12 Autografting for chronic myeloid leukaemia

O’Brien, Stephen G.

doi:10.1016/s0950-3536(97)80013-3

Cited by 12 publications

(7 citation statements)

References 79 publications

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“…9 It is this observation that provided the rationale for our attempt at Ph-negative progenitor cell collection during the post-PBSCT phase. In this instance, we were able to obtain sufficient CD34…”

Section: Discussionmentioning

confidence: 99%

Collection and analysis of peripheral blood mononuclear cells during haemopoietic recovery following PBSCT for CML: autografting as an in vivo purging manoeuvre?

Spencer

Granter

Fagan

et al. 1998

Bone Marrow Transplant

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Summary:A 47-year-old man with a 2-year history of Philadelphia chromosome-positive chronic phase (CP) chronic myeloid leukaemia (CML) underwent autologous PBSCT. During the period of haemopoietic reconstitution he underwent five leucapheretic (LP) harvests yielding a total of 2.6 ؋ 10 6 /kg CD34 + cells. Cytogenetic analyses revealed 94, 83, 83, 96 and 85% Ph negativity respectively for the five harvests. RT-PCR analyses for BCR-ABL performed on randomly picked CFU-GM from the five LP products were negative in all cases. These observations suggest that the majority of harvested cells, including the more primitive clonogenic cells, were BCR-ABL (Ph) negative and presumably were not part of the leukaemic clone. These findings support the notion that autologous PBSCT in CML whilst serving as a therapeutic manoeuvre may also facilitate the collection of non-leukaemic progenitor cells for further transplantation procedures. Keywords: CML; PBSCT; leucapheresis; purging Potentially curative alloSCT is presently unavailable to the majority of CML patients because of patient age and/or the lack of availability of a suitably matched donor.1 Interferon is reported in some multicentre randomised studies to be associated with a prolongation of survival when compared to chemotherapy, 2,3 however, no discernible plateauing of survival curves has been demonstrated, thus suggesting that IFN is unlikely to be curative. Comparison with historical controls suggests that autologous PBSCT may be associated with a prolongation of survival for CP CML patients and in instances can result in prolonged periods of Philadelphia chromosome-negative haemopoiesis.4 Thus, the demonstration that significant numbers of Ph-negative peripheral blood MNC could be obtained by LP after the administration of high-dose chemotherapy 5 has led to the development of numerous therapeutic strategies based on Correspondence: Dr A Spencer, Hunter Haematology Unit, Locked Bag 7, Hunter Region Mail Centre, NSW 2310, Australia Received 8 July 1997; accepted 2 September 1997 this perceived in vivo purging effect. Whether PBSCT following in vivo purging is more beneficial when compared to the use of unmanipulated PBSC is uncertain but theoretically it is a more attractive approach. Based on these observations we chose to examine whether sufficient numbers of PBSC could be obtained during the recovery phase from PBSCT to enable a second autografting procedure, thus combining a potential therapeutic benefit with high-dose chemotherapy in vivo purging and subsequent progenitor cell collection. Case reportIn March 1995, a 47-year-old male was incidentally found to have a total leucocyte count of 97 ϫ 10 9 /l with a normal haemoglobin and platelet count. The peripheral blood features were consistent with CP CML. Bone marrow aspirate confirmed the diagnosis with 100% of metaphases showing t(9;22)(q34;q11). RT-PCR revealed b2a2 BCR-ABL transcripts. Initial disease control was achieved with hydroxyurea. He was then started on daily alpha-interferon (IFN) and received subc...

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Section: Discussionmentioning

confidence: 99%

Collection and analysis of peripheral blood mononuclear cells during haemopoietic recovery following PBSCT for CML: autografting as an in vivo purging manoeuvre?

Spencer

Granter

Fagan

et al. 1998

Bone Marrow Transplant

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“…4,5 Manipulation of the graft to increase the proportion of putatively normal PhϪ cells is theoretically attractive in order to help reestablish PhϪ haemopoiesis after myeloablative therapy. There is as yet no evidence to suggest that this will be of benefit and only large-scale prospective comparative studies could be expected to provide any.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Studies do however suggest a possible survival advantage for patients treated with this procedure, a significant proportion of patients showing reduced or absent Ph+ metaphases, usually transiently, after transplant. 4,6,7 The evidence from IFN responders and transplanted patients implies that reduction of the Ph+ clone may correlate with improved survival.…”

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confidence: 99%

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

Pratt

Johnson

Rawstron

et al. 1998

Bone Marrow Transplant

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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...

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“…352 However, all these results are single-arm studies with selected patient groups making firm conclusions hard to draw. 353 A major disadvantage of autografting as compared to allogeneic grafting is the lack of GVL. In this respect it can be argued that results obtained with autografts will at best resemble the results obtained with identical twins which have a probability of relapse of almost 60% at 1 year post-transplant.…”

Section: Autologous Bone Marrow Transplantation In CMLmentioning

confidence: 99%