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CASE REPORT
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Successful combination of crizotinib and hematopoietic stem cell transplantation in relapsed ALK-positive ALCL


 Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

Date of Submission02-Nov-2019
Date of Decision03-Nov-2019
Date of Acceptance24-Mar-2020
Date of Web Publication17-Oct-2020

Correspondence Address:
Xiaosheng Fang,
Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_961_19

  Abstract 


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



How to cite this URL:
Sun X, Fang X, Jiang Y. Successful combination of crizotinib and hematopoietic stem cell transplantation in relapsed ALK-positive ALCL. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 20]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=298289





  Background Top


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.[1] 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.[2],[3] 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,[4] 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.[5] However, many patientswith R/R ALCL experience pooroutcomes and short survival.[6] 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 Top


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 Top


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.[7] 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].[8],[9],[10],[11],[12],[13] Some patients could achieve CR on the continuous application of crizotinib as shown in patients 1-6.[8],[9] However, patients 7–8 showed that single-agent crizotinib is not a perfect therapeutic method, as sudden recurrence occurred after discontinuation.[10] For patients 9–17, crizotinib was used as a bridge therapy before allo-HSCT and only 3 of them relapsed after transplantation.[9],[11],[12] 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,[9],[13] 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.[14] Domingo-Domènech et al. also demonstrated the effectiveness of autologous transplantation in ALCL.[15] Fukano et al. reported that some patients who have not achieved CR or relapsed with chemotherapy could achieve CR after allo-HSCT.[16] 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.[9] 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,[17] 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.[18] 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.

Acknowledgments

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Seidemann K, Tiemann M, Schrappe M, Yakisan E, Simonitsch I, Janka-Schaub G, et al. Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is effective curative treatment for pediatric anaplastic large cell lymphoma: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 2001;97:3699-706.  Back to cited text no. 1
    
2.
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994;263:1281-4.  Back to cited text no. 2
    
3.
Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer 2013;13:685-700.  Back to cited text no. 3
    
4.
Boi M, Zucca E, Inghirami G, Bertoni F. Advances in understanding the pathogenesis of systemic anaplastic large cell lymphomas. Br J Haematol 2015;168:771-83.  Back to cited text no. 4
    
5.
Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, et al. ALK-anaplastic large cell lymphoma is clinically and immunophenotypically different from both ALK+ALCL and peripheral T-cell lymphoma, not otherwise specified: Report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111:5496-504.  Back to cited text no. 5
    
6.
Mak V, Hamm J, Chhanabhai M, Shenkier T, Klasa R, Sehn LH, et al. Survival of patients with peripheral T-cell lymphoma after first relapse or progression: Spectrum of disease and rare long-term survivors. J Clin Oncol 2013;31:1970-6.  Back to cited text no. 6
    
7.
Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res 2008;68:4971-6.  Back to cited text no. 7
    
8.
Mahuad CV, Repáraz Mde L, Zerga ME, Aizpurua MF, Casali C, Garate G. Three years sustained complete remission achieved in a primary refractory ALK-positive anaplastic T large cell lymphoma treated with Crizotinib. Rare Tumors 2016;8:6266.  Back to cited text no. 8
    
9.
Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase–positive lymphoma patients. J Natl Cancer Inst 2014;106:djt378.  Back to cited text no. 9
    
10.
Gambacorti Passerini C, Mussolin L, Brugieres L. Abrupt relapse of ALK-positive lymphoma after discontinuation of crizotinib. N Engl J Med 2016;374:95-6.  Back to cited text no. 10
    
11.
John TD, Naik S, Leung K, Sasa G, Martinez C, Krance RA. Allogeneic hematopoietic cell transplant following Crizotinib monotherapy for relapsed/refractory anaplastic large cell lymphoma. Pediatr Transplant 2018;22:e13210.  Back to cited text no. 11
    
12.
Ordemann R, Stöhlmacher J, Beuthien-Baumann B, Platzek I, van den Hoff J, Kroschinsky F, et al. Use of targeted therapy for refractory ALK-positive anaplastic large cell lymphoma as a bridging strategy prior to allogeneic transplantation. Ann Hematol 2013;92:125-7.  Back to cited text no. 12
    
13.
Cleary JM, Rodig S, Barr PM, Shinagare AB, Clark JW, Shapiro GI, et al. Crizotinib as salvage and maintenance with allogeneic stem cell transplantation for refractoryanaplastic large cell lymphoma. J Natl Compr Canc Netw 2014;12:323-6.  Back to cited text no. 13
    
14.
Domingo-Domènech E, Boumendil A, Climent F, Socié G, Kroschinsky F, Finel H, et al. Allogeneic hematopoietic stem cell transplantation for patients with relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant 2020;55:633-40.  Back to cited text no. 14
    
15.
Domingo-Domènech E, Boumendil A, Climent F, Sengeloev H, Wahlin B, Wattad W, et al. Autologous hematopoietic stem cell transplantation for relapsed/refractory systemic anaplasticlarge cell lymphoma. A retrospective analysis of the lymphoma working party (LWP) of the EBMT. Bone Marrow Transplant 2020;55:796-803.  Back to cited text no. 15
    
16.
Fukano R, Mori T, Kobayashi R, Mitsui T, Fujita N, Iwasaki F, et al. Haematopoietic stem cell transplantation for relapsed or refractory anaplastic large cell lymphoma: A study of children and adolescents in Japan. Br J Haematol 2015;168:557-63.  Back to cited text no. 16
    
17.
Rothenstein JM, Letarte N. Managing treatment-related adverse events associated with ALK inhibitors. Curr Oncol 2014;21:19-26.  Back to cited text no. 17
    
18.
Solomon B. Refining the toxicity profile of Crizotinib. J Thorac Oncol 2014;9:1596-7.  Back to cited text no. 18
    



 
 
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