Occurrence and Treatment of Isolated Extramedullary Relapses after Allogeneic Hematopoietic Stem Cell Transplantation for Leukaemias: A Single Institute Experience with 442 Patients.
Authors: Kata Dariusz , Holowiecki Jerzy , Wojnar Jerzy , Stella-Holowiecka Beata , Krzemien Slawomira , Wozniczka Krzysztof , Helbig Grzegorz 
Published: October 2019

Abstract
Isolated extramedullary (EM) relapses of leukaemias are rare after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the data regarding their incidence in larger series of patients (pts) and long-term outcome are scarce. We retrospectively analysed this pattern of leukaemia recurrence in a cohort of 442 consecutive pts with leukaemias (103 with ALL, 155 with AML, 184 with CML) who underwent allo-HSCT in our center between June 1993 and December 2005. 7 out of 68 pts who relapsed (4 B-line ALL, 2 AML, 1 CML, F/M 4/3, median age 28 years, range 28–38 years) developed isolated EM infiltrates after a median time of 15 months (range, 8 – 33 months) post allo-HSCT. There was no evidence of leukaemic bone marrow involvement at relapse in 7/7 pts. We revealed complete donor chimerism in 5/7 studied pts. The leukaemic origin of pathologic masses was confirmed in each case by immunohistochemical methods or flow cytometry.
Our data indicate that isolated EM disease following allo-HSCT occurs predominantly in high-risk ALL pts, being rarely observed in pts with CML. Sites of relapses varies widely among the pts, however, in most of them EM infiltrates are localized outside the well-defined sanctuaries (CNS or testis), predominantly within the skin and/or subcutaneous tissue. Local radiation therapy seems to be effective treatment option, but it does not prevent from dissemination and should be followed by other therapeutic modalities. In selected pts individualized management, such as intraarterially administered anthracyclines or “total skin irradiation” may be of value. Tyrosine kinase inhibitors such as imatinib or dasatinib should also be considered in cases of Ph+ ALL or c-kit positive AML. Occurrence of EM relapse offers only a narrow window for quick intervention, however, optimal treatment remains a challenge.
Characteristics and clinical course of pts with isolated EM relapse post allo-HSCT Case no. Age/Sex Disease/subtype, cytogenetics Sites of relapse (post-allo-HSCT months) Treatment after relapse Survival post relapse (months) Outcome ND = not done, CNS = central nervous system, DLI = donor lymphocyte infusion, BP = blastic phase 1 30/F ALL/CD10+, t(9;22) Skin (13) Imatinib, chemotherapy 18 Systemic relapse;death following induction 2 29/F ALL/pre-preB, ND Tibia with soft tissue (23), then soft tissues and skin at various sites, lymph nodes (30–52) Radiotherapy (including “total skin irradiation”), IFN-alpha, DLI, daunorubicine intraarterially, chemotherapy 30 Systemic relapse; death following palliative chemotherapy 3 28/F ALL/pre-preB, t(4;11) Subcutaneous tissue (17) Radiotherapy, oral cytostatics (mercaptopurine, methotrexate), IFN-alpha 17 Systemic relapse, death during induction treatment due to pneumonia 4 28/F ALL/CD10+, t(9;22) CNS, leptomeningeal (8) High-dose cytarabine, methotrexate + steroids intrathecally, imatinib 10 Death due to fulminant gastrointestinal infection 5 38/M AML/M2, 45, X,-Y, t(8;21) Small intestine and the root of mesentery (8) Surgery 1 Immediate systemic relapse; death due to infectious complications 6 28/M AML/M4 (CD117+), 46, XY, t(19;11), del 13 Skin (33) Imatinib, dasatinib 6+ Alive with systemic relapse, treated with dasatinib 7 28/M CML/BP, Ph+, t(3;21)(q34;q11) Testicle, paraspinal (15) Surgery, local radiotherapy 3 Death due to cytomegalovirus pneumonia