, could give physicians a more reliable indication of PTMC behavior. The other area where Sugitani and colleagues would like to see more research is in patient-reported outcomes. They noted that the AS strategy can be anxiety producing; thus, further investigation into the psychological and quality-of-life impacts of the strategy is appropriate.

Sugitani I, Ito Y, Takeuchi D, et al. Indications and Strategy for Active Surveillance of Adult Low-Risk Papillary Thyroid Microcarcinoma: Consensus Statements from the Japan Association of Endocrine Surgery Task Force on Management for Papillary Thyroid Microcarcinoma. 

. Published online November 2, 2020. doi:10.1089/thy.2020.0330

Active surveillance can be a safe and appropriate management strategy for patients with T1aN0M0 low-risk papillary thyroid microcarcinoma, though the decision to use the strategy requires multidisciplinary teams and patient input, according to a new report.

Jared Kaltwasser | Authors

Articles

MCL35 Assay Stratifies Risk in Patients With Mantle Cell Lymphoma

Surveillance for Second Primary Malignancy Recommended in Select Patients With Myelofibrosis Treated With Ruxolitinib

New Community-Setting Data Affirm Ibrutinib’s Efficacy in R/R MCL

Task Force Recommends Active Surveillance for Many Low-Risk Papillary Thyroid Microcarcinoma Patients