ALK positive

The patient was treated with a modified MARIETTA protocol (without rituximab) and consolidated with a carmustine-based autologous stem cell transplant. shows complete metabolic response on PET-CT and MRI brain. This case presents the first successful treatment of a synchronous presentation of CNS and systemic ALK-positive ALCL, and the importance of a multidisciplinary approach for diagnosis.

P=N/A, N=200, Not yet recruiting, Shandong First Medical University and Shandong Academy of Medical Sciences (Shandong Cancer Hospital ＆Institute); Shandong First Medical University

P4, N=178, Not yet recruiting, Beijing chest hospital capital medical university; Beijing Chest Hospital Capital Medical University

P2, N=61, Not yet recruiting, Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen Un

From first-generation Crizotinib to third-generation Lorlatinib, successive agents have been refined for target selectivity, central nervous system penetration, and coverage of resistance-associated mutations, substantially improving patient survival and intracranial disease control. Nonetheless, the emergence of acquired resistance remains an overarching challenge, mediated by secondary kinase domain mutations, activation of bypass signaling pathways, and tumor phenotypic transformation. This review presents an integrative synthesis of ALK-targeted therapeutic developments, elucidates underlying resistance mechanisms, and surveys emerging strategies, providing a comprehensive perspective on current advances and future directions in precision management of ALK-driven malignancies.

Their diagnosis requires careful consideration to accurately distinguish rare indolent entities, recently defined large B‑cell lymphomas, and reactive mimics. Recent classifications, including the newly introduced WHO Classification of Pediatric Tumors, increasingly reflect these unique aspects.

The discussion emphasizes the importance of consideration of drug efficacy, safety outcomes, potential treatment resistance, and development of brain metastases when determining treatment strategies. Ultimately, it is essential to select the best treatment first and proactively manage any potential adverse events to ensure that patients can derive clinical benefit and safely remain on therapy.

Here, we report a case of an ALK-positive lung adenocarcinoma patient who developed resistance following sequential treatment with the ALK-TKI alectinib and lorlatinib, accompanied by histological transformation to LCNEC and concurrent genetic alterations including TP53 deletion, CDKN2A deletion, and MYC amplification. This case expands the spectrum of ALK-TKI resistance mechanisms and highlights the potential value of exploring combinatorial approaches incorporating immunotherapy, antiangiogenic therapy, and chemotherapy for the management of such cases.

In further studies, RNA sequencing confirmed the presence of NPM1::ALK gene fusion in this case; whole-exome sequencing (WES) detected somatic mutations in multiple genes of the JAK-STAT pathway (including JAK1, PTPN6, MTOR, and TYK2). It is noteworthy that such genetic alterations are more commonly observed in ALK-negative anaplastic large cell lymphoma (ALK-ALCL) but are less commonly reported in ALK+ALCL.

The patient received whole-brain radiotherapy (30 Gy in 10 fractions), cisplatin-pemetrexed chemotherapy, and sequential targeted therapy with alectinib and lorlatinib. During three years of follow-up, MRI showed complete resolution of all lesions, and the patient remained neurologically intact and systemically stable. This case underscores the rarity of non-enhancing brain metastases in ALK-positive NSCLC and highlights the importance of recognizing this atypical imaging presentation for timely diagnosis and management.

The condition exhibited a typical positive rechallenge feature of "discontinuation and recurrence," providing critical clinical evidence to establish this causal relationship. The case aims to enhance the understanding of crizotinib's metabolic side effects, underscores the importance of dynamic lipid monitoring, and offers empirical support for the standardized management of such rare adverse reactions.