The Effect of Cytogenetic Abnormalities on Organ Involvement and Survival in Patients with AL Amyloidosis

Introduction: Systemic light chain amyloidosis (AL) is a clonal plasma-cell neoplasm that carries a poor prognosis. Efforts are being made at recognizing this disease earlier and developing better prognostic tools as AL is frequently diagnosed at an advanced stage. Cytogenetic analysis and its prognostic relevance have been well studied in multiple myeloma (MM), a related disorder, but remain relatively unknown and less widely reported in AL literature. Previous studies have demonstrated that AL amyloidosis exhibits an increased incidence of translocation t(11;14). However, with an extensive array of fluorescence-in-situ hybridization (FISH) probes now available, multiple other cytogenetic abnormalities are being identified in AL at diagnosis. In addition, it is well known that cardiac involvement in AL is an independent negative prognostic factor for these patients; however, the implications of cytogenetics for these high-risk patients remains largely unexplored. Finally, with the advent of novel non-transplant therapy options for AL patients, we look to evaluate the relevance of daratumumab in this setting. As such, the present study aims to a) determine the most relevant FISH abnormalities in AL patients and establish their importance as independent prognostic factors for response to therapy and in survival, b) assess the impact of cytogenetics on the survival of cardiac AL patients, and c) determine the effect of daratumumab on the survival of patients with AL.

Methods: A retrospective chart review was performed on 140 consecutive AL patients treated at The Ohio State University. This cohort included 20 patients who received daratumumab. Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS), and Kaplan Meier curves were used to calculate PFS and OS.

Results: The median age at diagnosis was 62 years (range: 33-88) and 55% were male. Median number of organs involved was 2, and 49% and 65% had cardiac and kidney involvement, respectively. Chromosomal abnormalities were detected in 86 (61%) patients. Translocation t(11;14) was the most prevalent (44%) aberration followed by hyperdiploidy (43%). We observed a statistically significant relationship between several FISH abnormalities and increased plasma cell burden (PC) (≥10%), including gain (+) 5p/5q (p=0.025), del13q (0.009), +11q (p<0.001), and hyperdiploidy (p<0.001). In addition, hyperdiploidy was associated with worsening of PFS (p=0.019) and OS (p=0.032) (Figure 1A). In multivariable analysis, hyperdiploidy was confirmed to be a poor prognostic marker after adjusting for other confounding variables. In patients with cardiac involvement, hyperdiploidy was also associated with worsening of PFS (p=0.0497) and OS (p=0.006) (Figure 1B). Del 13q was found to be associated with cardiac involvement (p=0.01) but showed no prognostic impact on survival. Conversely, survival benefit was seen among these patients with cardiac involvement who had no FISH abnormalities at diagnosis, both in terms of OS and PFS (p=0.019 and p=0.042, respectively). In addition, the overall presence of t(11;14) did not have any prognostic impact on OS (p=0.76) or PFS (p=0.41). However, on further stratification, we did observe a marginal difference in PFS (p=0.09) among four groups (Figure 1C), and more specifically, patients with presence of only t(11;14) did worse compared to those patients with normal FISH in terms of PFS (p=0.021). This potentially suggests that patients with t(11;14) only are at risk for earlier progression. Finally, we evaluated the efficacy of daratumumab, and observed a median OS of 6.1 years and median PFS 2.6 years. Of note, presence of gain 1q was associated with a trend toward better response to daratumumab. 100% of patients (5/5) with gain 1q achieved a hematologic partial response (PR) or better versus only 60% of patients without +1q.

Conclusion: Our findings reveal the effect of hyperdiploidy on PC tumor burden, overall survival, and its importance within the high-risk cardiac AL patient population. The results with daratumumab in our patient subset with gain 1q is intriguing in its own right but identification of the mechanism by which the effect of this mutation is abrogated merits further exploration as its use only continues to grow.

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