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Table of Contents
CASE REPORT
Year : 2022  |  Volume : 9  |  Issue : 3  |  Page : 112-116

Donor origin precursor B-cell lymphoblastic leukemia post beta-thalassemia haploidentical transplant – A rare case report


Department of Hematology and Molecular Biology, BLK-MAX Super Speciality Hospital, Delhi, India

Date of Submission19-Jan-2022
Date of Decision08-Feb-2022
Date of Acceptance13-Feb-2022
Date of Web Publication09-Jun-2022

Correspondence Address:
Dr. Anil Handoo
Department of Hematology and Molecular Biology, BLK-MAX Super Speciality Hospital, Delhi - 110 005
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_1_22

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  Abstract 


Secondary malignancy of donor origin in the form of acute lymphoblastic leukemia (ALL), post-allogeneic hematopoietic stem cell transplant (HSCT) for beta thalassemia (BT) major, is exceedingly rare. A10 year old male child, the first and only product of non-consanguineous conception, was diagnosed with BT major at the age of 9 months when he had diarrhea and his parents (both of whom had thalassemia minor) noticed yellowing of the skin. Until the age of 10 years, he received regular blood transfusion and iron chelation, when the requirements got escalated and he consequently had to undergo myeloablative haploidentical HSCT from his mother. The post-transplant period was uneventful, and follow up with short tandem repeat chimerism analysis revealed complete donor chimerism on all occasions. Five years after the transplant, he developed fever with pancytopenia. Peripheral smear (PS) and bone marrow revealed blasts that were immunophenotypically precursor B-ALL. Cytogenetics revealed twenty diploid female metaphases with modal karyotype 46, XX[20], and again, complete donor chimerism was noted. Thus, a diagnosis of donor cell leukemia (DCL) was considered. Induction chemotherapy was initiated; however, the patient succumbed to systemic sepsis midway through induction therapy. No evidence of leukemia was noted in the patient's mother, who was followed up with PSs for 5 years. DCL has a poor prognosis. Greater understanding of the disease biology could allow for appropriate donor screening, notification and shielding the recipient from DCL and its grave consequences.

Keywords: Acute lymphoblastic leukemia, beta-thalassemia major, chimerism analysis, donor cell leukemia, short tandem repeat analysis


How to cite this article:
Gupta N, Dadu T, Mittal A, Handoo A. Donor origin precursor B-cell lymphoblastic leukemia post beta-thalassemia haploidentical transplant – A rare case report. J Cancer Res Pract 2022;9:112-6

How to cite this URL:
Gupta N, Dadu T, Mittal A, Handoo A. Donor origin precursor B-cell lymphoblastic leukemia post beta-thalassemia haploidentical transplant – A rare case report. J Cancer Res Pract [serial online] 2022 [cited 2022 Sep 28];9:112-6. Available from: https://www.ejcrp.org/text.asp?2022/9/3/112/347055




  Introduction Top


Secondary malignancies are an infrequent cause of morbidity post-allogeneic hematopoietic stem cell transplant (HSCT) for beta thalassemia (BT) major and are commonly of recipient origin.[1],[2],[3] However, secondary malignancy of donor origin in the form of acute lymphoblastic leukemia (ALL) is exceedingly rare.[4] Since the first description of donor cell leukemia (DCL) in 1971, an increasing number of cases of DCL are being recognized along with advances in diagnostic modalities such as conventional karyotyping, fluorescence in situ hybridization, and polymerase chain reaction (PCR)-based chimerism monitoring of short tandem repeat (STR) markers.[5]


  Case Report Top


We present the case of a 10 year old male child, the first and only product of non-consanguineous conception, who had an uneventful perinatal period and was diagnosed with BT major at the age of 9 months when he had fever with diarrhea and his parents noticed yellowish discoloration of his skin and sclera. He was started on regular packed red blood cell (PRBC) transfusion and iron chelation therapy, beginning with one unit of PRBC every 30 days. His transfusion requirement increased to two units every 21 days along with 1000 mg/day deferiprone and 1500 mg/day deferasirox by the age of 10 years, when he was planning for transplant. Both his parents had BT minor. The child (blood group O+) received myeloablative haploidentical HSCT (Lucarelli Class-II) with peripheral blood stem cells harvested from his mother (blood group B+) following treatment with thymoglobulin, fludarabine, and busulfan, which were well tolerated. He received posttransplant cyclophosphamide, mycophenolate, and tacrolimus as graft-versus-host disease (GVHD) prophylaxis along with the requisite transfusion support. Satisfactory engraftment was documented by day 24 post-bone marrow (BM) transplant, and PCR was negative for cytomegalovirus (CMV), following which he was discharged. The posttransplant period was uneventful with no GVHD. Subsequent chimerism monitoring with STR amplification and fragment analysis revealed complete donor chimerism on all occasions [Figure 1]a.
Figure 1: Chimerism post-engraftment (fragment analysis on a 3500DX Genetic analyzer; Applied Biosystems, USA) with 16 short tandem repeat loci using ChimerMarker™ automated analysis software (SoftGenetics, USA); Outsourced to an external laboratory, Dr. Lal Path Labs, India. (a) Donor chimerism trend over a period of 5 years showing complete donor chimerism on all occasions. (b) Electropherograms showing 12 informative short tandem repeat loci. The 4 non-informative loci were not taken into consideration for average chimerism calculation. D1: Donor peak; R: Recipient peak; D1R shared peak, Auto: Automatic, STR: Short tandem repeat

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He remained well with normal blood counts until the age of 15 years when he presented with a 1-week history of fever, generalized body aches, and epistaxis. Complete blood count (CBC) revealed pancytopenia (total leukocyte counts 3.2 × 109/L, hemoglobin 6.4 g/dL, and platelet count 4 × 109/L), and a peripheral smear (PS) showed 52% blasts [Figure 2]a. BM aspiration [Figure 2]b and biopsy [Figure 2]c revealed near-total replacement by blasts. Flow cytometry was consistent with the precursor B-cell ALL immunophenotype [Figure 2]d, [Figure 2]e, [Figure 2]f, [Figure 2]g, [Figure 2]h, [Figure 2]i, [Figure 2]j, [Figure 2]k, [Figure 2]l, [Figure 2]m, [Figure 2]n.
Figure 2: (a) Peripheral smear (Wright-Giemsa, ×1000) showing 52% blasts (b) Bone marrow aspirate (Wright-Giemsa, ×200) and (c) Bone marrow biopsy (H and E, ×200) showing replacement by blasts. (d-l) Flow cytometry scatterograms showing blasts (blue) positive for CD34, CD38 (e), CD10, CD20 (f), HLADR (g), CD19 (k), and cCD79a (l), and negative for CD13, CD33, cMPO, CD14, CD64 (i), and CD3, cCD3 and CD7 (j). (m) and (n) showing flow cytometric ploidy using FxCycle VioletTM dye. Blasts in blue have a diploid deoxyribonucleic acid index (DNA Index) of 1.01 which is calculated by dividing the median fluorescence intensity (MFI) of G0G1 peak of blasts to that of lymphocytes in red (50,957/50,212)

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Leukemia translocation PCR panel which incorporated the BCR-ABL gene rearrangements, t(12;21)(p13; q22)/ETV6-RUNX1, t(4;11)(q21; q23)/MLL-AF4, t(9;11) (p21-22; q23)/MLL-AF9, t(1;19)(q23; p13.3)/TCF3-PBX1, and t(11;19)(q23; p13.3)/MLL-ENL, were negative. Conventional karyotyping revealed normal female karyotype 46, XX(20) [Figure 3]. STR fragment analysis showed complete donor chimerism [Figure 1]b, and PCR for CMV was negative. A final diagnosis of DCL was considered.
Figure 3: Chromosomal analysis revealing 20 diploid female metaphases with modal karyotype 46, XX[20] (Image courtesy: Dr. Lal Path Labs, Delhi, India)

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The patient was started on induction chemotherapy with the BFM2002 protocol; however, he succumbed to multiorgan failure midway through induction therapy due to systemic sepsis with Candida haemulonii and multidrug-resistant Klebsiella pneumoniae, sudden cardiac arrest being the terminal event. In view of ALL being of donor origin, the donor (patient's mother) was followed up for 5 years with yearly CBC and PS, which were essentially within normal limits and she is currently doing well.


  Discussion Top


DCL has intriguing multifactorial pathogenesis, the most plausible hypothesis being the interplay of an occult undetectable malignant clone present within the donor experiencing subsequent “hits” after transplantation into an aberrant recipient marrow micro-environment, which has already experienced toxic insult due to prior chemotherapy, radiation, or viral integration.[5],[6]

Most previously reported cases of DCLs have occurred in transplants done for primary malignancies and very rarely in transplants for nonmalignant disorders such as BT and aplastic anemia. DCLs are associated with sibling donors (compared to match-related donors, unrelated donors, and cord blood), advancing donor age, BM as the source of stem cells (compared with peripheral blood stem cells and cord blood), and myeloablative conditioning regimen (compared to reduced intensity or nonmyeloablative conditioning). DCL is a relatively late complication, with the median time to DCL being 31 months (range 2–312 months).[5],[6],[7]

Multiple diagnostic modalities have been used to diagnose DCL, although most of the approaches provide only indirect evidence of donor origin. Conventional karyotyping was among the first techniques used to diagnose DCL in the early 1960s. It relies on capturing spontaneously dividing cells in metaphase. Leukemic cells can display lower proliferative rates than healthy cells, and in contrast to healthy cells, leukemic metaphases are often of poor quality, because of inherent genomic instability.[8] Hence, it may be argued that in our case, karyotyping may have captured normal nonmalignant cells. However, leukemic cells (86% of all nucleated BM cells) clearly outnumbered normal cells, and as this was a sex-mismatched transplant, the finding of twenty normal female metaphases with near-total replacement by blasts on morphology favored donor cell origin. These findings were also confirmed by STR fragment analysis, the current gold standard investigation to diagnose DCL,[9] which revealed complete donor chimerism, and also flow cytometric DNA ploidy analysis using FxCycle Violet™ dye,[10] on specifically gated blasts, which showed blasts with a diploid DNA index of 1.01.

In the present era, where an increasing number of transplants are being done with advancing donor age, recognizing DCL is of the utmost importance, as it has tremendous implications in donor selection, the choice of appropriate therapy pre-transplant and post-transplant, and ethical considerations of donor notification with respect to their health in times to come, even though most previous studies have reported that donors were healthy with a follow up duration of as long as 9 years after the detection of DCL in the recipient.[5],[9] Overall, DCL has a poor prognosis, and greater understanding of the disease biology could allow for appropriate donor screening, shielding the recipient from DCL, and its grave consequences.


  Conclusion Top


Herein, we describe a case of donor origin precursor B-cell ALL occurring 5 years after transplant in a 10-year-old male child with BT major. The donor (mother) was fundamentally normal before and 5 years post-transplant.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's parents have given consent for their child's images and other clinical information to be reported in the journal. The patient's parents understand that their child's names and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rahal I, Galambrun C, Bertrand Y, Garnier N, Paillard C, Frange P, et al. Late effects after hematopoietic stem cell transplantation for β-thalassemia major: The French National experience. Haematologica 2018;103:1143-9.  Back to cited text no. 1
    
2.
Caocci G, Orofino MG, Vacca A, Piroddi A, Piras E, Addari MC, et al. Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment. Am J Hematol 2017;92:1303-10.  Back to cited text no. 2
    
3.
Chaudhury S, Ayas M, Rosen C, Ma M, Viqaruddin M, Parikh S, et al. A multicenter retrospective analysis stressing the importance of long-term follow-up after hematopoietic cell transplantation for β-Thalassemia. Biol Blood Marrow Transplant 2017;23:1695-700.  Back to cited text no. 3
    
4.
Baker KS, Leisenring WM, Goodman PJ, Ermoian RP, Flowers ME, Schoch G, et al. Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood 2019;133:2790-9.  Back to cited text no. 4
    
5.
Wiseman DH. Donor cell leukemia: A review. Biol Blood Marrow Transplant 2011;17:771-89.  Back to cited text no. 5
    
6.
Sala-Torra O, Hanna C, Loken MR, Flowers ME, Maris M, Ladne PA, et al. Evidence of donor-derived hematologic malignancies after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006;12:511-7.  Back to cited text no. 6
    
7.
Wang E, Hutchinson CB, Huang Q, Lu CM, Crow J, Wang FF, et al. Donor cell-derived leukemias/myelodysplastic neoplasms in allogeneic hematopoietic stem cell transplant recipients: A clinicopathologic study of 10 cases and a comprehensive review of the literature. Am J Clin Pathol 2011;135:525-40.  Back to cited text no. 7
    
8.
Moorman AV, Enshaei A, Schwab C, Wade R, Chilton L, Elliott A, et al. A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. Blood 2014;124:1434-44.  Back to cited text no. 8
    
9.
Engel N, Rovo A, Badoglio M, Labopin M, Basak GW, Beguin Y, et al. European experience and risk factor analysis of donor cell-derived leukaemias/MDS following haematopoietic cell transplantation. Leukemia 2019;33:508-17.  Back to cited text no. 9
    
10.
Gupta N, Parihar M, Banerjee S, Brahma S, Pawar R, Rath A, et al. FxCycle™ based ploidy correlates with cytogenetic ploidy in b-cell acute lymphoblastic leukemia and is able to detect the aneuploid minimal residual disease clone. Cytometry B Clin Cytom 2019;96:359-67.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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