High Response Rates To Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma Patients

In hematological disorders ALK expression is present in >50% of Anaplastic Large Cell Lymphomas (ALCL) as a result of a t(2;5)(p23;q35) translocation that causes the ALK gene on chromosome 2 to fuse with the NPM gene on chromosome 5. ALK + ALCL respond to cytotoxic drugs, but relapses occur and bear a poor prognosis(Stein, Foss et al. Blood 96 3681-95 2000; Ferreri, Govi et al. Crit Rev Oncol Hematol 83 293-302 2012). ALK-positive large B-cell lymphoma (ALK+ LBCL) is a rare lymphoma with a most frequent t(2;17)(p23;q23) translocation responsible for Clathrin-ALK fusion protein(Swerdlow, Campo et al. 2 2008). Crizotinib is the first ALK inhibitor which entered clinical practice: it is an orally bioavailable small-molecule inhibitor active on the ALK and MET receptor tyrosine kinases. While the activity of crizotinib in ALK+ lung cancer is documented (Kwak, Bang et al. N Engl J Med 363 1693-703 2010)no report on long term effects of crizotinib in ALK+ lymphomas exists; impressive short-term therapeutic activity was reported in two patients (Gambacorti-Passerini, Messa et al. N Engl J Med 364 775-6 2011), but no long-term data are available.

In the present study, crizotinib was administered (250 mg BID) as monotherapy to 11 ALK+ lymphoma patients, diagnosed with ALK+ Non-Hodgkin lymphoma (NHL) by immunohistochemistry and FISH. Nine patients had a ALCL histology while the remaining 2 were DLBCL Patients had a refractory or relapsed disease after at least one prior chemotherapy regimen and measurable disease. All had involvement at multiple sites (nodal and extranodal) as well as B symptoms and an ECOG performance score of 1-4. Response to therapy was assessed according to RECIST criteria (Therasse, Arbuck et al. J Natl Cancer Inst 92 205-16 2000)

The Overall Response Rate (ORR) was 10/11 (91%, 95% CI: 60-99%) and included 9 CR (82%, 95% CI: 51-96%) and 1 PR. Evidence of response by PET/CAT scan was present as early as 12 days. B symptoms disappeared promptly and LDH levels normalized within 30 days after the start of crizotinib.

Disease status at the latest follow-up (June 2013) is as follows: 4 patients are in CR under continuous crizotinib treatment; they also test negative by RT-PCR for NPM/ALK (Mussolin, Damm-Welk et al. Leukemia 27 416-22 2012). Three patients (2 with LBCL and 1 with ALCL) died due to disease progression; 1 patient obtained CR, relapsed after 2 months of treatment and is now in CR on continued brentuximab treatment (month 29); 1 patient obtained CR on crizotinib and after 2 months stopped treatment, received an alloBMT and is still in CR; 2 patients treated for relapses post alloBMT obtained CR and are still in CR but they stopped crizotinib after 8-10 months. The two patients with ALK+ LBCL died within 3 months; in those with ALCL the CR rate was 9/9 (100%, 95% CI, 74-100%) with a median duration of 10 months (range 2-37).

The 3 years PFS and OS rates are 62% (95% CI, 35-85%) and 73% (95% CI, 40-93%) respectively, with a plateau in the curve after the initial 6 months.

In two relapsed patients the kinase domain of NPM-ALK could be amplified from peripheral blood samples obtained at the time of relapse (month 5 and 2). Deep sequencing of these products revealed the presence of different mutations: Q1064R at high prevalence (95%,) in patient (pt) #2 and I1171N (33%) plus M1328I (14%) in pt #6. All these mutations were not present in samples obtained before crizotinib treatment. I1171N was already discovered in an in-vitro screening (Ceccon, Mologni et al. Mol Cancer Res 11 122-32 2012): it commands an intermediate level of resistance to crizotinib (RI: 5.8) which however is cross resistant with other anti-ALK TKI such as AP26113 and NVP-TAE684. The other two mutations were not previously described: they present a RI to crizotinib of 2.4 (M1328I) and 8.5 (Q1064R). Since these residues do not form direct contacts with crizotinib, they probably interact with different structures within the catalytic domain such as the hydrophobic R-spine (I1171N) (Ceccon, Mologni et al. Mol Cancer Res 11 122-32 2012), the activation loop (M1328I), or yet unidentified regions (Q1064R).

In conclusion, these positive results extend our initial observation on two patients (Gambacorti-Passerini, Messa et al. N Engl J Med 364 775-6 2011) and provide long-term follow up data. Crizotinib exerted a potent antitumor activity in advanced ALK+ lymphoma and produced durable responses in this population of heavily pre-treated patients, with a benign safety profile.