Outcomes of Waldenström Macroglobulinemia Patients Requiring Therapeutic Plasma Exchange. Higher Rates of Progression and Resistance of Initial Systemic Therapy
Authors: Leng Jessica , Khouri Jack , Winter Allison M. , Jagadeesh Deepa , Dean Robert M. , Brooks Taylor R. , Williams Louis , Anwer Faiz , Sauter Craig S. , Hill Brian T. , Caimi Paolo F. 
Published: December 2024

BACKGROUND
A subgroup of patients (pts) with Waldenstrom macroglobulinemia (WM) develop symptomatic hyperviscosity (HV). This medical emergency can be effectively managed with therapeutic plasma exchange (TPE) and systemic treatment. HV has not been associated with an effect on overall survival (OS), but there are limited data regarding the clinical course of pts who require TPE.

METHODS
This was a retrospective study using an IRB - approved institutional lymphoma registry. Adult pts meeting WHO criteria for diagnosis of WM between 2008 and 2023 were included. Outcomes were observed from the time of diagnosis and from the initiation of the first systemic therapy, including time to next therapy (TTNT), progression free survival (PFS) and OS. The Kaplan Meier method was used to evaluate time to event outcomes, comparisons were done using log - rank and the effect was quantified using Cox regression model.

RESULTS
138 pts were identified. Median age at diagnosis was 69 years (IQR 61-74), 66 pts (48%) were women. International prognostic scoring system for WM was available for 79 pts, 23 (29%) had low risk, 41 (52%) intermediate risk and 15 (19%) high risk. The Cumulative Illness Rating Scale - Geriatric score was 9 (IQR 7-12). Median IgM plasma concentration at diagnosis was 2.6g/dL (IQR 1.3-5.1), with baseline viscosity available for 59 pts, median 2.5 cP (IQR 1.9-3.6). MYD88 testing was available for 107 pts (78%), 101 (94%) of whom had a mutation. After a median follow up from diagnosis of 65 months (95% CI 38-96), median survival has not been reached.
Systemic therapy for WM was prescribed in 114 pts (83%). The median time from diagnosis to first systemic therapy (1L) was 31 days (IQR 12-146). TPE was administered to 17 pts prior to or in conjunction with 1L. Indications for TPE included neurologic manifestations of HV (n = 5), funduscopic abnormalities indicating retinal vein changes or hemorrhage (n = 7), oronasal bleeding (n = 6), other non-specific HV symptoms (n = 4); 5 pts had more than one indication for TPE.
The median time from diagnosis to 1L was 14 days for pts receiving TPE vs. 41 days for those who did not. Median IgM concentration and viscosity were 6.1g/dL and 4.9cP for pts receiving TPE vs. 2.6 g/dl and 2.3cP in pts not receiving TPE, respectively. There was a statistically significant difference in the best response to 1L; 31% of pts receiving TPE had progressive disease as best response to 1L vs. 5.9% of those not receiving TPE (p = 0.04). There were no differences in the proportion of pts receiving chemoimmunotherapy (TPE 6/17 = 35%, no TPE 35/96, 36%), single agent rituximab (TPE 3/17 = 18%, no TPE 35/96 (36%), whereas the number of pts treated with BTK inhibitor was numerically lower in pts receiving TPE (1/17 [6%] vs. 18/96 [19%], p = 0.3).
Median follow up from 1L was 66.3 months (95% CI 31.5-94.3). Median TTNT for pts treated with TPE after 1L was 2.61 months vs. 54 months for pts not prescribed TPE (hazard ratio [HR] 3.37 [95% CI 1.78 - 6.37], p = &lt;0.001), median PFS was 3.4 months vs. 55.0 months, respectively (HR 1.92, [95% CI 1.05 - 3.52], p = 0.03). The median OS was not reached for either group, 5-year estimates of 85% and 75%, respectively. The median number of lines of therapy was 2 for pts receiving TPE vs. 1 for those not prescribed TPE (p = 0.008).
To determine whether urgent treatment after diagnosis correlates with PFS on pts not prescribed TPE, we used maximally selected rank statistic to identify treatment within 18 days form diagnosis as the cutoff below which pts had worse PFS. Cox proportional hazards modeling showed that, compared with pts receiving TPE, pts treated without TPE ≤18 days of diagnosis had similar PFS (HR 0.7 [95% CI 0.4-1.54], p = 0.5), whereas pts treated without TPE and &gt;18 days had prolonged PFS (HR 0.4 [95% CI 0.21-0.78], p = 0.007). Median TTNT for pts with TPE was shorter than either comparator: 2.6 months vs. 10.3 months for pts receiving 1L within 18 days of diagnosis (HR 0.41 [95% CI 0.19-0.87], p = 0.02) and 13 months for 1L &gt; 18 days after diagnosis (HR 0.25 [95% CI 0.13-0.5], p &lt;0.001). There were no statistically significant differences in OS between the three groups.

CONCLUSIONS
The subgroup of WM pts prescribed TPE for HV in conjunction with their initial therapy have a more aggressive disease, with increased risk of progression and shorter TTNT. Improved strategies to incorporate more effective treatments in earlier lines of therapy are warranted in this high-risk patient population.