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Researchers created a Modified Staging System for Waldenström macroglobulinemia that could improve risk stratification for treatment-naïve patients.

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Outcomes for Waldenström macroglobulinemia (WM) are often disparate, but newer therapies have emerged in recent years. According to the authors of a study in the Journal of Clinical Oncology, this calls for a re-examination of prognostic parameters.

“The recently proposed, revised (r) International Prognostic Scoring System for WM (IPSS-WM), on the basis of age, lactate dehydrogenase (LDH), albumin, and β2M, addressed some of the deficiencies [of the IPSS-WM] but did not examine the impact of molecular parameters, including the myeloid differentiation primary response 88 (MYD88)^L265P mutation, which is now routinely assessed at diagnosis,” wrote corresponding author Prashant Kapoor, MD, and colleagues.

Recognizing these limitations, the researchers created a new risk stratification model called the Modified Staging System (MSS-WM).

In an interview with Physician’s Weekly, Dr. Kapoor said the MSS-WM is easier to use in practice and has been validated in an external cohort, including medical centers across the United States and Europe.

A New Prognostic Model

To develop the tool, the researchers leveraged data from 889 Mayo Clinic patients with symptomatic, treatment-naïve WM between 1996 and 2017. Using baseline characteristics, including MYD88^L265P mutational status, the researchers identified and scored statistically significant factors that were independent determinants for survival.

The researchers “assigned a score of 1 point each to serum albumin less than 3.5 g/dL and age 66-75 years” and “2 points each to age greater than 75 years and elevated serum LDH.” From there, the researchers created a derivation cohort and assigned each patient a composite score ranging from 0 to 5.

Composite scores aligned with one of four risk levels:

• 0: low risk (21% of patients);
• 1: low-intermediate risk (32% of patients);
• 2: intermediate risk (24% of patients); and
• 3-5: high risk (23% of patients).

The researchers combined scores 3 through 5 because patients in these groups often have similar outcomes.

Overall Survival Rates With MSS-WM

Among 341 patients in the derivation cohort with complete data, the estimated median overall survival (OS) was 9.9 years (95% CI, 8.5-11.4). Stratified by risk level via the MSS-WM, the estimated median OS (all P<0.001) was:

• 6 years (95% CI, 9.1-NR) for the low-risk group;
• 2 years (95% CI, 9.1-15.2) years for the low-intermediate risk group;
• 3 years (95% CI, 6.4-12.2) for the intermediate-risk group; and
• 5 years (95% CI, 3.9-11.0) for the high-risk groups.

The 5-year OS rates for each respective risk group were 93%, 82%, 69%, and 55%, and 10-year OS rates were 60%, 53%, 45%, and 30%.

The external validation cohort included 335 patients with a median follow-up of 6.3 years (95% CI, 5.5-7.2). The MSS-WM stratified 26% of patients as low-risk, 32% as low-intermediate risk, 25% as intermediate-risk, and 59 as high-risk.

“The 5-year OS rates were 93%, 90%, 75%, and 57%, and 10-year OS rates were 91%, 80%, 64%, and 35% for the low-risk, low-intermediate risk, intermediate-risk, and high-risk cohorts, respectively (P<0.001),” the researchers reported. “Similar to the derivation cohort, the MYD88 genotype did not significantly affect the OS of the validation cohort (5-year OS of 64% vs 81% for the MYD88^L265P and MYD88^WT genotypes, respectively, P=0.1).

Comparison With Existing Models

In the derivation cohort, the rIPSS-WM effectively stratified patients into five risk categories: very low- (n=46), low- (n=64), intermediate- (n=58), high- (n=46), and very high-risk groups (n=27). The 5-year OS rates for these groups were 96%, 76%, 72%, 77%, and 32%, respectively.

The concordance index for rIPSS-WM was 0.67 (95% CI, 0.61-0.73), similar to the derivation cohort’s concordance index of the MSS-WM model, which was 0.68 (95% CI, 0.63-0.73). However, survival curves for patients in the low-, intermediate-, and high-risk groups showed significant overlap, suggesting limited discrimination among these categories.

When validated in a cohort of 273 patients, rIPSS-WM showed poor discrimination across the very low-, low-, and intermediate-risk groups. In a subset of 220 patients, the MSS-WM reclassified 65% of patients categorized as high-risk by IPSS-WM to lower-risk groups while upstaging 44% of patients classified as low-risk.

Modified Staging System’s Limitations

“I would say this staging system is ready to be used in clinical practice because it uses very simple tools that are routinely assessed before patients begin their therapy,” Dr. Kapoor says, cautioning that the current staging system is for symptomatic patients who have yet to start treatment.

Although this model gives clinicians a clear tool for prognosis, Dr. Kapoor says, “We are not proposing changing our management approach based on the patient’s risk stratification because there are no data to suggest that certain therapies work better in the high-risk group compared with other treatments.”