Background. Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. Methods. Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes. Results. Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/ Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance. Conclusion. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors.

Peripheral T-cell lymphoma (PTCL) comprises a heterogenous group of rare mature T-cell neoplasms. While some PTCL subtypes are well-characterized by histology, immunophenotype, and recurrent molecular alterations, others remain incompletely defined. In particular, the distinction between CD30+ PTCL, not otherwise specified and anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma can be subject to disagreement. We describe a series of 6 JAK2 rearrangements occurring in a cohort of 97 CD30+ ALK− PTCL (6%), assembled after identifying an index case of a novel PABPC1-JAK2 fusion in a case of ALK− anaplastic large cell lymphoma with unusual classic Hodgkin lymphoma (CHL)-like features. Fusions were identified using a comprehensive next-generation sequencing based assay performed between 2013 and 2020. Five of 6 cases (83%) showed JAK2 rearrangements with 4 novel partners: TFG, PABPC1, ILF3, and MAP7, and 1 case demonstrated a previously described PCM1-JAK2 fusion. By morphology, all cases showed anaplastic large cells and multinucleated Reed-Sternberg–like cells within a polymorphous inflammatory background with frequent eosinophilia reminiscent of CHL. By immunohistochemistry, atypical large cells expressed CD30 with coexpression of at least 1 T-cell marker, aberrant loss of at least 1 T-cell marker and, in 4 of 5 cases stained (80%), unusual CD15 coexpression. These findings suggest that a subset of CD30+ ALK− systemic PTCL with anaplastic morphology carry JAK2 rearrangements, some of which appear to show CHL-like morphologic features. The presence of JAK2 rearrangements in cases of CD30+ PTCL augments current classification and may provide a therapeutic target via JAK2 inhibition.

We are presenting a case of a middle-aged woman with history of remote kidney transplantation who had multiple admissions for septic shock-like picture, recurrent fever, and hypotension. Her shock manifestation would resolve after stress dose steroid administration and less than 24 hours of vasopressor administration. Initially, extensive workup was performed without revealing etiology. Eventually, a bone marrow biopsy was carried out leading to the diagnosis of hemophagocytic lymphohistiocytosis, most likely related to recent cytomegalovirus infection.

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Clinical Features: A middle-aged man with history of kidney transplantation was diagnosed with multiple myeloma (MM); he was treated with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for induction therapy. However, a repeat bone marrow biopsy after treatment revealed 10% clonal plasma cell involvement. Given residual disease, his treatment regimen was changed to daratumumab, bortezomib, and dexamethasone in an attempt to achieve minimal residual disease. Therapeutic Challenge: Daratumumab was recently approved for treatment of relapsed or refractory MM; there are no data regarding the safety and effectiveness in solid organ transplant patients. Solution: Our patient was treated with a daratumumab-based regimen for MM. His renal function was monitored closely along with donor-specific antibody to assess for risk of graft rejection. His renal function remained stable with minimal proteinuria and negative donor-specific antibody during the treatment course.

Background: Alterations (particularly biallelic deletions) of the tumor suppressor gene CDKN2A are frequent in the ultra-aggressive lymphoblastic (Quesnel et al, Blood 1995) and Burkitt lymphomas (Schmitz et al, Nature 2012). They also occur in DLBCL, and in prior studies they were associated with poor prognosis in conjunction with TP53 mutations (Jardin, Blood 2010). However, recent genomic classifications of DLBCL have noted frequent CDKN2A alterations in the MCD subtype (characterized by MYD88L265P and CD79 mutations; Wright et al, Cancer Cell 2020-LymphGen classifier). MCD tumors show propensity for extranodal invasion, immune evasion, and are enriched among relapsed/refractory DLBCL (Ollila et al, Blood 2021). There is an interest in targeting the MCD subgroup with novel treatment approaches, but prognostic factors specific to MCD DLBCL are uncertain. We examined the association between CDKN2A deletions and other mutations, genomic subtypes, and prognosis in DLBCL. Methods: We selected DLBCL cases submitted for next generation sequencing (NGS) as part of routine clinical care (FoundationOne Heme assay, Foundation Medicine, Inc., Cambridge, MA). All samples underwent central review by a board-certified pathologist. NGS was performed on hybridization-captured, adaptor ligation-based libraries in up to 405 cancer-related genes (Frampton et al, Nat Biotechnol, 2013), identifying clinically relevant base pair substitutions, indels, copy number alterations, and rearrangements. Co-occurrence/exclusivity was evaluated by odds ratios (OR) with P-values corrected for multiple testing using false discovery rate (FDR). Prognostic analysis was performed using publicly available data from the Haematological Malignancy Research Network (HMRN) study of 648 patients treated with RCHOP chemotherapy for DLBCL (Lacy et al, Blood 2020). Results: Among 165 patients with confirmed DLBCL, median age was 67 (interquartile range, 56-76), and 48% were women. Biopsies were from an extranodal site in 113 cases (68%). CDKN2A alterations were present in 42 samples (25%): most commonly biallelic deletions (N=34), short variant alterations (N=7), and 1 rearrangement. CDKN2A deletions were found in 28 (25%) of extranodal and 6 (12%) of nodal biopsies (Fisher's exact P=.06). MYC-IGH rearrangement was detected in 3 (7%) of tumors with CDKN2A deletions and 5 (4%) of those without them (P=.42), but BCL2-IGH rearrangement was rare in tumors with CDKN2A deletions (2% vs. 33%, respectively; P&lt;0.001). Mutations in only 3 genes were statistically significantly associated with CDKN2A deletions: MYD88 (OR=12.6, Pcorr=3.9 x 10 -6), CD79B (OR=20.4, Pcorr =.00031) were highly co-occurring, whereas TP53 (OR=0.09, Pcorr=.0072) was highly mutually exclusive (Fig. A/B). Among tumors with CDKN2A deletions, 56% had mutations in MYD88, 32% in CD79B, and 32% in PIM1, but only 6% in TP53. Conversely, in DLBCL without CDKN2A deletions, TP53 mutations were present in 41%, while &lt;10% had mutations in MYD88, CD79B, or PIM1. When studied using the LymphGen DLBCL classifier, CDKN2A deletions were present in 14 out of 16 MCD (88%), 2 out of 10 (20%) BN2, 18 out of 111 (16%) of unclassifiable tumors, and in no tumors classified as A53, EZB, or ST2 (Fig. C; P&lt;.001 for MCD vs others). CDKN2A deletions were also specific to the hc-MCD subtype using our simplified hierarchical classifier developed for multi-gene NGS panels (Fig. D). In the HMRN data, CDKN2A deletions were observed in 10% of cases, significantly more often (34%) in the MYD88 cluster (corresponding to LymphGen MCD) than in other clusters (6.3%; P&lt;.001). Conversely, TP53 alterations were significantly less frequent in the MYD88 cluster (7% vs 21% in others, P=.004). CDKN2A deletions were associated with significantly worse progression-free and overall survival (Fig. E/F) within the MYD88 cluster (independently of the International Prognostic Index), but not in others. Conclusions: CDKN2A deletions are specific to the MCD genomic subtype of DLBCL and indicate particularly poor prognosis within this class. Relative mutual exclusivity with TP53 mutations suggests that CDKN2A deletion may constitute an alternative, critical "hit" to a tumor suppressor gene in MCD DLBCL. Further research should examine the clinical relevance of CDKN2A deletions for refractoriness to standard therapy and its role in immune evasion that is characteristic of relapsed/refractory MCD DLBCL. Figure 1 Figure 1. Disclosures Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Sharaf: Foundation Medicine: Current Employment. Marcus: Foundation Medicine: Current Employment. Albacker: Foundation Medicine: Current Employment. Vergilio: Foundation Medicine: Current Employment.