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LETTER TO EDITOR
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 614-617

Clofarabine-based conditioning for T-cell replete haploidentical hematopoietic stem cell transplant for relapsed/refractory acute leukemia using peripheral blood stem cell grafts and post-transplantation cyclophosphamide


Department of Medical Oncology/Hematology/BMT, Asian Institute of Medical Sciences, Faridabad, Haryana, India

Date of Submission16-Jan-2020
Date of Decision17-Feb-2020
Date of Acceptance01-Apr-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Prashant Mehta
Department of Medical Oncology/Hematology/BMT, Asian Institute of Medical Sciences, Faridabad, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_27_20

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How to cite this article:
Mehta P, Arora R. Clofarabine-based conditioning for T-cell replete haploidentical hematopoietic stem cell transplant for relapsed/refractory acute leukemia using peripheral blood stem cell grafts and post-transplantation cyclophosphamide. Cancer Res Stat Treat 2020;3:614-7

How to cite this URL:
Mehta P, Arora R. Clofarabine-based conditioning for T-cell replete haploidentical hematopoietic stem cell transplant for relapsed/refractory acute leukemia using peripheral blood stem cell grafts and post-transplantation cyclophosphamide. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 21];3:614-7. Available from: https://www.crstonline.com/text.asp?2020/3/3/614/295513



Relapsed/refractory acute leukemia has a very poor outcome. There is an unmet need of novel treatment regimens for heavily pretreated patients with an acceptable toxicity profile. Clofarabine (2-chloro-2′-fluoro-deoxy-9-β-D-arabinofuranosyl) adenine is a second generation purine nucleoside with substantial responses in acute leukemia in the relapsed refractory setting.[1] The dose-limiting neurotoxicity observed with fludarabine and cladribine is not observed with clofarabine.[2] With clofarabine, the typical dose-limiting toxicities are skin and hepatic.[2]

Clofarabine has demonstrated significant anti-leukemic effects in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).[1],[3],[4],[5] Clofarabine combinations have been used successfully to achieve durable remission in acute leukemia. In addition, clofarabine is at least equal and may be superior to fludarabine, with regard to the immunosuppressive properties and anti-leukemia properties.[6] Substituting fludarabine with clofarabine in conditioning therapy before hematopoietic stem cell transplant (HSCT) has previously shown improved survival in the setting of acute leukemia.[6],[7],[8],[9] For haploidentical transplants, clofarabine has been utilized for both T-cell deplete[8] and replete (using posttransplantation cyclophosphamide [PTCy] Clo-Baltimore Clo-Baltimore regimen)[9] strategies, though the literature is scarce in this context. To the best of our knowledge, clofarabine has not been utilized in combination with busulfan or melphalan with or without total body irradiation (TBI) (Clo-Bu-PTCy and Clo-Mel-PTCy) for T-cell replete haploidentical peripheral blood stem cell (PBSC) transplant.

We describe here three patients [Table 1] with relapsed/refractory acute leukemia treated with haploidentical transplantation with clofarabine as a part of a reduced-intensity conditioning regimen with busulfan (one patient) or melphalan (two patients) with 2 Gy TBI. All the three patients received cyclosporine and mycophenolate mofetil (MMF) as graft-versus-host-disease (GvHD) prophylaxis.
Table 1: Case summary of three patients with relapsed/refractory acute leukemia treated with haploidentical transplantation with clofarabine as a part of the reduced-intensity conditioning regimen with busulfan (one patient) and melphalan (two patients) with total body irradiation of 2 Gy

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  Case 1 Top


A 2-year-old male child who was diagnosed with AML with bilateral proptosis and orbital granulocytic sarcomas received 3 + 7 induction (cytarabine at 200 mg/m2 × 7 days and daunomycin at 60 mg/m2 × 3 days) therapy with intrathecal methotrexate after which the patient was in complete remission (CR). The patient received 1 dose of high-dose ara-c (HiDAC) and was taken up for a T-cell replete haploidentical HSCT using his father as the donor. The patient had an autologous recovery on day + 17 post-HSCT, but the disease relapsed after about 1 month of autologous recovery. Thereafter, salvage protocol was given and the patient achieved CR2. He again relapsed just after the first HiDAC and had to be taken up for a second haploidentical transplant in active disease. Clofarabine and busulfan as conditioning therapy and PTCy-CSA-MMF as GvHD prophylaxis was given. The patient engrafted on day + 18 and posttransplant bone marrow was in morphological remission. The day + 28 chimerism was 99.6% donor (whole blood), while the lineage specific chimerisms were 96.6% (myeloid) and 97% (T-cell). Immunosuppression was withdrawn on day + 45 and repeat bone marrow examination showed no evidence of disease. Around day + 60, the child had an extramedullary relapse (skin deposits) followed by a bone marrow relapse. A donor lymphocyte infusion was given, but the child succumbed to his disease on day + 70.


  Case 2 Top


A 15-year-old male was diagnosed with pre-B-cell ALL, intermediate risk in September 2014, and was treated with BFM-95 induction protocol (prednisolone, vincristine, daunorubicin, and L-asparaginase). At the end of induction, bone marrow was positive for minimal residual disease (MRD) by flow cytometry at 0.03%. He was continued on protocol therapy, received consolidation, and achieved MRD negativity. Subsequently, the patient received re-induction and late intensification followed by maintenance till April 2017. In December 2018, the patient developed a central nervous system (CNS) and medullary relapse and received salvage chemotherapy with the modified St. Jude protocol. At the end of induction, MRD was 1.5%, while CNS disease cleared completely. He was referred to our center for HSCT and was taken up for haploidentical HSCT with clofarabine, melphalan, and TBI as conditioning therapy and PTCy-CSA-MMF as GvHD prophylaxis. He is now 6 months posttransplant, MRD is negative, and there is no evidence of GvHD.


  Case 3 Top


A 14-year-old male was diagnosed with AML, intermediate risk in April 2018. He received 3 + 7 induction therapy followed by three cycles of HiDAC. In February 2019, on routine follow-up, he relapsed with a treatment free interval of 6 months. He received salvage chemotherapy (CLAG: cladribine, cytarabine, mitoxantrone, G-CSF) and achieved CR2; he then received 1 cycle of HiDAC. He was referred to us for HSCT but on evaluation was found to have relapsed again. We took him up for a high-risk haploidentical transplant with active disease with clofarabine, melphalan, and TBI as the conditioning therapy and PTCy-CSA-MMF as GvHD prophylaxis. The patient engrafted on D + 16 and the posttransplant period was complicated by cytomegalovirus reactivation which was managed with antiviral medication and other supportive care. The patient also had pancytopenia and culture-negative fever which was managed with steroids and other supportive care. Postrecovery bone marrow was in morphological remission. The patient is now on follow-up for more than 6 months, is in CR, and doing well with whole blood 97.77% donor chimerism and 100% donor myeloid chimerism.

Relapsed/refractory acute leukemia has uniformly dismal outcomes. In this setting, HSCT can offer a chance of cure to some patients. However, for relapsed/refractory acute leukemia, especially those previously exposed and resistant to salvage chemotherapy and drugs like fludarabine, newer and more effective conditioning regimens offer a better chance of cure and survival.

Clofarabine is a second-generation nucleoside analog which has a stronger anti-leukemia and immunosuppressive effect over and above its first-generation counterpart fludarabine.[6] Clofarabine-based regimens are effective even when conventional or first-line salvage chemotherapy fails or the patient relapses after salvage chemotherapy. It has been employed earlier in conditioning regimens for leukemia utilizing matching donors,[7],[8] T-cell deplete haploidentical strategy,[8] or as a substitute for fludarabine in the Baltimore protocol.[9] A retrospective analysis conducted by conducted by Thomas et al. concluded that treatment with clofarabine as a bridge to reduced-intensity HSCT was an effective treatment strategy in patients with refractory AML.[10] In a randomized Phase II study of clofarabine-based consolidation in younger adults with AML, it was observed that relapse-free survival was prolonged in patients receiving clofarabine-based combination (CLARA), although the use of SCT was found to reverse this benefit.[11]

Our findings are important because they suggest an additional rescue strategy for patients suffering from refractory disease with no fully matched donor. These three cases show that it is feasible to incorporate clofarabine in the conditioning regimens alongside busulfan or melphalan as a part of a reduced intensity protocol. This approach provides sufficient anti-leukemia activity to ensure disease eradication and stable engraftment for patients with active disease at the time of transplantation without untoward toxicity. Conditioning chemotherapy before stem cell transplantation aims at the elimination of residual blasts and at the suppression of the recipient's immune system to allow engraftment of allogeneic cells. Clofarabine has the potential to achieve both in resistant leukemias. Although our follow-up is short, this strategy merits further exploration in future and has the potential to be useful in patients with resistant leukemias.

To conclude, clofarabine is potentially a new addition in the armamentarium for the treatment of relapsed and refractory leukemia and can be safely and effectively incorporated in the conditioning therapy for T-cell replete haploidentical HSCT using PBSC grafts with good disease control, stable and robust engraftment, and acceptable toxicity. Larger studies are required in future to help determine the best place of the drug in conditioning in the setting of haploidentical HSCT using PTCy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sproat LO, Betcher J, Chiffelle R, Gerber S, Loewen B, Olsen J. et al. Clofarabine salvage in refractory acute myeloid leukemia before allogeneic stem cell tranplant. Biol Blood Marrow Transplant 2013;19:S229-30.  Back to cited text no. 1
    
2.
Harned TM, Gaynon PS. Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manag 2008;4:327-36.  Back to cited text no. 2
    
3.
Pession A, Masetti R, Kleinschmidt K, Martoni A. Use of clofarabine for acute childhood leukemia. Biologics 2010;4:111-8.  Back to cited text no. 3
    
4.
Ho KV, Solimando DA, Waddell JA. Cancer chemotherapy update: Clofarabine and cytarabine regimen for acute myeloid leukemia. Hosp Pharm 2015;50:969-74.  Back to cited text no. 4
    
5.
Scheckel C, Betcher JA, Sproat LZ, Khera N, Slack JL, Leis JF. et al. A single center analysis of clofarabine use prior to bone marrow transplantation in patients with relapsed/refractory acute myeloid leukemia. Biol Blood Marrow Transplant 2018;24:S330.  Back to cited text no. 5
    
6.
Chevallier P, Labopin M, de La Tour RP, Lioure B, Bulabois C E, Huynh A. et al. Clofarabine versus fludarabine-based reduced-intensity conditioning regimen prior to allogeneic transplantation in adults with AML/MDS. Cancer Med 2016;5:3068-76.  Back to cited text no. 6
    
7.
Soni S, Abdel-Azim H, McManus M, Nemecek E, Sposto R, Woolfrey A. et al. Phase I study of clofarabine and 2-Gy total body irradiation as a nonmyeloablative preparative regimen for hematopoietic stem cell transplantation in pediatric patients with hematologic malignancies: A therapeutic advances in childhood leukemia consortium study. Biol Blood Marrow Transplant 2017;23:1134-41.  Back to cited text no. 7
    
8.
Sharma A, Kang G, Sunkara A, Inaba H, Jeha S, Cross SJ. et al. Haploidentical donor transplantation using a novel clofarabine-containing conditioning regimen for very high-risk hematologic malignant neoplasms. J Pediatr Hematol Oncol 2018;40:e479-85.  Back to cited text no. 8
    
9.
Chevallier P, Peterlin P, Garnier A, Bourgeois AL, Mahé B, Dubruille V. et al. Clofarabine-based reduced intensity conditioning regimen with peripheral blood stem cell graft and post-transplant cyclophosphamide in adults with myeloid malignancies. Oncotarget 2018;9:33528-35.  Back to cited text no. 9
    
10.
Thomas CM, Ippoliti C, Roboz GJ, Feldman E, Savva D, James S, et al. Clofarabine as a bridge to hematopoietic stem cell transplant. Leuk Lymphoma2016;58:230-2.  Back to cited text no. 10
    
11.
Thomas X, de Botton S, Chevret S, Caillot D, Raffoux E, Lemasle E. et al. Randomized phase II study of clofarabine-based consolidation for younger adults with acute myeloid leukemia in first remission. J Clin Oncol2017;35:1223-30.  Back to cited text no. 11
    



 
 
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