Prognostic stratification in DLBCL patients with aberrant MYC gene.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high-risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC-related genetic and molecular aberrations, enhancing the accuracy of prognostic evaluations compared to conventional MYC biomarkers. Our results indicate that MYCSS significantly refines prognostic accuracy beyond that of conventional MYC biomarkers focused on genetic aberrations. More importantly, we found that nearly 50% of patients identified as high risk by traditional MYC metrics actually share similar survival prospects with those having no MYC aberrations. These patients may benefit from standard GCB-based therapies rather than more aggressive treatments. MYCSS provides a robust signature that identifies high-risk patients, aiding in the precision treatment of DLBCL, and minimizing the potential for overtreatment.

Prognostic Implications of Circulating Plasma Cell Percentage in Multiple Myeloma and Primary Plasma Cell Leukemia Defined by New Criteria.

INTRODUCTION: The definition of primary plasma cell leukemia (pPCL) has been revised from ≥20% to ≥5% circulating plasma cells (CPC). However, the precise prognosis associated with CPC remains controversial. This study aimed to investigate prognostic biomarkers for myeloma patients based on CPC presence. METHODS: A comprehensive analysis was conducted on 309 consecutive patients diagnosed with either multiple myeloma or pPCL, utilizing peripheral blood smears stained with Wright-Giemsa. RESULTS: Patients were grouped by CPC percentage: 0% (221, 71.5%), 1-4% (49, 15.9%), 5-19% (16, 5.2%), ≥20% (23, 7.4%). CPC >5% correlated with unfavorable characteristics, including anemia, renal dysfunction, and advanced International Staging System. Common cytogenetic abnormalities such as 1q21 amplification, 17p deletion, and Myc rearrangement were prevalent among CPC-positive patients. Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with CPC ≥5% (29.47 vs. 10.03 months; 64.10 vs. 12.30 months). Additionally, PFS and OS were shorter in CPC-positive patients without autologous hematopoietic stem cell transplantation (ASCT) and those with response < partial remission to the first-line regimen. Furthermore, an association emerged between soft tissue-related extramedullary disease and inferior PFS, while Myc rearrangement correlated with abbreviated OS. CONCLUSION: Biological characteristics displayed greater aggressiveness in patients with positive CPC, leading to significantly shorter PFS and OS. The presence of CPC, ASCT, and overall response rate were independent prognostic factors. While no new threshold for pPCL with CPCs is proposed, Myc rearrangements and CPC positivity could serve as ultra-high-risk factors for multiple myeloma.

Myc rearrangement redefines the stratification of high-risk multiple myeloma.

BACKGROUND: Myc rearrangement (Myc-R) is a controversial factor linked to adverse outcomes in newly diagnosed multiple myeloma (NDMM). AIMS: This study aimed to evaluate the impact of Myc-R on the prognosis of NDMM patients and its role in risk stratification compared with traditional high-risk cytogenetic abnormalities (HRCAs). MATERIALS & METHODS: A total of 417 NDMM patients enrolled from May 2009 to September 2022 were included. Fluorescence in situ hybridization (FISH) was used to detect Myc-R and other Myc abnormalities (Myc-OA). Median progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and log-rank tests. Multivariate Cox regression analysis was used to identify independent risk factors. RESULTS: Myc-R was identified in 13.7% of patients, while 14.6% had Myc-OA. Patients with Myc-R had significantly shorter median PFS (15.9 months) and OS (25.1 months) compared with those with Myc-OA (24.5 months PFS; 29.8 months OS) and Myc-negative (Myc-N) status (29.8 months PFS, 29.8 months OS). Myc-R was independently associated with worse PFS and OS compared to Myc-OA. Patients with Myc-R alone had inferior median PFS (15.9 months vs. 28.1 months, p = 0.032) and OS (25.1 months vs. 61.2 months, p = 0.04) compared to those with traditional single HRCA. DISCUSSION: The study suggests that traditional single HRCA may not significantly impact survival in NDMM patients. However, incorporating Myc rearrangement or traditional double/triple-hit HRCAs into the risk stratification model improves its predictive value, highlighting the importance of Myc rearrangement in risk assessment. CONCLUSION: Myc rearrangement is an independent adverse prognostic factor in NDMM. The incorporation of Myc rearrangement or multiple HRCAs into risk stratification models improves their prognostic value, providing a novel perspective on high-risk factors in NDMM.

Performance of MYC, BCL2, and BCL6 break-apart FISH in small biopsies with large B-cell lymphoma: a retrospective Cytopathology Hematopathology Interinstitutional Consortium study.

Introduction: Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies. Methods: We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens. Results: FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement. Discussion: FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing.

Cytogenetic and pathologic characterization of MYC-rearranged B-cell lymphomas in pediatric and young adult patients.

MYC-rearranged B-cell lymphoma (BCL) in the pediatric/young adult (YA) age group differs substantially in disease composition from adult cohorts. However, data regarding the partner genes, concurrent rearrangements, and ultimate diagnoses in these patients is scarce compared to that in adult cohorts. We aimed to characterize the spectrum of MYC-rearranged (MYC-R) mature, aggressive BCL in the pediatric/YA population. A retrospective study of morphologic, immunophenotypic, and fluorescence in situ hybridization (FISH) results of patients age ≤ 30 years with suspected Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL), and a MYC-R by FISH between 2013-2022 was performed. Two-hundred fifty-eight cases (129 (50%) pediatric (< 18 years) and 129 (50%) YA (18-30 years)) were included. Most MYC-R BCL in pediatric (89%) and YA (66%) cases were BL. While double-hit (DH) cytogenetics (MYC with BCL2 and/or BCL6-R, HGBCL-DH) was rare in the pediatric population (2/129, 2%), HGBCL-DH increased with age and was identified in 17/129 (13%) of YA cases. Most HGBCL-DH had MYC and BCL6-R, while BCL2-R were rare in both groups (3/258, 1%). MYC-R without an IG partner was more common in the YA group (14/116 (12%) vs 2/128 (2%), p = 0.001). The pediatric to YA transition is characterized by decreasing frequency in BL and increasing genetic heterogeneity of MYC-R BCL, with emergence of DH-BCL with MYC and BCL6-R. FISH to evaluate for BCL2 and BCL6 rearrangements is likely not warranted in the pediatric population but should continue to be applied in YA BCL.