Case report Relapse of chronic myeloid leukaemia 14 years ... - Nature

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Allogeneic bone marrow transplantation (BMT) is the treatment of choice for ... In March 1984, she had right loin pain which was due to renal vein thrombosis.
Bone Marrow Transplantation, (1999) 23, 827–828  1999 Stockton Press All rights reserved 0268–3369/99 $12.00

Case report Relapse of chronic myeloid leukaemia 14 years after allogeneic bone marrow transplantation ASM Yong and JM Goldman

Summary: Allogeneic bone marrow transplantation (BMT) is the treatment of choice for patients with chronic myeloid leukaemia (CML) who are relatively young and have suitable donors. Relapse is rare more than 5 years after allografting. We describe a patient who relapsed with myeloid blast transformation 14 years after allografting. This case suggests that leukaemia stem cells may on occasion remain quiescent for long periods and emphasises the importance of long-term follow-up after transplantation for CML. Keywords: late relapse; chronic myeloid leukaemia; bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling or ‘matched’ unrelated donor offers the best prospect of cure for patients with chronic myeloid leukaemia (CML). Long-term leukaemia-free survival for patients transplanted in chronic phase is 40–60%.1–3 The majority of patients who relapse do so within 3 years of the transplant procedure and thereafter the actuarial incidence of relapse in patients surviving is about 1.5% per annum.4 Thus far no patient has been reported who relapsed more than 10 years after allografting. We report a patient who relapsed in myeloid blast transformation 14 years after sibling donor BMT for CML in chronic phase. Case report A 26-year-old woman from Pakistan presented in July 1976 with a history of lethargy, easy bruising and abdominal fullness. The spleen was palpable 20 cm below the left costal margin. The haemoglobin was 11.1 g/dl, WBC 328 × 109/l and platelets 312 × 109/l. The bone marrow morphology was consistent with CML and cytogenetic studies showed the Philadelphia chromosome. She was treated initially with busulphan. Splenectomy was performed in April 1978. Correspondence: Prof JM Goldman, Department of Haematology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, U.K. Received 24 August 1998; accepted 24 November 1998

From January 1980 she received hydroxyurea in place of busulphan. In June 1983, while still in chronic phase, she received an allogeneic bone marrow transplant from her HLA-identical brother. Conditioning comprised daunorubicin, cyclophosphamide and total body irradiation at standard dosage. Cyclosporin A was administered for prophylaxis of graft-versus-host disease (GVHD). She engrafted promptly and had mild GVHD of the skin and gut controlled with oral steroids. Immunosuppression was discontinued by December 1983 and she returned to Pakistan. In March 1984, she had right loin pain which was due to renal vein thrombosis. CT scans showed a mass anterior to the right renal hilum, which proved on laparotomy to be due to extensive retroperitoneal fibrosis. Histology showed normal renal parenchyma and non-specific inflammatory changes in the other tissues biopsied. There was no evidence of a lymphoproliferative disorder. Bone marrow cytogenetics at the time revealed 100% normal male metaphases. She remained well in Pakistan. Molecular and cytogenetic studies were not performed on a regular basis, but a routine blood count in February 1997 was normal. In September 1997 she experienced some backache and in November 1997 her blood count was abnormal so she returned to London. The haemoglobin was 11.0 g/dl, WBC 59.3 × 109/l and platelets 58 × 109/l. The blood showed 29.9% blasts and the bone marrow 52.3% blasts; immunophenotyping showed CD13 and CD33 positivity with weak expression of terminal deoxynucleotidyl transferase. Cytogenetics showed 94% 46,XX metaphases with t(2;12)(q36.2;q13), t(9;22)(q34;q11), and 6% 46,XY metaphases. Polymerase chain reaction studies showed b3a2 BCR-ABL transcripts. No pretransplantation material was available for comparison. She was treated initially with two courses of cytotoxic drugs which reduced substantially the proportion of blast cells in her bone marrow. When the proportion of blasts began to rise again, she received a third course of cytotoxic drugs. She died of fungal infection during the recovery phase in April 1998. Discussion This patient received an allogeneic BMT from her HLAidentical brother as treatment for CML in chronic phase

Relapse of CML 14 years after BMT ASM Yong and JM Goldman


and relapsed 14 years later with myeloid blast transformation. This sequence of events is unusual for two reasons. First, relapse, when it occurs, usually does so within 3 years of transplant and later relapses, although reported, are rare.3,4 Occasional patients are described with molecular evidence of leukaemia up to 10 years post-transplant, but this finding does not necessarily herald relapse.5 A single patient who relapsed with advanced phase CML 10 years after allografting for CML in chronic phase has recently been reported.6 Second, relapse after allografting performed in chronic phase usually proceeds in a sequential manner, showing first a rising number of BCR-ABL transcripts, then cytogenetic evidence of leukaemia and then haematological evidence of CML in chronic phase. Relapse directly to advanced phase CML has been reported previously6,7 but is rare. A relapse 14 years after BMT suggests the possibility that a proportion of CML patients might continue to harbour a small number of leukaemic stem cells for many years post-transplant. These cells must escape eradication by the combined effects of the chemoradiotherapy preceding the transplant and the so-called graft-versus-leukaemia (GVL) effect presumed to be mediated by lymphoid cells of donor origin. Such cells might be restrained from generating a ‘chronic phase’ disease, but might still be susceptible to ‘transformation’. A transformed cell population might be able to escape the GVL effect.8 These observations suggest that there may be two patterns of susceptibility of CML to GVL. In the first, GVL is sufficient to eradicate disease, particularly if BMT is performed in chronic phase, and the patient achieves a ‘cure’. In the second, GVL is sufficient only to suppress chronic phase disease but fails to eradicate it. Such patients would therefore be at risk of relapse in transformation. This speculation implies that the latter group of patients might benefit from efforts to enhance a GVL effect, as might be achieved by ‘prophylactic’ infusion of donor lymphocytes.

This case serves to emphasise the importance of longterm follow-up of patients after allogeneic BMT. Such follow-up should presumably include molecular studies, which were incomplete in this case. References 1 Thomas ED, Clift RA, Fefer A et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 1986; 104: 155–163. 2 Marks DI, Hughes TP, Szydlo R et al. HLA-identical sibling donor bone marrow transplantation for chronic myeloid leukaemia: influence of GVHD prophylaxis on outcome. Br J Haematol 1992; 81: 383–390. 3 Gratwohl A, Hermans J, Niederwieser D et al. Bone marrow transplantation for chronic myeloid leukaemia: long-term results. Bone Marrow Transplant 1993; 12: 509–516. 4 van Rhee F, Szydlo RM, Hermans J et al. Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1997; 20: 553–560. 5 van Rhee F, Lin F, Cross NCP et al. Detection of residual leukaemia more than 10 years after allogeneic bone marrow transplantation for chronic myelogenous leukaemia. Bone Marrow Transplant 1994; 14: 609–612. 6 Guimaraes A, Machado A, Carvalho S et al. Relapsed chronic myeloid leukemia in accelerated phase 10 years after allogeneic bone marrow transplantation: full chimera reconversion with donor peripheral blood stem cells infusion. Bone Marrow Transplant 1998; 22: 595–597. 7 Cullis JO, Marks DI, Schwarer AP et al. Relapse into blast crisis following bone marrow transplantation for chronic phase chronic myeloid leukaemia: a report of five cases. Br J Haematol 1992; 81: 378–382. 8 Dermime S, Mavroudis D, Jiang YZ et al. Immune escape from a graft-versus-leukemia effect may play a role in the relapse of myeloid leukemias following allogeneic bone marrow transplant. Bone Marrow Transplant 1997; 19: 989–999.

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