Case report Successful bone marrow transplantation in a ... - Nature

Bone Marrow Transplantation (2000) 26, 689–690  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt

Case report Successful bone marrow transplantation in a child with red blood cell pyruvate kinase deficiency VS Tanphaichitr1, V Suvatte1, S Issaragrisil2, C Mahasandana1, G Veerakul1, V Chongkolwatana3, W Waiyawuth4 and H Ideguchi5 Departments of 1Pediatrics, 2Medicine, 3Transfusion Medicine and 4Forensic Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; and 5Department of Clinical Chemistry and Laboratory Medicine, School of Medicine, Fukuoka University, Japan

Summary:

Case report

We report the first successful use of BMT for the treatment of RBC pyruvate kinase (PK) deficiency in a boy who developed neonatal jaundice and severe transfusion-dependent hemolytic anemia a few months after birth. He received a BMT at the age of 5 from an HLAidentical sister who has normal PK activity after conditioning with busulfan and cyclophosphamide. The post-transplant course was uneventful. At present, 3 years after transplant, he is 8 years old and has a normal hemoglobin level and normal RBC PK activity without evidence of hemolysis. DNA analysis has confirmed full engraftment. Bone Marrow Transplantation (2000) 26, 689–690. Keywords: BMT; PK deficiency; pyruvate kinase; stem cell transplantation; DNA-short tandem repeat markers; enzymopathies

The patient was the product of uneventful pregnancy delivered by caesarean section because of a previous caesarean. His birth weight was 3.2 kg and 12 h after birth, pallor and jaundice were noticed. The Hb was 9.6 g/dl, reticulocytes 9.6%, RBC morphology revealed mild hypochromia, anisocytosis, poikilocytosis, polychromasia and the presence of 445 nucleated RBC per 100 WBC. The mother was blood group ‘O’ and the patient blood group ‘B’. His bilirubin level was 14.9 mg/dl. Blood group ‘B-O’ incompatibility was diagnosed and an exchange blood transfusion was given on the second day of life followed by phototherapy for a few days. He was sent home at the age of 7 days. At the age of 4 months, he was markedly anemic with a Hb level of 5.5 g/dl. RBC glucose-6-phosphate dehydrogenase (G-6-PD) was normal and Hb typing revealed E F A (21.7, 13.1, 65.2%). Several packed red cell transfusions were given to improve symptoms of anemia. At the age of 13 months mild hepatosplenomegaly was noted with a Hb level of 6 g/dl. He was diagnosed at the age of 3 years as having PK deficiency and Hb E trait. His father was heterozygous for both Hb E and PK deficiency, his mother was heterozygous for PK deficiency and his elder sister had Hb E trait but normal red blood cell PK activity.9 Since he was markedly anemic and the spleen was getting larger, he received hypertransfusion and iron chelation at the age of 3 years. His Hb was maintained above 10 g/dl with an average Hb of 13 g/dl and serum ferritin of 950 ng/ml. BMT was undertaken in an attempt to cure the patient. Conditioning included busulfan (total dose 16 mg/kg) orally over 4 days followed by cyclophosphamide (total dose 200 mg/kg) intravenously over 4 days. He received marrow from his ABO and HLA-identical sister on 1 November 1996. The BM dose was 1.5 × 108 MNC/kg. Short-course methotrexate and cyclosporin A were given for GVHD prophylaxis for 6 months post transplant. G-CSF of 10 ␮g/kg/day was given from day 1 to day 32. The clinical course was uneventful; ANC ⬎0.5 × 109/l on day 18, ⬎1.0 × 109/l on day 21; platelet ⬎20 × 109/l on day 22 and ⬎50 × 109/l on day 30; Hb ⬎10 g/dl on day 35. Blood transfusions were given on three occasions post transplant with the last transfusion on day 12 and the last

Pyruvate kinase (PK) deficiency is the most common hereditary RBC enzymopathy of the glycolytic pathway. To date, nearly 400 patients have been reported.1 The clinical manifestations of PK deficiency are heterogenous, ranging from fetal anemia, neonatal jaundice, severe chronic hemolytic anemia to a fully compensated hemolytic anemia.1–3 Treatment of this disease is mostly symptomatic, including blood transfusion and splenectomy.1 Bone marrow transplantation has been used to cure the disease in mice and dogs.4–6 In humans, gene transfer of human PK cDNA has been attempted.7 We briefly reported the first successful use of BMT for the treatment of PK deficiency in a boy who had severe chronic hemolytic anemia from birth.8 This report describes this case in detail, with long-term follow-up.

Correspondence: Dr VS Tanphaichitr, Hematology–Oncology Unit, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Received 13 March 2000; accepted 8 June 2000

BMT for pyruvate kinase deficiency VS Tanphaichitr et al

690

Table 1

DNA analysis: short tandem repeat markers in the donor and recipient pre- and post BMT

Recipient Donor Recipient post BMT 2 years

Amelogenin

D8S1179

D21S11

D18S51

D3S1358

VwA

FGA

D5S818

D13S317

D7S820

XY XX XX

14, 15 10, 12 10, 12

32.2, 32.2 31, 32.2 31, 32.2

18, 18 13, 18 13, 18

15, 16 15, 17 15, 17

14, 16 14, 16 14, 16

22, 23 22, 23 22, 23

10, 11 9, 11 9, 11

9, 13 11, 13 11, 13

8, 11 11, 11 11, 11

platelet transfusion on day 19. The patient was healthy thereafter without anemia or hepatosplenomegaly. However, he was placed on iron chelation therapy to reduce his iron overload. His serum ferritin fell from 1460 to 1000 ng/ml after a few months of therapy. On re-evaluation of RBC PK of the patient and his sister 2 years post BMT, both siblings had PK activities at 110% of normal control compared with a pretransplant level of 20% in the patient. DNA analysis with short tandem repeat (STR) markers of the patient showed the same genotype as the donor in all nine loci studied and female sex at the amelogenin locus in both of them (Table 1).10 The patient is currently 8 years old. He is healthy and normal physically and socially. Discussion In Thailand, thalassemias and hemoglobinopathies are the most common hereditary cause of hemolytic anemia.11 There are more than 60 clinical syndromes with different gene interactions.11 RBC PK deficiency is rare. Recently, we reported the first case of PK deficiency in an alphathalassemia family.12 BMT can cure patients with thalassemia especially those in Lucarelli’s class I (no hepatomegaly and no portal fibrosis).13 Patients who undergo BMT early in the course of thalassemia have a very high probability of cure whereas those with severe manifestations have a high recurrence rate of thalassemia after transplant. It is suggested that the severity of the disease should be determined on the basis of genotype and BMT should be performed as soon as possible in children with severe disease.13 Based on our experience of BMT in thalassemia, we successfully treated a child with severe chronic hemolytic anemia due to RBC PK deficiency with a BMT from his HLAidentical sister. Before transplant, hypertransfusion had been used to reduce compensated erythropoiesis in the bone marrow and extramedullary sites. BMT was performed when hepatosplenomegaly had already disappeared. The rate of engraftment after BMT in this patient was comparable to those with thalassemia.13 Stable complete chimerism was demonstrated by DNA analysis with STR and sex markers. PK activities reached normal levels indicating that this patient has been cured. BMT can therefore be used to treat patients with severe RBC enzymopathies.

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