Review of the Impact of FISH-Detected Cytogenetic Abnormalities on Prognosis in AL Amyloidosis in the Era of Daratumumab Therapy

Background

Immunoglobulin light chain (AL) amyloidosis is a rare disease characterized by organ dysfunction caused by the deposition of light chain proteins secreted by abnormal plasma cells. However, the heterogeneous clinical manifestations and complex molecular pathology pose significant challenges for treatment and prognosis assessment. In recent years, the incorporation of the anti-CD38 monoclonal antibody daratumumab (DARA) into combination regimens (e.g., Dara-VCD: daratumumab with bortezomib, cyclophosphamide, and dexamethasone) has achieved significant breakthroughs. This approach has markedly improved hematologic complete response (Heme-CR) rates, organ responses, and event-free survival. Despite this, approximately 20% of patients fail to achieve very good partial response (VGPR) or better, highlighting the need to reassess prognostic factors in the era of DARA therapy.

Cytogenetics using fluorescence in situ hybridization (FISH) plays an important role in prognostic evaluation for plasma cell disorders. However, while the prognostic significance of FISH abnormalities has been extensively studied in multiple myeloma, data in AL amyloidosis remain limited. Specifically, in the context of DARA-based therapy, it is unclear if cytogenetic abnormalities still significantly impact treatment outcomes and survival. This study aims to systematically evaluate the clinical impact of FISH-detected cytogenetic abnormalities in a cohort of patients with AL amyloidosis receiving first-line DARA therapy.

Source and Collaborating Institutions

This study was conducted by a consortium of experts from seven leading academic institutions across three countries, including Columbia University, Mayo Clinic, and Heidelberg University. It was published in the renowned hematology journal Blood on December 19, 2024. The study was led by co-first authors Dr. Rajshekhar Chakraborty and Dr. Saurabh Zanwar, with senior authors Dr. Suzanne Lentzsch and Dr. Eli Muchtar.

Methods and Study Design

This is a multicenter retrospective cohort study that included 283 newly diagnosed systemic AL amyloidosis patients from seven institutions across three countries. Key inclusion criteria required biopsy-confirmed light chain AL amyloidosis treated with a DARA-based regimen (Dara-VCD or Dara-VD) as first-line therapy. Patients participating in clinical trials of clone- or fibril-directed therapies were excluded. All patients underwent baseline FISH testing to evaluate common cytogenetic abnormalities, including t(11;14), +1q (gain/amplification of chromosome 1q), hyperdiploidy, high-risk translocations (HR translocations), deletion(13q), and deletion(17p).

Primary endpoints included Heme-CR, VGPR or better, and hematologic event-free survival (Heme-EFS) stratified by cytogenetic subgroups. Secondary analyses examined organ responses (cardiac and renal) and overall survival (OS). Kaplan-Meier analysis was used to calculate survival probabilities, and Cox proportional hazards models were applied for univariate and multivariate analyses.

Key Findings

Distribution of Cytogenetic Abnormalities and Patient Characteristics

FISH results revealed that the most common abnormalities were t(11;14) (53.4%), deletion(13q) (28.9%), and +1q (22.3%). Among 58 patients with +1q, 82.2% exhibited three copies (gain[1q]) and 17.8% had four or more copies (amp[1q]). Patients with +1q were associated with higher clonal burden, as evidenced by elevated baseline difference in free light chains (dFLC ≥ 18 mg/dL) and increased bone marrow plasma cell percentages (BMPC ≥ 10%).

Hematologic and Organ Responses

Among 240 evaluable patients, 44.2% achieved Heme-CR, while 75.4% achieved VGPR or better. The presence of +1q significantly impacted treatment outcomes, with Heme-CR rates being markedly lower in patients with +1q (30.2%) compared to those without (47.9%; P = 0.022). Similarly, VGPR or better rates were lower in the +1q group (64.2% vs. 79.0%; P = 0.033). However, there were no significant differences in cardiac or renal organ response rates between cytogenetic subgroups.

Survival Outcomes

At a median follow-up of 19.5 months, the cohort’s median Heme-EFS was 49.6 months, while the median OS was not reached. The presence of +1q was strongly associated with worse Heme-EFS, with a median of only 14.3 months compared to not reached for patients without +1q (P = 0.006). Hyperdiploidy was also linked to significantly worse Heme-EFS (20.0 months vs. 51.2 months; P = 0.024).

Multivariate Cox regression analysis identified +1q (HR = 2.02; 95% CI: 1.13–3.59, P = 0.016), NYHA class IV (HR = 26.99; P < 0.001), and NT-proBNP >8500 pg/mL (HR = 2.35; P = 0.012) as independent predictors of poor Heme-EFS.

Prognostic Shift of t(11;14)

Unlike findings from the bortezomib era where t(11;14) was a negative prognostic factor, the presence of t(11;14) did not significantly impact Heme-EFS or OS in the DARA era. This indicates that DARA may mitigate the adverse effects associated with t(11;14).

Implications and Future Directions

This study provides critical insights into the prognostic role of FISH-detected cytogenetic abnormalities in the era of DARA-based therapy for AL amyloidosis:

1. Role of +1q as a Prognostic Marker: The findings underscore +1q’s predictive value for poor hematologic response and inferior Heme-EFS. Identifying this high-risk subgroup can inform treatment intensification strategies.
2. Neutralization of t(11;14): The absence of t(11;14) as an adverse prognostic factor highlights DARA’s therapeutic potential in overcoming cytogenetic risk in these patients.
3. Future Research Necessities: Future trials should focus on enriching cohorts with +1q patients to explore novel immunotherapy strategies targeting this high-risk subgroup. Long-term studies are also needed to validate the survival impact of hyperdiploidy and other rare abnormalities.

These findings pave the way for precise risk stratification and individualized treatment approaches, contributing to improved outcomes for AL amyloidosis patients.