Inflammatory myofibroblastic tumor (IMT) is a rare type of childhood neoplasm characterized
by intermediate biological behavior. The main method of treatment of this tumor is a complete
surgical removal. It should be said, that in 2-5% of patients the presence of distant
metastases was noted at the time of diagnosis, in addition, the complex anatomical
localization of the process sometimes does not allow a radical surgical intervention. In
patients with unresectable IMT, the presence of distant metastases, residual tumor after
initial resection or progression of the disease, attempts have been made to prescribe therapy
with steroids , nonsteroidal anti-inflammatory drugs (NSAIDs), cytostatic drugs. However, the
effectiveness of this therapy was low.
Since the late 90s, it is known that with the identification of a number of specific
cytogenetic changes, this type of neoplasm is a true neoplastic process. In 50% of all cases
of IMT there are clonal translocations of the ALK gene located at the 2p23 encoding the
anaplastic lymphoma kinase (ALK). It was shown that ALK gene activation is based on
translocations involving a large number of partner genes with tyrosine kinase activity.
Currently, there are more than 21 partner genes involved in the formation of chimeric
transcripts. The most frequent are TPM3, TPM4, CLTC, CARS, RANBP, EML4, TFG.
The introduction of modern molecular genetic methods, including the next generation
sequencing (NGS), has expanded the understanding of the mechanisms of carcinogenesis in IMT.
Along with ALK gene rearrangements, the ROS1 gene (YWHAE-ROS1 and TFG-ROS1) and PDGFRB (NAB2)
genes were detected in the group of patients with ALK-negative IMT.
The therapy with tyrosine kinase inhibitors (crizotinib) has become possible not only in
patients with ALK-positive tumor, but also in a group of patients who do not have an ALK gene
rearrangement, but in whom a rearrangement of the ROS1 gene has been detected [4].
Previously, large-scale studies using tyrosine kinase inhibitors (crizotinib) have not been
conducted in patients under 18 with IMT.
The Phase 1 study, conducted by the Children's Cancer Group (USA), showed the response rate
on therapy with crizotinib in 3/7 patients, and . disease stabilization in 4/7 patients
(Mosse Y., 2013).
The median age of patients with IMT, included in the study, was 8.4 years (range 1.1 - 21.4).
In this study, it was noted that the use of crizotinib in a dose regimen of 280 mg / m2 twice
a day in this group of patients does not lead to an increase in the incidence of side effects
of grade 3 and 4. Thereby, the maximum permissible dose was determined, which amounted to 560
mg / m2 / day in two doses.
In the phase 2 study, it was shown that in the group of patients with IMO a response in 86%
of cases has been achieved, with complete response in 36% (5/14), partial response in 50%
(7/14), and stabilization of the disease in 14% (Mosse Y., 2017).
In the recently published single-drug, open-label, non-randomized phase 2 study the objective
response rate on crizotinib in ALK+ patients was 50% (n=6/12) Schöffski P., et al. Lancet
Respir Med. 2018 Jun;6(6):431-441. doi: 10.1016/S2213-2600(18)30116-4. Epub 2018 Apr 15).
The investigator's study is designed in order to show if the treatment with ALK-inhibitor
crizotinib is able to improve the outcome of pediatric IMTs in Russia.
