ALK-negative anaplastic large cell lymphoma in pediatric and adolescent patients: a mini-review

Abstract

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a rare and diagnostically challenging entity in children, adolescents, and young adults. Although ALCL accounts for a meaningful subset of young patients diagnosed with non-Hodgkin lymphoma, the vast majority of cases are ALK-positive, while ALK-negative disease is seen predominantly in older adults. As a result, pediatric-specific data are limited to small series and case reports, with treatment strategies often extrapolated from adult peripheral T-cell lymphoma or pediatric ALK-positive ALCL clinical trials. Despite morphologic overlap with ALK-positive ALCL, ALK-negative ALCL is biologically heterogeneous, with recurrent alterations involving DUSP22, TP63, JAK/STAT pathway genes, TYK2, ROS1, ERBB4, and other potential molecular drivers. These alterations may have prognostic and therapeutic implications, but their frequency and significance in children and adolescents remain incompletely defined. Accurate diagnosis of ALK-negative ALCL requires expert hematopathology review, with integration of morphology, immunophenotype, and molecular testing. Emerging therapeutic approaches include CD30-directed therapy, JAK/STAT pathway inhibition, and checkpoint blockade. This review summarizes the diagnostic, biologic, and therapeutic challenges affecting young patients with ALK-negative ALCL and the healthcare teams that care for them. We highlight the need for further collaborative and multidisciplinary work, systematic molecular profiling, and consideration of this group in future clinical trials to ultimately advance care for this group of pediatric and adolescent cancer patients.

Introduction

Anaplastic large cell lymphoma (ALCL) is a distinct subtype of non-Hodgkin lymphoma (NHL) characterized by the uniform expression of CD30 (Ki-1) and a T-cell or null-cell immunophenotype (1, 2). Based on the presence or absence of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene at chromosome 2p23, systemic ALCL is classified into two entities recognized by the World Health Organization (WHO) and the International Consensus Classification (ICC): ALK-positive ALCL and ALK-negative ALCL (3, 4). ALK-negative ALCL is defined as a CD30-positive T-cell lymphoma that morphologically resembles ALK-positive ALCL but lacks ALK gene rearrangements and ALK protein expression (1, 2). Although these two entities share overlapping histopathological features—they differ substantially in their epidemiology, molecular pathogenesis, and clinical outcomes (5, 6).

In pediatric populations, ALCL accounts for approximately 10–15% of all childhood NHL (7, 8). However, the vast majority of pediatric ALCL cases—exceeding 90–95%—are ALK-positive, driven by the NPM1::ALK fusion resulting from the t(2;5)(p23;q35) translocation or variant ALK gene rearrangements (9). ALK-negative ALCL, by contrast, is predominantly a disease of adults, with a median age at diagnosis around 54–61 years and a male predominance (1, 10). In the largest prospective cohort to date, the International T-Cell Project enrolled 235 ALK-negative ALCL patients from 74 sites across 13 countries, with all patients aged 18 years or older (10). Given that ALK-negative ALCL constitutes fewer than 5% of pediatric ALCL cases, the true incidence of this entity in children and adolescents remains unknown and is likely exceedingly low—on the order of isolated case reports and small institutional series rather than population-level estimates (11–14). This extreme rarity has precluded the development of pediatric-specific epidemiological data, prospective clinical trials, or evidence-based treatment guidelines for ALK-negative ALCL in patients under 18 years of age.

The clinical problem posed by ALK-negative ALCL in pediatric patients is compounded by the historically guarded outcomes associated with this entity. In adults, ALK-negative ALCL carries a significantly inferior prognosis compared to ALK-positive disease, with 5-year overall survival (OS) rates of approximately 30–49% versus 70–90%, respectively, and 5-year failure-free survival (FFS) of 36% versus 60% (10, 15). Even among the more common pediatric NHL subtypes, outcomes for ALCL have lagged behind those of other childhood lymphomas. Historically, event-free survival (EFS) for pediatric ALK-positive ALCL plateaued at approximately 70% with intensive multiagent chemotherapy, with treatment failure rates of 25–30% (16–18). For the rare pediatric patient diagnosed with ALK-negative ALCL, the prognosis is expected to be even more guarded through extrapolating from reported adult outcomes (19). The absence of ALK as a therapeutic target in ALK-negative disease eliminates the use of ALK inhibitors (e.g., crizotinib, brigatinib), which have shown remarkable efficacy and improved contemporary outcomes for ALK-positive ALCL, further narrowing therapeutic choices (16). ALK-independent targeted strategies, particularly CD30-directed therapy, have expanded treatment options, but their optimal role in pediatric ALK-negative ALCL remains largely undefined (1).

This review aims to comprehensively examine the current state of knowledge regarding ALK-negative ALCL in pediatric and adolescent patients, synthesizing available data on its biology, clinical features, molecular subtypes, treatment approaches, and emerging therapeutic strategies, while highlighting the critical gaps in evidence that must be addressed to improve outcomes for this exceptionally rare and challenging disease.

Diagnostic challenges and pathology considerations in children and adolescents

First described in 1985, ALK-negative ALCL is a heterogeneous group of mature T-cell lymphomas that is morphologically similar to ALK-positive ALCL, with large pleomorphic cells, abundant cytoplasm, “hallmark” horseshoe- or kidney-shaped nuclei, and strong, uniform CD30 expression (4, 20). A cytologic spectrum of tumor cells can be seen in ALK-negative ALCL, including small cell variant, monomorphic variant and, in a subset of cases, the inflammatory background is reminiscent of classic Hodgkin lymphoma with numerous eosinophils and prominent eosinophilic nucleoli (Figure 1). These have been referred to as Hodgkin-like ALCL. By definition, ALK-negative ALCL lacks rearrangement of the ALK gene on chromosome 2p23. The most common translocation in ALK-positive ALCL, t(2;5)(p23;q35), fuses the 5’ portion of the NPM1 gene on chromosome 5q35 to the 3’ portion of ALK, producing the chimeric NPM1::ALK fusion protein. ALK-negative ALCL lacks this and all other ALK rearrangements, as confirmed by immunohistochemistry or fluorescence in situ hybridization (21). The diagnosis can be particularly challenging in children and adolescents because ALK-positive ALCL accounts for the overwhelming majority of pediatric ALCL cases, while ALK-negative ALCL is exceedingly rare, comprising fewer than 5% of cases (9, 22, 23). As a result, expert hematopathology review is essential, especially given overlap with other CD30-positive T-cell lymphomas, such as peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).

Figure 1.

Histopathologic features of ALK-negative ALCL in children and adolescents. (A) H&E stained section of lymph node tissue involved by a pleomorphic population of neoplastic cells with large anaplastic cells, a subset demonstrating multiple nuclei and prominent eosinophilic nucleoli resembling Hodgkin Reed-Sternberg cells. There is an inflammatory background composed of eosinophils and small lymphocytes. (B) The neoplastic cells show aberrant downregulation of CD3. (C) The neoplastic cells express strong uniform CD30 highlighting membranous and Golgi staining pattern. (D) The neoplastic cells are CD2 positive providing evidence for a T-cell lineage.

ALK-negative ALCL lacks a defining chromosomal aberration and has a more complex genome compared to ALK-positive tumors in sequencing analyses (24). Discovery of newer genetic and molecular findings has helped with diagnostic clarity and has identified prognostic differences between subtypes. For example, gene expression profiling (GEP) can aid in distinguishing PTCL with high CD30 expression from ALK-negative ALCL (25). Most of the genetic and molecular data published to date is from adult patients with ALK-negative ALCL due to its rarity in pediatric patients. Three main categories that have emerged are DUSP22-rearranged, TP63-rearranged, and “triple-negative” (lacking ALK, DUSP22, and TP63 rearrangements) ALK-negative ALCL.

Rearrangement of the DUSP22-IRF4 locus on 6p25.3, most commonly involving a translocation with FRA7H at 7q32.3, leads to DNA hypomethylation, overexpression of cancer-testis antigens, low PD-L1, and high HLA class II expression (26, 27). These features may explain the favorable immunogenic biology of this subtype (28). DUSP22-rearranged ALCL accounts for approximately 30% of ALK-negative ALCL cases. Reported outcomes in adults have varied across studies. Parrilla Castellar and colleagues reported a 5-year OS of 90% (1), and the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) study reported a 5-year OS of 95% (29). In contrast, the LYSA study reported a 5-year OS of 65% (30) and Qiu and colleagues reported a 5-year OS of only 40% (31). These discrepancies may reflect differences in patient populations, treatment approaches, and sample sizes. The prognostic significance of DUSP22 rearrangement remains an area of active investigation for children.

TP63 rearrangements, found in approximately 2–8% of ALK-negative ALCL cases in adults, most commonly produce the TBL1XR1::TP63 fusion protein (1, 32, 33). This fusion lacks the transactivation domain, analogous to oncogenic ΔNp63 isoforms, and has been shown to coordinate recruitment of epigenetic modifying complexes (NCoR-HDAC3 and KMT2D), driving enhancer rewiring and upregulation of MYC and EZH2 (34). Rearrangements involving DUSP22 and TP63 are typically mutually exclusive. TP63-rearranged ALK-negative ALCL exhibits the worst prognosis within the ALCL subtypes, with a 5-year OS of 17% (1).

Recently, the LLMPP identified two overarching types and four molecularly distinct subtypes of ALK-negative ALCL: Type I ALCL, which includes DUSP22-rearranged and pSTAT3-positive triple-negative (TN-I) cases, and Type II ALCL, which includes TP63-rearranged and pSTAT3-negative triple-negative (TN-II) cases (29). Oncogenic mutations in JAK1 and/or STAT3, which contribute to consistent activation of the STAT3 signaling pathway, have been identified in nearly 20% of cases. In addition, oncogenic fusion genes involving a transcription factor and a tyrosine kinase, such as NFKB2::ROS1, NCOR2::ROS1, NFKB2::TYK2, and PABPC4::TYK2, have been identified in ALK-negative ALCL. These fusion chimeras result in increased STAT3 activity and develop an ALCL phenotype via STAT3 signaling, suggesting that intercepting STAT3 activation may have therapeutic potential.

Other molecular findings include aberrant expression of truncated ERBB4 transcripts in 24% of ALK-negative ALCL (35). The most common copy number alterations involve 6q21 (PRDM1) and 17p13 (TP53), seen in approximately 52% of ALK-negative ALCL (24). Rearrangements involving VAV1 and ROS1 have also been reported (27). Lastly, ALK-negative ALCL overexpresses transcription factor genes including HOXC6 and HOXA3 compared to ALK-positive ALCL (36). Together, these findings support a model in which ALK-negative ALCL in children and adolescents is a diagnostically challenging but biologically heterogeneous disease in which comprehensive immunophenotypic and molecular evaluation may increasingly inform classification, prognosis, and future biomarker-directed therapy.

Evolving therapeutic strategies

Frontline management

Given the rarity of ALK-negative ALCL in children and the absence of prospective trials specific to this population, frontline treatment recommendations generally follow protocols developed for ALK-positive ALCL. The ALCL99 protocol, consisting of short-pulse polychemotherapy, historically served as the backbone of frontline therapy for pediatric ALCL internationally (37). Only 16 of 420 enrolled patients in the ALCL99 study had ALK-negative disease; these patients achieved a progression-free survival of 75%, compared with 70% for the 404 ALK-positive patients (16). Although these results suggest that children adolescents with ALK-negative ALCL may achieve comparable outcomes with multiagent chemotherapy, this conclusion is limited by the very small sample size.

The Children’s Oncology Group trial ANHL12P1 subsequently demonstrated the addition of brentuximab vedotin or crizotinib to multiagent chemotherapy was associated with favorable outcomes in children with newly diagnosed ALK-positive ALCL (17, 18). Unfortunately, patients with ALK-negative disease were not eligible for enrollment. Therefore, in the absence of disease-specific data, the frontline approach to ALK-negative ALCL at most pediatric institutions consists of upfront multiagent chemotherapy with or without brentuximab vedotin (38).

Relapsed and refractory disease

The optimal approach to relapsed and refractory ALK-negative ALCL in children remains undefined. Available evidence derives from ALK-positive studies, those that included very few ALK-negative patients, and case reports/series. For example, in a multi-institutional retrospective analysis by Marks and colleagues, outcomes for 85 pediatric patients with relapsed or refractory ALCL were discussed (39). However, only four patients were ALK-negative, and their outcomes were not specifically analyzed due to small sample size (40). A separate European Society for Blood and Marrow Transplantation analysis of HSCT in pediatric mature T-cell lymphomas included only non-anaplastic histologies (41). The prospective international ALCL-Relapse trial evaluated a risk-stratified approach based on timing of relapse and CD3 expression (42). Of 105 evaluable patients, only two had ALK-negative disease and both classified as low-risk. The study demonstrated that allogeneic HSCT provided effective consolidation for high-risk relapse, while vinblastine monotherapy induced durable remissions in patients with late relapse. Autologous HSCT was not effective in the intermediate-risk group, and this arm was terminated prematurely. Whether these risk-stratified conclusions can be extrapolated to ALK-negative disease remains unclear.

More recent data have begun to challenge the paradigm that HSCT is required for patients with relapsed/refractory ALCL. In Marks and colleagues’ retrospective analysis, of patients with ALK positive ALCL who achieved a second complete response (CR), 5-year OS was 94% for those who received allogeneic HSCT, 91% for those with autologous HSCT, and 88% for those who did not go to transplant (40). These findings suggest that in the era of targeted therapies, HSCT may not be necessary for all patients.

Targeted agents and emerging therapies

Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, has demonstrated significant activity across ALCL subtypes regardless of ALK status. In the pivotal phase II study leading to FDA approval for relapsed or refractory systemic ALCL in adults, the overall response rate was 86% with a complete response rate of 57% (43). Real-world data from a multi-center Chinese cohort further support the efficacy of brentuximab vedotin–based regimens, with an overall response rate of 100% (89.3% complete response) in newly diagnosed systemic ALCL and 70% (50% complete response) in relapsed or refractory disease (44). Brentuximab vedotin is currently listed as a preferred second-line agent for ALCL regardless of ALK status in the NCCN Guidelines for T-Cell Lymphomas (45).

Several of the molecular alterations described in the preceding section represent emerging therapeutic targets for ALK-negative ALCL (Table 1). Preclinical studies have demonstrated that JAK inhibitors, including ruxolitinib, are effective against ALK-negative ALCL cell lines with activated JAK/STAT signaling, regardless of whether activating mutations are present (46). A biomarker-driven clinical study in adults with relapsed or refractory PTCL, including ALCL, demonstrated preferential responses to ruxolitinib among patients with activated JAK/STAT signaling (47). Ruxolitinib is now included as a category 2B recommendation for second-line ALCL therapy in the NCCN Guidelines (45). ERBB4 expression, identified in a subset of ALK-negative ALCL, represents another potential therapeutic target, though clinical data remain limited (48).

Table 1.

Molecular alterations described in children and adolescents with ALK-negative ALCL and existing targeted therapies.

Molecular alteration	Therapy class	Targeted therapy	Developmental stage
CD30 overexpression	Anti-CD30 antibody-drug conjugate	Brentuximab vedotin	FDA-approved for systemic ALCL and CD30+ PTCL
JAK1 activating mutations	JAK1/2 inhibitor	Ruxolitinib, fedratinib	NCCN-listed for ALCL (category 2B) (45); Phase II data in adults with R/R PTCL (60); pediatric case report (51)
	JAK1-selective inhibitor	Golidoctinib	Phase II data in adults with R/R PTCL (61)
	JAK2/IRAK1 dual inhibitor	Pacritinib	Preclinical (60)
STAT3 activating mutations	JAK1/2 inhibitor	Ruxolitinib, fedratinib	NCCN-listed for ALCL (category 2B) (45); Phase II data in adults with R/R PTCL (60); pediatric case report (51)
	STAT3 degrader	KT-333	Phase I trial for R/R NK/T-cell lymphoma (62)
JAK2 fusions (e.g., ATXN2L::JAK2, PCM1::JAK2, NFkB2::JAK2)	JAK1/2 inhibitor	Ruxolitinib, fedratinib	NCCN-listed for ALCL (category 2B) (45); Phase II data in adults with R/R PTCL (60); pediatric case report (51)
TYK2 fusions (e.g., NPM1::TYK2, RAN::TYK2, NCOR2::TYK2)	JAK/TYK2 inhibitor	Ruxolitinib; TYK2-selective inhibitors (e.g., deucravacitinib)	Preclinical
	SYK/JAK dual inhibitor	Cerdalutinib	Phase IIa in adult R/R PTCL (63)
ROS1 fusions (e.g., NCOR2::ROS1)	ROS1/ALK inhibitor	Crizotinib; entrectinib	Crizotinib FDA-approved for R/R ALK+ ALCL (pediatric) (64)
DUSP22::IRF4 rearrangement	No direct targeted therapy; associated with immunogenic phenotype (low PD-L1, high HLA class II)	Checkpoint inhibitors (anti-PD-1) may be considered; BET inhibitors (for co-occurring MSC mutations)	NCCN recommends considering for DUSP22-rearranged ALK-negative ALCL (45)
ERBB4 aberrant expression	ERBB/HER family inhibitor	Pan-HER inhibitors (e.g., afatinib, neratinib)	Preclinical
EZH2 overexpression/H3K27me3	EZH2 inhibitor	Tazemetostat	Preclinical
	Dual EZH1/EZH2 inhibitor	Valemetostat	Phase II in adult R/R PTCL (65)
PDGFR expression	PDGFR/ABL/KIT inhibitor	Imatinib	Preclinical
PD-L1 expression (enriched in pSTAT3+ ALK-negative ALCL)	Anti-PD-1 checkpoint inhibitor	Geptanolimab, pembrolizumab; nivolumab	Geptanolimab: phase II in adult R/R PTCL (response rate 50–54% in ALCL subset); pembrolizumab and nivolumab FDA-approved for other indications (47, 49)
MSC (musculin) E116K mutation	BET inhibitor (targets CD30-IRF4-MYC axis)	JQ1	Preclinical
PI3K pathway alterations (e.g., PIK3R1 mutations)	PI3K inhibitor	Duvelisib, idelalisib, copanlisib, alpelisib	Duvelisib: NCCN-listed for ALCL (preferred second-line) (45); phase II trial in R/R PTCL (ORR 48%, CR 33%) (66); Idelalisib/Copanlisib/Alpelisib: No data in PTCL

Checkpoint inhibitors have also been explored in T-cell lymphomas. The anti-PD-1 antibody geptanolimab demonstrated an overall response rate of 50% in adult patients with relapsed or refractory ALCL in a Phase II study (49). However, checkpoint inhibitor therapy in T-cell lymphomas carries a unique risk of disease hyperprogression, as PD-1 may function as a tumor suppressor in certain T-cell malignancies (50). Current guidelines recommend use primarily within clinical trials, which precludes widespread use in pediatric patients with ALK-negative ALCL.

Discussion

ALK-negative ALCL in children and adolescents remains one of the least understood entities in pediatric oncology. Available data is almost entirely from cohorts where adult-aged patients or those with ALK-positive ALCL are the majority. Although adult ALK-negative ALCL is molecularly heterogeneous, with subtypes carrying disparate prognoses, these classifications have not been systematically applied to pediatric cases (1). As a result, treatment is typically extrapolated from adult PTCL paradigms or pediatric ALK-positive ALCL protocols, without prospective evidence in this population (29).

Whether ALK-negative ALCL in children represents a biologically distinct entity from its adult counterpart is unknown. Cohen et al. recently described a 13-year-old boy with relapsed ALK-negative ALCL harboring a rare ATXN2L::JAK2 fusion, who achieved complete remission with ruxolitinib monotherapy prior to consolidative allogeneic HSCT (51). This case suggests that JAK/STAT-activating fusions can drive pediatric disease and may be therapeutically actionable. Relatedly, Fischer et al. identified recurrent JAK2 and TYK2 fusions in pediatric cutaneous T-cell lymphoproliferative disorders, including primary cutaneous ALCL, supporting a broader role for kinase fusions in pediatric T-cell lymphomas (52). Without systematic and universal molecular profiling of pediatric ALK-negative ALCL specimens, the fundamental question of biological distinctness cannot be answered.

There is an active debate regarding the optimal therapeutic intensity for these patients. The traditional approach of intensive multiagent chemotherapy, which historically yielded a plateau of approximately 70% EFS in pediatric ALK-positive ALCL over three decades, may not be the ideal backbone for ALK-negative disease (9, 17, 18, 53). The emergence of targeted biologics—particularly brentuximab vedotin, which is effective independent of ALK status—has prompted consideration of whether early integration of CD30-directed therapy could improve outcomes while reducing chemotherapy-related toxicity. For ALK-positive disease, the field is already moving toward a “chemotherapy-free” paradigm using ALK inhibitors and brentuximab vedotin; whether a parallel de-escalation strategy is feasible for ALK-negative ALCL, which lacks the ALK target, remains an open question (16).

An additional challenge specific to ALK-negative disease is the absence of validated tools for disease monitoring. In ALK-positive ALCL, the prognostic significance of minimal disseminated disease (MDD) and minimal residual disease (MRD), detected by PCR amplification of the ALK fusion transcript in peripheral blood and bone marrow, has been increasingly recognized as a tool for risk stratification (16–18). Because this approach relies on detection of the ALK fusion transcript, it is not directly applicable to ALK-negative disease, representing a significant gap in prognostic capabilities. The development of alternative MRD detection strategies—such as circulating tumor DNA or immunophenotypic approaches—will be important for advancing risk-adapted therapy in this population.

The relationship between ALK-negative ALCL and PTCL-NOS in children also warrants further investigation. While these entities are classified separately, current NCCN Guidelines group ALK-negative ALCL with other PTCL histologies for treatment purposes (45). As the molecular landscape of ALK-negative ALCL continues to be elucidated, clarifying the biological boundaries between these entities will be essential for appropriate risk stratification and treatment selection.

Lastly, the extreme rarity of pediatric ALK-negative ALCL has precluded prospective trials and evidence-based guidelines. This gap will require collaborative, international efforts like those employed by the Paediatric Rare Tumours Network–European Registry (PARTNER) (54), the COG study ANHL04B1 (55), and ongoing work through the COG NHL Committee’s Rare NHL Subcommittee to develop multi-institutional cohorts of rare pediatric and AYA NHL, including ALK-negative ALCL (56). Such efforts serve the dual purpose of characterizing the disease biology in children and providing the infrastructure for future interventional studies.

Future progress will require molecularly stratified, risk-adapted approaches and inclusion of ALK-negative ALCL as a defined arm or stratum within broader pediatric lymphoma trials or biomarker-driven basket trials such as NCI-COG Pediatric MATCH (29, 57–59). Published case reports remain important, as they demonstrate how comprehensive profiling can identify actionable targets even in single patients (51). Ultimately, improving outcomes for children and adolescents with ALK-negative ALCL will depend on moving beyond extrapolation toward molecular profiling, collaborative data-sharing, and biomarker-informed therapy tailored to this ultra-rare population.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. LS receives support from the National Cancer Institute (L40CA274778), US Department of Defense (CA240267), and Conquer Cancer, The ASCO Foundation (Career Development Award).

Author contributions

KD: Writing – original draft, Validation, Writing – review & editing, Investigation. JS: Writing – original draft, Validation, Writing – review & editing, Investigation. ML: Visualization, Writing – original draft, Writing – review & editing, Investigation. LS: Visualization, Conceptualization, Validation, Writing – review & editing, Funding acquisition, Project administration, Writing – original draft.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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