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Successful matched sibling cord blood transplant for ALL in a child with constitutional mismatch repair deficiency syndrome

Bone Marrow Transplantation volume 51, pages 848–849 (2016)Cite this article

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DNA mismatch repair (MMR) contributes to genome integrity and the MLH1, MSH2, MSH6 and PMS2 genes have a central role in the process.1 Lynch syndrome (LS) is a well-recognized autosomal dominantly inherited disorder of cancer susceptibility caused by a monoallelic (heterozygous) germline mutation in one of the MMR genes, with an estimated carrier frequency of 1 in 440.2 Carriers are at substantially increased risk of multiple adult cancers, mostly colorectal but also cancer of the endometrium, stomach, ovary, ureter, renal pelvis, brain, small bowel and hepatobiliary tract.3 More recently, inheritance of either homozygous or compound heterozygous biallelic germline MMR gene mutations has been recognized to predispose to a range of childhood cancers, and is now called constitutional mismatch repair deficiency (CMMRD) syndrome.4 CMMRD syndrome is characterized by the presence of café-au-lait spots and a broad spectrum of early-onset malignancies. Neoplasms are generally divided into four groups: hematologic malignancies, brain tumors, LS-associated tumors and other malignancies.4 Concerns about the effectiveness and long-term effects of intensive therapy, including alkylators and radiation, in children with CMMRD syndrome have been expressed.5 Here we describe the first successful allogeneic cord blood transplant (CBT) for relapsed ALL in a child with CMMRD syndrome.

A previously healthy 3-year-old boy with a negative family cancer history presented with a short history of decreased appetite, pallor and bruising. Physical examination revealed bilateral cervical lymphadenopathy and hepatosplenomegaly. Initial investigations included a full blood count showing Hb 5.2 g/dL, white cell count 7.9 × 106/L (30% blasts) and platelets 3 × 106/L. He was diagnosed with standard risk pre-B-cell ALL (bone marrow aspirate contained 94% blasts; CD10, CD20 and CD38 positive with normal karyotype). There was no central nervous system involvement. The patient was treated with multi-agent chemotherapy according to the Australian and New Zealand Children’s Cancer Study Group Trial VI. The protocol consisted of a four-drug induction, consolidation phase, one asparaginase-based intensification and maintenance therapy for a total of 2 years (full protocol available on request). He achieved a CR at the end of induction and remained so for over 2 years from the completion of all chemotherapy. Following an asymptomatic bone marrow relapse (pancytopenia), he received further chemotherapy before undergoing an HLA-identical sibling CBT in second CR. Before conditioning for CBT, he had received a total cumulative dose of cyclophosphamide of 3.5 g m/m2. CBT conditioning included 120 mg/kg cyclophosphamide, 10 mg/kg thiotepa and fractionated TBI (12 Gy). The thawed CB graft contained 4.5 × 107/kg total nucleated cells and 0.7 × 105/kg CD34+ cells. GvHD prophylaxis consisted of cyclosporine alone. The early post-transplant course was complicated by moderate mucositis and an episode of Gram positive bacteremia. Engraftment was delayed with granulopoietic engraftment established on day +30 and platelet engraftment on day +55. A erythematous facial rash developed 2 months post transplant. A skin biopsy was not diagnostic and autoimmune markers were all negative. The rash responded rapidly to systemic corticosteroids and flared, but eventually resolved during tapering. All immunosuppression was ceased 7 months post transplant. Marrow engraftment analysis utilizing variable number of tandem repeats and cytogenetic analysis showed 100% donor chimerism from day 21 to day 365 post transplant. Long-term monitoring included regular physical examinations, full blood counts and echocardiograms. No adverse events directly attributable to the CBT were noted. He remained in complete hematological remission for 16 years, until his death from a second malignancy.

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Authors and Affiliations

  1. Department of Oncology, Sidra Medical and Research Center, Doha, Qatar

    J A Heath

  2. Children’s Cancer Centre, Royal Children’s Hospital, Parkville, Victoria, Australia

    M Campbell & K Tiedemann

  3. Children’s Cancer Centre, Monash Children’s Hospital, Clayton, Victoria, Australia

    P A Downie

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  1. J A Heath
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  2. M Campbell
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  4. P A Downie
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Correspondence to J A Heath.

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Heath, J., Campbell, M., Tiedemann, K. et al. Successful matched sibling cord blood transplant for ALL in a child with constitutional mismatch repair deficiency syndrome. Bone Marrow Transplant 51, 848–849 (2016). https://doi.org/10.1038/bmt.2015.353

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