|Ahead of print
Successful combination of crizotinib and hematopoietic stem cell transplantation in relapsed ALK-positive ALCL
Xue Sun, Xiaosheng Fang, Yujie Jiang
Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
|Date of Submission||02-Nov-2019|
|Date of Decision||03-Nov-2019|
|Date of Acceptance||24-Mar-2020|
|Date of Web Publication||17-Oct-2020|
Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong
Source of Support: None, Conflict of Interest: None
We report a case wherein a combination of crizotinib and hematopoietic stem cell transplantation (HSCT) cured a 20-year-old woman with relapsed and refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma
(ALK-positive ALCL). Although she received cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) as the first-line chemotherapy from the beginning, the disease progressed rapidly with the emergence of bone marrow invasion and hemophagocytic syndrome. Vincristine, idarubicin, l-asparaginase, and prednisone (VILP) chemotherapy was not effective. Therefore, the patient received off-label use of crizotinib (an ALK inhibitor) and her condition improved rapidly. Subsequently, she received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and achieved complete remission (CR) a month later. Later, crizotinib was used as a maintenance treatment for 3 months and discontinued because of adverse reactions. Our patient has been in CR for 3 years.
Keywords: ALK-positive anaplastic large cell lymphoma, crizotinib, hematopoietic stem cell transplantation
| » Background|| |
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma that often occurs in children and accounts for 10–15% of pediatric lymphomas. ALCL develops rapidly and 85% of patients with t(2;5)(p23;q35) translocation will form the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion gene., The activity of these fusion genes is essential for the process of cell transformation and lymphoma survival, but it also creates an opportunity for treatment with ALK inhibitors.
Crizotinib is an ALK tyrosine kinase receptor inhibitor and was approved for the treatment of non-small cell lung cancer patients with the EML4-ALK fusion gene by the Food and Drug Administration (FDA) in 2011. US NCCN (National Comprehensive Cancer Network) guidelines also recommend crizotinib for the treatment of relapsed/refractory (R/R) ALK-positive ALCL, which is currently in clinical trials internationally.
ALK- positive ALCL generally has a good response to standard chemotherapy and comparatively good prognosis, with approximately 60% of patients remaining in remission 5 years after front-line therapy. However, many patientswith R/R ALCL experience pooroutcomes and short survival. In the following R/R ALK-positive ALCL case, crizotinib was successfully used as salvage therapy, bridge therapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT), and maintenance therapy after transplantation.
| » Case Summary|| |
A 20-year-old woman was diagnosed with stage IV ALK-positive ALCL along with bone marrow (BM) involvement. Flow cytometry (FCM) revealed 8.15% of abnormal T lymphocytes in the BM. She received six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) and only obtained a partial response. One month after the last chemotherapy, she showed signs of disease progression such as rapid enlargement of right retroauricular lymph node, fever, sustained elevation of the peripheral blood leukocyte, and pain in the region of the spleen. BM biopsy showed involvement of lymphoma cells, and the abnormal T lymphocytes accounted for 0.31% by FCM.
The disease was complicated by hemophagocytic syndrome, which progressed rapidly and was treated with the vincristine, idarubicin, l-asparaginase, and prednisone (VILP) regimen. Myelosuppression occurred during chemotherapy, including neutropenia, thrombocytopenia, and recurrent fever. After 1 cycle of chemotherapy, her symptoms were still present and her condition was critical. BM aspiration indicated that abnormal T lymphocytes accounted for 11.02%.
Crizotinib, at a dose of 250 mg twice a day, was given to this patient. No other antineoplastic drugs were given at the same time based on the patient's poor condition. Adverse reactions of crizotinib appeared, including nausea, vomiting, and diarrhea, which were significantly alleviated after symptomatic treatment. After 7 days of crizotinib treatment, her lung infection improved and hemogram returned to normal. BM aspiration performed at 20 days showed normal cell morphology, and abnormal T lymphocytes accounted for 2.37% by FCM which was less than before.
Three weeks later, the patient underwent a haploidentical peripheral blood stem cell transplantation. Crizotinib was discontinued 1 day before the conditioning therapy with total body irradiation, etoposide, cyclophosphamide, and anti-human T-cell rabbit immunoglobulin. Computed tomography (CT) image and BM aspiration performed at 1 month after HSCT indicated complete regression of previous lesions. After that, crizotinib was used as a maintenance treatment for 3 months and discontinued because of the severe gastrointestinal side effects. So far, the patient has been followed up and has been in continuous complete remission (CR) for 3 years.
| » Discussion|| |
This case indicates the sensitivity of crizotinib in the treatment of R/R ALK-positive ALCL. Although most of the ALK-positive ALCL patients have good responses to first-line chemotherapy, 40% of them will suffer from R/R disease and generally bear a poor prognosis. There is still no standard treatment for the R/R ALK-positive ALCL patients. Compared with the significant side effects and unfavorable clinical outcomes of traditional chemotherapy, targeted therapies with limited side effects and considerable curative effects are very promising. ALK inhibitors play a crucial role in promoting tumor cell apoptosis and inhibiting tumor cell growth by restraining the phosphorylation of ALK, Akt, STAT3, and ERK in the cellular pathway and blocking the ALK signaling pathway. Therefore, crizotinib was successfully used in the treatment of ALK-positive lung cancer. However, it has not been approved by the FDA for the treatment of ALK-positive ALCL.
Several case reports discuss the effect of crizotinib and HSCT in patients with relapsed ALK-positive ALCL which are summarized in [Table 1].,,,,, Some patients could achieve CR on the continuous application of crizotinib as shown in patients 1-6., However, patients 7–8 showed that single-agent crizotinib is not a perfect therapeutic method, as sudden recurrence occurred after discontinuation. For patients 9–17, crizotinib was used as a bridge therapy before allo-HSCT and only 3 of them relapsed after transplantation.,, Currently, the maintenance treatment strategy of ALK-positive ALCL after transplantation is not clear. Patients 18–20 obtained long-term CR under continuous crizotinib administration after HSCT,, which may indicate a desirable prospect.
|Table 1: Characteristics of patients treated with crizotinib and hematopoietic stem cell transplantation|
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There are no prospective clinical trials that could confirm the efficacy of allo-HSCT in ALCL treatment and the results of retrospective studies are controversial. Domingo-Domènech et al. proved that allo-HSCT is a curative treatment strategy in a retrospective study about R/R ALCL patients, no matter whether or not brentuximab vedotin (BV) was used before transplantation. Domingo-Domènech et al. also demonstrated the effectiveness of autologous transplantation in ALCL. Fukano et al. reported that some patients who have not achieved CR or relapsed with chemotherapy could achieve CR after allo-HSCT. Although allo-HSCT was proven to be an effective treatment for R/R ALCL in the above studies, further prospective and larger studies are needed to confirm its efficacy.
Reports mentioned in [Table 1] indicate that ALK-positive ALCL patients could achieve CR with single-agent crizotinib; however, the follow-up time is relatively limited (up to 3 years) and some patients will relapse after the discontinuation of crizotinib. Besides, Gambacorti et al. discovered the phenomenon of crizotinib resistance in ALCL, which is mainly related to ALK gene mutations. Therefore, whether a single-agent crizotinib can cure R/R ALCL remains unclear. Crizotinib also presented some common adverse events including visual disorders, nausea, vomiting, diarrhea, edema, and elevated transaminases, and due to the increased application of crizotinib, other less common toxicities such as Q-T interval prolongation, bradycardia, hypogonadism, and kidney damage are emerging. All these adverse events and the high price of crizotinib restrict its long-term clinical application.
In this case, we used crizotinib as salvage therapy and bridge therapy before allo-HSCT, and as maintenance therapy after the transplantation. Although crizotinib is used for a short time due to adverse reactions, the patient might benefit from the synergy effect of crizotinib and allo-HSCT. At the time of this study, she had been in CR for about two years and lived a normal life without disturbance of adverse events. Thus, the combination of crizotinib and allo-HSCT has shown impressive results for the treatment of R/R ALK-positive ALCL patients, but further studies may be warranted to confirm and support the feasibility of this treatment regimen.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
This study was funded by National Natural Science Foundation (No. 81270598, No. 81473486, and 81770210, No. 81700159); Key Research and Development Program of Shandong Province (No. 2018CXGC1213); Technology Development Projects of Shandong Province (No. 2017GSF18189, No. 2016GSF201029); Technology Projects of Jinan (No. 201704092); Taishan Scholar Foundation of Shandong Province; Program of Shandong Medical Leading Talent.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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