Autologous stem cell transplantation in chronic myeloid leukaemia using Philadelphia chromosome negative blood progenitors mobilised with hydroxyurea and G-CSF

Abstract

Summary:Autologous transplantation in CML has been a focus of interest over the last few years. Determining the indications, optimal timing and method for this procedure remains controversial. One approach has been the mobilisation of Philadelphia chromosome negative (Ph؊) peripheral blood stem cells following high-dose chemotherapy as a method of purging the graft. We have described a mobilisation regimen of 7 days of hydroxyurea followed by G-CSF and have shown it to be substantially less toxic than other methods. We now report further experience with this technique in a total of 18 patients and the outcome of transplantation in seven patients using cells so-derived. Following mobilisation, approximately a third of patients had 100% Ph؊ collections and half had less than 50% Ph+ collections. All patients were 100% Ph+ prior to mobilisation. Six out of seven transplanted patients showed sustained engraftment and two of these patients became 18 and 34% Ph+ 3 months post-transplant. Five patients remain alive and well 13 to 25 months post-autograft. In conclusion, we have developed a well-tolerated regimen for Ph؊ PBSC mobilisation and have demonstrated that such cells are capable of sustained engraftment and of producing significant cytogenetic responses. Keywords: blood stem cells; chronic myeloid leukaemia; autologous stem cell transplantation; hydroxyurea; G-CSF Treatment for the majority of patients with chronic myeloid leukaemia (CML) remains unsatisfactory. The only potentially curative approach is allogeneic bone marrow transplantation which is only available to a minority of patients. Alpha-interferon (IFN) has been shown to reduce the size of the Philadelphia positive (Ph+) clone in some patients leading to a survival advantage but the ability of IFN to prolong survival in patients not achieving a major cytogenetic response remains controversial. [1][2][3] Autografting with blood-or bone marrow-derived stem 4,6,7 The evidence from IFN responders and transplanted patients implies that reduction of the Ph+ clone may correlate with improved survival. The rationale for selecting PhϪ cells for autologous transplantation in CML is based on the presence of residual PhϪ cells in the marrow of many patients with CML especially in the early stages of their disease 8 and by the demonstration that malignant cells present in autografts can contribute to relapse. 9,10 Purging approaches have included in vitro techniques using chemotherapy, antisense oligonucleotides and long-term liquid cultures. 11-13 An alternative in vivo approach is to take advantage of the preferential mobilisation of PhϪ cells during the early regenerative phase following myelosuppressive therapy and to collect them by apheresis. 14 This approach is however associated with considerable morbidity and some mortality. We have investigated the use of a less toxic regimen for PhϪ PBSC mobilisation using oral hydroxyurea and G-CSF. 15 We now report further experience with this technique in a total of 18 patients and the outcome of transplantation in...

Autografting of peripheral-blood progenitor cells early in chronic myeloid Leukemia

“…Following initial studies which showed that autografting CML patients with re-infusion of chronic phase cells after transformation of the disease to an acute phase was successful in re-establishing a chronic phase, 4,5 it became evident from several studies that autografting in chronic phase may induce a sustained period of Phnegative hematopoiesis in patients who received PBPC obtained after chemotherapy. 9,13,18,21,26,28 Although these studies have provided interesting information from a biological point of view and have suggested a potential role for chemotherapy in the management of CML patients, the selection of patients and the heterogeneity of treatments received and purging procedures have limited the evaluation of the clinical responses of autografting in disease.…”

“…All products of leukapheresis obtained from available patients enrolled in the study were contaminated by Ph+ cells, using predominantly HU as the mobilizing regimen. It is clear that higher numbers of Ph-negative cells can be obtained after mobilization of PBPC with ICE or Mini-Ice 33 than with HU regimen, 12,18 but near 5% of mortality rate related to the effects of intensive chemotherapy has been described. 14,16 PBPC mobilized with HU were clearly capable of sustained engraftment in our patients, and determined mainly cytogenetic and molecular cytogenetic responses in all of them during variable periods of time, in accordance with previous reports.…”

Analysis of CD34+ cell subsets in stem cell harvests can more reliably predict rapidity and durability of engraftment than total CD34+ cell dose, but steady state levels do not correlate with bone marrow reserve

“…Patients Eighty‐six patients, median age 42 years (20–67), with Hodgkin's disease (HD; n = 27), non‐Hodgkin's lymphoma (NHL; n = 28, mostly follicular n = 8, diffuse large B cell n = 5 or centrocytic/centroblastic lymphoma n = 4), multiple myeloma ( n = 19), chronic granulocytic leukaemia (CGL; n = 5), chronic lymphocytic leukaemia (CLL; n = 4) or breast cancer ( n = 3). Patients were mobilized with cyclophosphamide 2 g/m 2 , followed by 300 µg/d granulocyte colony‐stimulating factor (G‐CSF) from d +1, except for the CGL patients who were mobilized with a combination of hydroxyurea (average 3·5 g/m 2 for 7 d) and G‐CSF as above (Pratt et al , 1998) . CD34 selections were performed on nine patients (myeloma: CELL‐PRO n = 1, ISOLEX n = 1; lymphoma: ISOLEX n = 3; CLL ISOLEX n = 4, followed by CD19/CD23 depletion).…”

Autotransplantation in chronic myeloid leukemia

“…We read with interest the report of Pratt et al 1 concerning the use of autotransplantation using Ph-negative blood progenitor cells mobilized with hydroxyurea and G-CSF in chronic myeloid leukemia (CML) patients. The main conclusion of this study is that such a method provided a less toxic procedure for obtaining progenitor cells to support an intensive conditioning regimen.…”