Pediatr Blood Cancer

BRIEF REPORT Graft Versus Tumor Effect in the Brain of a Child With Recurrent Metastatic Medulloblastoma Hisham Abdel-Azim,

1 MD, MS, *

Neena Kapoor, MD,1 Kris M. Mahadeo, and Jonathan L. Finlay, MB, ChB, FRCP3

Marrow ablative chemotherapy (MAC) with autologous hematopoietic stem cell transplantation (HSCT) is limited by poor bone marrow reserve after chemotherapy and/or radiotherapy, and the extent of bone/bone marrow disease. We report a child with recurrent metastatic medulloblastoma who received an allogeneic HSCT while in relapse and subsequently achieved radiological resolution of disease and favorable marrow minimal residual disease (MRD)

MD, MPH,

2

response. Disease recurred intra-cranially at 304 days post-HSCT. Tumor biopsy 488 days post-HSCT showed infiltration with donor lymphocytes demonstrating graft-versus-tumor (GVT) effect. The patient remained alive >2 years post-HSCT. Allogeneic HSCT may be a consideration for high-risk recurrent medulloblastoma. Pediatr Blood Cancer # 2015 Wiley Periodicals, Inc.

Key words: allogeneic stem cell transplantation; graft versus tumor effect in brain; medulloblastoma

INTRODUCTION Myeloablative doses of radiotherapy and thiotepa-based chemotherapy have been used to cure most children with radiotherapy naive and chemo-responsive recurrences. Children who developed local or systemic recurrences after craniospinal radiotherapy had poorer outcomes, with a minority benefiting from autologous HSCT.[1] Allogeneic HSCT has been effectively used for the treatment of leukemia with brain chloromas, and high-risk or refractory solid tumors including melanomas, renal cell and breast carcinomas. Anti-neoplastic effects have been noted in response to donor lymphocyte infusions in patients with solid tumors; and responses to allogeneic HSCT for solid tumors have been associated with graft-versus-host disease (GVHD).[2–4] These findings suggest a potential GVT effect for patients with solid tumors, receiving allogeneic HSCT. Mouse models have demonstrated the potential collaboration between donor CD4þ helper T-lymphocytes to cooperate with, and induce host CD8þ suppressor T-lymphocytes to induce tumor regression.[5,6] In animal models, cytotoxic T-lymphocytes cause regression of medulloblastoma and other brain tumors.[6–8] In humans, donor cytotoxic Natural Killer (NK) cells may enhance GVT effects without GVHD in leukemia and solid tumors.[9–11]

RESULTS We report a 2.5-year-old male who presented with disseminated anaplastic large cell medulloblastoma. He received induction chemotherapy, with high-dose methotrexate, vincristine, cisplatin, cyclophosphamide, and vinblastine, with radiographic response on magnetic resonance imaging (MRI). He received consolidation chemotherapy, with topotecan and cyclophosphamide, but brain and spine MRI demonstrated widespread leptomeningeal recurrence. He subsequently received 3,600 cGy craniospinal irradiation with 5,400 cGy posterior fossa boost. Within 4 months, he complained of back and leg pain; brain MRI was negative for tumor but pelvic and spine MRI demonstrated widespread bone metastases. Iliac crest biopsy was positive for medulloblastoma. He received salvage chemotherapy with irinotecan, temozolomide, and  C

2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25525 Published online in Wiley Online Library (wileyonlinelibrary.com).

cyclophosphamide, with achievement of stable disease. This was followed by etoposide, oxaliplatin, and doxorubicin, with achievement of partial response. An attempt to harvest autologous hematopoietic stem cells (HSC), for consideration of MAC with autologous HSCT, was unsuccessful due to mobilization failure and residual pelvic bony disease. Subsequent cerebrospinal fluid (CSF) cytology was positive for malignant cells and MRI brain showed a new 2  2 mm local lesion. He received CNS-directed therapy consisting of etoposide, irinotecan, temozolomide, and cyclophosphamide with a favorable CNS response but his disease evaluation showed gross residual bone and bone marrow disease. Due to the chemo-sensitivity of his disease, the inability to mobilize autologous HSC and the presence of a histocompatible 9year-old brother, the patient and his legal guardians were consented for allogeneic HSCT. He received MAC with thiotepa (900 mg/m2), melphalan (140 mg/m2), etoposide (300 mg/m2), and fludarabine (90 mg/m2), followed by HLA-matched sibling allogeneic HSCT (total nucleated and CD34þ cell dose of 5.2  108 cells/kg and 7.2  106 cells/kg, respectively). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil (discontinued by days þ90 and þ50, respectively). The patient successfully engrafted on day þ12 with 100% donor chimerism by short tandem repeats (STR). No serious regimen related toxicity was noted. On day þ183, he developed mild, skin 1

Division of Hematology, Oncology, Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, California; 2Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York; 3 Division of Hematology, Oncology and BMT, Nationwide Children’s Hospital, Ohio State University, Columbus, Ohio Financial Disclosures: None. Conflicts of interest: Nothing to declare. 

Correspondence to: Hisham Abdel-Azim, Division of Hematology, Oncology, Blood and Marrow Transplantation, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, 4650 Sunset Blvd Mail Stop #62, Los Angeles, CA 90027. E-mail: [email protected] Received 18 July 2014; Accepted 24 February 2015

2

Abdel-Azim et al.

Fig. 1. Panel A shows PET/CT pre- and post-HSCT. Panels B and C show immuno-histochemistry of the tumor biopsy after relapse; panel B shows CD3 expression and panel C shows CD56 expression.

chronic GVHD which resolved with topical steroids. Follow-up imaging studies on days þ30 and þ100 showed markedly decreased bony disease. By 7 months post-HSCT, he had complete resolution of residual disease by imaging studies (Fig. 1A) and no evidence of disease by CSF cytology, bone marrow aspirates, and biopsies. He achieved full hematologic and immune reconstitution based on persistent full donor chimerism, normalization of blood and T/B/NK lymphocytes counts, normal lymphocyte proliferation to antigens and mitogens, and normal immunogloublins levels. Pre-HSCT evaluation of his bone marrow with TaqMan lowdensity array assay (TLDA) showed evidence of favorable MRD response on re-evaluation post-HSCT (Table I). On day þ304, he had asymptomatic radiological evidence of local recurrence in the brain posterior fossa with no evidence of extra-cranial metastases/recurrence. He received intra-omaya therapy with thiotepa (5 mg) once weekly and topotecan (0.4 mg) twice weekly for 4 weeks, then radiolabeled monoclonal antibodies with activity against GD2 protein (12) with stabilization of his disease. Tumor biopsy (Figs. 1B and 1C) on dayþ488 showed infiltration with lymphocytes (CD3þ and CD56þ by immuno-histochemistry). STR analysis of his tumor tissue biopsy confirmed that these lymphocytes were of donor origin.

At 24 months post-HSCT, he maintained full marrow reconstitution, had no GVHD, or bone pain and a Lansky performance score of 80. However, 6 month later, he developed progressive increase in his brain local recurrence and expired.

DISCUSSION Medulloblastoma is the most common embryonal brain tumor among children. While long-term survival for patients with standard-risk medulloblastoma approaches 85%, the cure rate among patients with recurrent disease following craniospinal irradiation remains low (20%).[13–15] The use of MAC with autologous HSCT was pioneered among patients with recurrent disease and as upfront irradiation-sparing therapy for very young children.[16] A previous report demonstrated 83% 3-year event-free survival using thiotepa-based MAC followed by autologous stem cell rescue in patients who had no prior irradiation. On the contrary, patients with prior irradiation had 20% 3-year event-free survival.[1] The ability to rescue a patient with HSC allows the use of very high-doses of chemotherapy that could overcome resistance and achieve greater concentrations across the blood brain barrier. Adequate collection depends, however, on the bone marrow reserve after chemotherapy and/or radiotherapy, and bone/bone marrow

TABLE I. MRD Detection in Bone Marrow

Pre-HSCT Post- HSCT

Cells

GAPDH

B2M

HPRT1

SDHA

CHGA

DCX

DDC

PHOX2B

TH

Fresh BM Fresh BM

17.18 17.31

15.78 16.22

21.57 22.72

22.46 23.73

31.57260 39.1173

33.20609 Undetermined

35.37444 Undetermined

Undetermined Undetermined

39.85299 Undetermined

TaqMan low-density array assay (TLDA) was used to detect tumor load in the bone marrow aspirate pre- and post-HSCT. RNA of the five genes, chromogranin A (CHGA), doublecortin (DCX), dopadecarboxylase (DDC), paired-like homeobox 2B (PHOX2B), and tyrosine hydroxylase (TH), are expressed by medulloblastoma but not by normal blood cells, PBSC, and bone marrow. Value of 40 (Geometric mean expression) means gene expression is not detectable; the smaller the number, the greater the expression; 40 is the cycle threshold. Pediatr Blood Cancer DOI 10.1002/pbc

Graft Versus Tumor Effect in the Brain involvement with disease. Marrow that has been irradiated may be unable to mobilize sufficiently to provide the increased number of peripheral HSC needed for collection. Furthermore, if disease has disseminated to bones/bone marrow, subsequent fibrosis may reduce the marrow’s efficacy. Finally, disseminated bone marrow disease may increase the risk of potential contamination of an autologous HSC collection. Therefore, these patients are not ideal candidates for autologous HSCT. Allogeneic transplantation offers the added risk of GVHD and the potential benefit of GVT effect. There is evidence to suggest that allogeneic immune effect can be seen in solid tumors outside the central nervous system.[2,3,9–11,17,18] The same effect has been observed with reduced intensity conditioning regimens highlighting the benefit of the immune approach even in the absence of high dose therapy.[19] Donor T-lymphocytes in the allograft, reactive to host histocompatibility antigens, can directly kill human cancer cells. That this may occur even after donor T-lymphocytes are rejected suggests that host lymphocytes might mediate the anti-tumor effect of donor allogeneic lymphocytes.[20] Adoptive immune therapies using NK cells have emerged as novel treatment strategies for a heterogeneous group of diseases, including solid tumors. NK-mediated GVT effect has already been demonstrated in acute myeloid leukemia and neuroblastoma.[9–11] Our case demonstrates infiltration of tumor biopsy with CD3þ and CD56þ lymphocytes of donor origin. This suggests that in addition to donor derived T cells, donor cytotoxic NK cells may also exert GVT effect in medulloblastoma. Immunological response due to KIR (killer immunoglobulin-like receptor) mismatch is one potential mechanism for such an effect. Our results demonstrate GVT in the human brain against a primary CNS tumor. Although documentation of GVT effect does not guarantee effective eradication of tumor cells, the role of GVT effect in controlling primary CNS tumors warrants further investigation. Allogeneic HSCT may be a consideration for patients with highrisk recurrent medulloblastoma and may serve as a platform to deliver directed cell-mediated therapy. Prospective clinical trials are needed to evaluate the utility of this approach and impact of GVT effect on control of primary CNS tumors.

ACKNOWLEDGMENTS We thank the patient and family for their participation and assistance; Dr Robert Seeger and his lab for performing TLDA assay.

Pediatr Blood Cancer DOI 10.1002/pbc

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Graft versus tumor effect in the brain of a child with recurrent metastatic medulloblastoma.

Marrow ablative chemotherapy (MAC) with autologous hematopoietic stem cell transplantation (HSCT) is limited by poor bone marrow reserve after chemoth...
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