Lorlatinib Monotherapy in Relapsed/Refractory ALK + Lymphomas Previously Treated with Other Tyrosine Kinase Inhibitors: 5-Year Update of a Phase 2 Open Label Monocentric Study
Authors: Colombo Federica , Aroldi Andrea , Crippa Stefano , Cocito Federica , Guerra Luca , Monaco Lavinia , Granelli Bianca Maria , Mussolin Lara , Gambacorti-Passerini Carlo 
Published: December 2024

Introduction
ALK+ Anaplastic Large Cell Lymphoma (ALCL) and ALK+ Large B Cell Lymphoma (LBCL) are aggressive T- and B-cell lymphomas with a poor prognosis when chemo-immunotherapy (CIT) and salvage treatment with Crizotinib fail.
Preclinical trials have shown that Lorlatinib, a next-generation selective ALK and ROS1 TKI, inhibits all reported ALK kinase domain mutations responsible for resistance to Crizotinib.
Preliminary results of Lorlatinib monotherapy have demonstrated high response rates and no additional toxicities for ALK+ lymphoma patients (pts) who failed first-line TKI treatment. It also offers a promising bridging regimen to salvage Allogeneic Stem Cell Transplantation (ASCT).
Methods
We present a 5-year update of the phase 2 open-label monocentric study with Lorlatinib monotherapy (EudraCT2016-003970-41). We evaluate the primary endpoint: overall response rate (ORR) using 18F-FDG PET/CT scans and ALK RT-PCR. Secondary endpoints are progression-free survival (PFS), and overall survival (OS) from the start of Lorlatinib treatment to relapse and/or death. Additionally, we assess toxicity and quality of life (QoL).
From 2019 to 2024, we enrolled 7 pts with relapsed/refractory ALK+ neoplasms who had failed chemo-immunotherapy and salvage treatment with Crizotinib.
Four pts had ALK+ LBCL with Clathrin-ALK (CTCL::ALK) rearrangement (#1, 2, 3, 7), and two patients (#5 and #6) had ALK+ ALCL with ATIC::ALK fusion. One pt (#4) with ALK+ histiocytosis and EML4::ALK rearrangement was also included.
The median age was 23 years (range 19-57), 3 women and 4 men, and all patients were caucasian and in stage IV Ann Arbor. The median number of prior therapy lines was 3 (range 2-5); all pts had previously received Crizotinib after failing CIT, 2 pts received other TKI treatment with Alectinib and 1 pt with Ceritinib. Lorlatinib was administered daily at a dose of 100 mg.
Clinical, laboratory, radiological, and molecular data were collected at screening and during scheduled follow-ups. Responses were evaluated with 18F-FDG PET/CT (and contrast-enhanced CT scans) according to the Lugano Classification, and with ALK RT-PCR on peripheral blood and bone marrow. Side effects were classified according to CTCAEv4.03.
Results
The median follow-up is 19,3 months (1,3- 56 months). At month 1 (M1), 4 out of 7 patients achieved complete response (CR) and reached negativity by ALK RT-PCR. The remaining 3 patients obtained a partial response (PR), resulting in an overall response rate (ORR) of 100% (95% CI: 0.6-1.0) at M1.
Two pts with CR at M1 are still receiving Lorlatinib 100 mg daily without need to dose decrease and are still in CR at months 7 and 56.
Two CR pts at M1 underwent ASCT, then resumed Lorlatinib after ASCT. Lorlatinib dose reduction (from 100 mg to 75 mg or 50 mg/day) was due to transplant complications (hepatic GVHD and memory dysfunction) in which a role of Lorlatinib could not be excluded. Both pts are still in CR.
The 2 pts with PR relapsed within 3 months (both had ALK+ LBCL with CTCL-ALK rearrangement) and did not benefit from ASCT or salvage therapy.
The patient with ALK+ histiocytosis achieved PR at M1 and then CR at M3 with Lorlatinib and surgical resection of a residual lung mass. She remains in CR also after 36 months.
The median PFS and OS were not reached. The PFS at 3 month was 71%, which then, with no additional event occurring thereafter. The OS was 85% at 3 months, and 57% at 6 months, maintaining this level during subsequent follow-ups.
Hypertriglyceridemia /hypercholesterolemia and muscle cramps grade I-II were the most frequent events. Two pts reported difficulty concentrating during daily activities and occasional mental confusion. Additionally, two pts reported chronic gastrointestinal disorders such as bloating or abdominal pain. Two pts experienced grade 1 thrombocytopenia.
Conclusions
The 5-year update confirms the efficacy and safety of Lorlatinib monotherapy as salvage therapy for ALK+ lymphoma patients who have failed first-line TKI treatment. Additionally, our work confirms that obtaining CR at M1 remains the most important prognostic factor for the durability of response. No relapse was noted after the initial 90 days of treatment.