In chronic myelogenous leukemia (CML), autologous stem cell transplantation could be a promising new approach for patients with no cytogenetic response after interferon α (IFN-α) therapy. We report data on 28 CML patients autotransplanted in chronic phase with peripheral blood progenitor cells mobilized with G-CSF (5 μg/kg/day x 5 days) given subcutaneously while continuing IFN-α therapy. At mobilization, 23 patients (82%) were in complete hematological remission (CHR), 16 (57%) achieved a minor cytogenetic response (mcr). We obtained, after stimulation, a median of 37.4 × 109/l (6.9–108) white blood cells, 7.2 × 108/kg (2.2–16.6) mononuclear cells, 39 × 104/kg (4.8–403.5) CFU-GM and 4.2 × 106/kg (0–58.6) CD34+ cells. Six patients received GM-CSF after transplantation. All patients engrafted, with no significant influence stemming from the Sokal index score and pretransplantation IFN-α therapy duration. The first cytogenetic evaluation after transplantation showed 11 (39%) major cytogenetic response (Mcr), and nine (32%) mcr with no significant correlation between these responses, the Sokal index score, and pretransplantation IFN-α therapy duration, although there was a significant impact from GM-CSF administration (P = 0.01). After transplantation, 26 patients received IFN-α alone or associated with hydroxyurea. The median follow-up was 12 months after transplantation and 57 months after diagnosis. At the time of follow-up, nine patients were in CHR, six remained stable in chronic phase, three presented an mcr and one remained in Mcr. At the last follow-up, 22 patients were alive. We conclude that the results of this strategy are encouraging in poor IFN-α responders but that other prospective studies that try to maintain the cytogenetic responses obtained immediately after transplantation are needed.
Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling donor remains the only curative treatment for patients with chronic myelogenous leukemia (CML).1 Unfortunately, only 15% of all newly diagnosed CML patients are considered young enough for allogeneic BMT and have a suitable sibling donor.2 The remaining patients under the age of 50 years can undergo allogeneic marrow transplantation from phenotypically matched unrelated donors. The success of these transplantations requires totally identical class I and II HLA alleles between the recipient and the donor.34 Alpha interferon (IFN-α) therapy is associated with prolonged survival in chronic myelogenous leukemia following cytogenetic response.56 Recently, it has been demonstrated that the association of IFN-α and cytosine arabinoside improves cytogenetic response and survival.7 However, in patients who either cannot benefit from an allogeneic transplantation or do not respond to IFN-α, autologous stem cell transplantation must be considered.891011 Two main objectives are required when considering autotransplantation: an increase in the cytogenetic response and an improvement of overall survival.10 However, the potential contamination by leukemic progenitor cells that could induce relapse after transplantation1213 and the persistence of residual Ph-negative stem cells in long-term CML marrow cultures14 have prompted the search for methods of purging autologous stem cells. Different in vitro purging techniques have been experimented,151617181920 providing efficient suppression of leukemic cell growth in vitro. However, in vivo results do not differ from data obtained with a standard graft.21 Since 1978, different methods of in vivo purging have been evaluated, showing that it is possible to collect Ph-negative cells early in the course of hematopoietic recovery after intensive chemotherapy,22 with or without G-CSF.23 Reiffers et al24 reported that Ph-negative stem cells were mobilized with G-CSF in patients with CML in complete cytogenetic response or in major cytogenetic response (Mcr) after IFN-α therapy. More recently, Archimbaud et al25 have demonstrated that peripheral blood progenitor cell (PBPC) mobilization using G-CSF associated with IFN-α in CML patients in hematological remission, whatever the cytogenetic response, was feasible and allowed autografting.
This paper reports data on 28 CML patients who were autotransplanted long after diagnosis with PBPC collected by G-CSF associated with IFN-α. We analyzed the possible impact of different pre- and post-transplantation factors on PBPC mobilization and on the post-transplantation outcome.
Patients and methods
This study included 28 patients with CML Ph-positive in the first chronic phase. There were 21 males and seven females with a median age of 45 years (range 27–63 years). At diagnosis, 21 patients were evaluated for prognosis using the Sokal index: 12 patients (57%) had a low index score (<0.8), four (19%) an intermediate score, and five (24%) a high index score (>1.2). All patients received IFN-α for a median of 27 months (range 14–127) before apheresis and for a median of 29 months (range 16–128 months) before autotransplantation. The response to IFN-α therapy was analyzed according to MD Anderson criteria.26 After IFN-α therapy, all patients achieved complete hematological remission (CHR) and the best cytogenetic response observed in 25 evaluable patients was an Mcr for nine patients (36%) and a minor cytogenetic response (mcr) for 11 patients (44%). Five patients (20%) had no cytogenetic response during the progression of disease. Before mobilization, 23 patients (82%) remained in CHR. Cytogenetic responses observed at that time were: one Mcr (4%) with 20% Ph-positive cells, 16 mcr (57%) with a median of 74% Ph-positive cells (range 36–94%), and 11 with no cytogenetic response (39%).
Mobilization, harvest and cryopreservation of PBPCs
Patients were treated with G-CSF (filgrastim) at 5 μg/kg/day given subcutaneously until the last apheresis, while continuing IFN-α therapy at the same dosage given during the pretransplantation period. Harvest of PBPCs was performed daily, from day 5 of G-CSF therapy, with standard 2–3 blood volume aphereses using a Cobe Spectra (Cobe, Rungis, France) or a Fenwal CS-3000 (Baxter, Maurepas, France) blood separator. The target cell yield was greater than or equal to 6 × 108/kg mononucleated cells (MNC), containing more than 4 × 106/kg CD34+ cells and/or more than 10 × 104/kg CFU-GM. The PBSCs were then cryopreserved in 10% DMSO and 4% serum albumin using a controlled-rate freezer and stored in liquid nitrogen. In case of failure, IFN-α was stopped and patient PBPCs were harvested again after G-CSF administration alone at a dose of 10 μg/kg/day for 5 days.
The pretransplantation conditioning regimen associated busulfan at 4 mg/kg/day given orally from day 6 to day 13 and melphalan 140 mg/m2 given intravenously on day 2. All patients during the autotransplantation period were placed in laminar air flow rooms. In an attempt to improve the percentage of Ph-negative cells obtained after transplantation,27 six patients received GM-CSF given on day 1 after transplantation at a dose of 5 μg/kg/day until granulocytes were greater than 0.5 × 109/l. The IFN-α therapy was resumed at reduced dosages upon normalization of blood counts after transplantation.
Mobilization evaluation and post-transplantation outcome
Harvested cells were estimated on numbers of MNC × 108/kg, CD34+ cells × 106/kg and CFU-GM × 104/kg. Similarly, each apheresis product was submitted to a conventional cytogenetic analysis on 50 metaphases after a 48-h culture with no stimulation. Engraftment and post-transplantation outcome were analyzed, and a longitudinal cytogenetic study during the post-transplant period was performed. The impact of the Sokal index score, IFN-α therapy duration, and addition of GM-CSF on engraftment and on cytogenetic response after transplantation were also studied.
The relationship between the characteristics was studied using nonparametric statistics based on the Spearman rank correlation test and on the Mann–Whitney (or Wilcoxon) rank sum test. All P values reported are two-tailed and reported as statistically significant if <0.05. Computations were performed using the BMDP PC-90 statistical program (BMDP Statistical Software, Los Angeles, CA, USA).
Efficacy and safety of PBPC mobilization and harvest
Seventy-four aphereses were performed with a median of three procedures (range 1–6) per patient (Table 1). Four patients failed to mobilize with IFN-α and G-CSF. In case of mobilization failure, IFN-α was stopped. All four patients mobilized successfully with G-CSF alone given at a dose of 10 μg/kg/day for 5 days. The association of G-CSF and IFN-α was well tolerated. Only some patients developed moderate bone pain. The median white blood cell count was 37.4 × 109/l (range 6.9–108) after stimulation. A median of 7.13 × 108 MNC/kg (range 2.2–14.3), 4.4 × 106/kg CD34+ cells (range 0–58.6), and 34 × 104/kg CFU-GM (range 2.6–403.5) was harvested. Fifty-eight apheresis products were evaluable for cytogenetic study. There was no significant variation between the percentage of Ph-positive cells in the successive aphereses and the percentage observed before mobilization. The median percentage of Ph-positive cells before mobilization was 93% (range 20–100), while it was 94% (range 36–100) in the first apheresis (n = 23), 90% (range 29–100) in the second apheresis (n = 17), and 77% (range 13–100) in the third apheresis (n = 12) (Table 2).
Engraftment and post-transplantation outcome
All patients engrafted. The neutrophils reached a number greater than 0.5 × 109/l at a median of 17 days (range 12–57) and the platelets surpassed 50 × 109/l at a median of 20 days (range 10–149). The hematopoietic reconstitution was not influenced by the Sokal index score, nor by IFN-α therapy duration. The granulocyte recovery was faster for patients who received GM-CSF (P = 0.02). The first post-transplantation cytogenetic evaluation, performed 1 month after transplantation, is given in Table 3. All patients were evaluated immediately after transplantation for cytogenetic response. Eleven patients (39%) achieved an Mcr (vs one Mcr, nine mcr and one absence of cr before transplantation), nine patients (32%) achieved an mcr (vs five mcr and four absence of cr before transplantation) and eight patients had no cytogenetic response (vs two mcr and six absence of cr before transplantation). These cytogenetic responses corresponded to a median of 79% Ph-positive cells (range 0–100) for the entire population (n = 28), a median of 96% Ph-positive cells (range 30–100) for patients with no cytogenetic response before transplantation (n = 11) and a median of 32% (range 0–100) for pretransplantation cytogenetic responders (one Mcr and 16 mcr). No significant correlation was observed between cytogenetic response after transplantation and the Sokal score, nor between cytogenetic response and the duration of IFN-α therapy before transplantation (Table 4). The administration of GM-CSF had a significant effect on post-transplantation cytogenetic response (P = 0.01): in patients treated with GM-CSF, the median percentage of Ph-positive cells after transplantation was 66% (range 24–91) vs 93% before transplantation (range 56–100) while in patients without GM-CSF, the median percentage was 81% (range 0–100) vs 90% before transplantation (range 20–100%). Twenty-six patients received IFN-α after transplantation with a median interval of 120 days after transplantation (range 20–602). The IFN-α treatment was given at a median maximum dose of 29 millions of international units (MIU) (range 6–63 MIU) per week. In 16 patients, hydroxyurea was added to IFN-α. The median follow-up was 12 months (range 1–51) after transplantion and 57 months (range 27–142 months) after diagnosis. Fifteen patients had at least 12 months of follow-up after transplantation. At that time of follow-up, nine patients were in CHR and six patients remained stable in chronic phase, three patients presented an mcr (absence of cr immediately after transplantation), one patient remained in Mcr (Mcr immediately after transplantation) and 11 patients had no cr (four with no cr, three mcr, and four Mcr) immediately after transplantation. Six patients died after transplantation. Causes of death were severe infections (two cases: 9 months after transplantation/52 months after diagnosis; 10 months after transplantation/36 months after diagnosis), a neurologic problem (one case: 28 months after transplantation/55 months after diagnosis), pulmonary embolism (one case: 5 months after transplantation/36 months after diagnosis), osteosarcoma (one case: 16 months after transplantation/126 months after diagnosis), and blast crisis (one case: 11 months after transplantation/40 months after diagnosis).
Without an allogeneic transplant donor, patients who did not obtain a complete or major cytogenetic response after IFN-α therapy presented a severe prognosis. High-dose therapy followed by autologous stem-cell transplantation could be a promising new approach.891011 Pretransplantation preparative regimen favors regrowth of normal stem cells, by modifying the myeloid microenvironment, even when patients are infused with 100% Ph-positive stem cells harvested at diagnosis.9
Alpha-interferon has been shown to have an inhibitory effect on hematopoiesis in vitro and in vivo.28 Previous studies have shown that G-CSF can mobilize stem cells either in healthy volunteer donors29 or in patients with hematological malignancies or solid tumors.30 Reiffers et al24 have demonstrated the feasibility of PBPC mobilization by IFN-α associated with G-CSF in CML patients who have a good response to IFN-α. Concomitantly, Archimbaud et al25 showed the feasibility of PBPC mobilization by IFN-α and G-CSF in CML patients whatever the duration of previous IFN-α therapy and the cytogenetic response. Results of mobilization (7.2 × 108/kg MNC, 4.6 × 106/kg CD34+ cells, 39 × 104/kg CFU-GM) observed in these series are comparable to those obtained by Reiffers et al24 (7.4 × 108/kg MNC, 2.7 × 106/kg CD34+ cells, 10.2 × 104/kg CFU-GM). Both of these studies and the present results demonstrate that G-CSF is capable of reversing the hematological toxicity of long-term treatment with IFN-α and thus is a very safe hematopoietic stem-cell mobilization technique which could be performed at any time during CML progression.
One study had shown a differential effect of growth factors on normal vs CML progenitors.31 At relapse after an allogeneic transplantation, G-CSF reinduced complete remission, probably by preferential stimulation of Ph-negative cells.32 Results reported by Reiffers et al24 and by Carreras et al33 suggested that G-CSF preferentially mobilized Ph-negative cells in patients having responded to IFN-α. Moreover, it has been demonstrated that in CML patients either at diagnosis or not responding to IFN-α, it was possible to collect Ph-negative progenitor cells early in the course of hematopoietic recovery after intensive chemotherapy with or without G-CSF.2223 Carella et al23 have indeed shown that anthracycline-containing regimens plus G-CSF, used in patients cytogenetically refractory to IFN-α, were able to mobilize completely/partially Ph-negative PBPCs in 35% of the initial population. This percentage seemed inferior to that obtained when this type of mobilizing therapy was performed soon after diagnosis34 and particularly when patients had not received IFN-α previously.35 However, these mobilizing regimens seemed to give a lower proportion of Ph-negative aphereses after mobilization by G-CSF than that observed by Reiffers et al.24 In our series, all patients except one were poor cytogenetic responders to IFN-α. We demonstrated the feasibility of PBPC mobilization by G-CSF combined with IFN-α, whatever the IFN-α therapy duration and the cytogenetic response before mobilization. We observed no severe complication during mobilization but we observed no preferential Ph-negative-cell mobilization.
At this step, an important point remaining to be investigated is the usefulness of these mobilized PBPCs for reconstituting long-term (Ph-negative) hemopoiesis after transplantation. After initial studies of autotransplantations in CML,891011 related to the evidence that many CML patients harbor Ph-negative cells, recent trends in CML autografting concern in vitro and in vivo attempts to separate Ph-positive from Ph-negative cells.141736373839 There was no difference regarding the time to hematopoietic recovery after autotransplantation between our series and the study carried out by Carella et al.34 Interesting results have been observed in terms of cytogenetic response after transplantation using partially or completely Ph-negative progenitors mobilized after intensive chemotherapy plus G-CSF with three Ccr, two Mcr, and four mcr among 15 evaluated patients.22 However, Carella et al34 reported no data on long-term Ph-negative hemopoiesis after transplantation. In our series, we noted a very interesting cytogenetic conversion immediately after transplantation, particularly in patients with minor cytogenetic response before transplantation. Unfortunately, this good immediate cytogenetic response after transplantation was not maintained during the long-term progression of CML after transplantation in spite of IFN-α therapy at times combined with hydroxyurea. The small number of patients and the absence of a control arm should not invalidate the post-transplantation cytogenetic response observed with the addition of GM-CSF. Cortes et al27 showed an increase of cytogenetic response when GM-CSF was associated with IFN-α. Three hypotheses were proposed to explain the favorable effect of the combination of GM-CSF and IFN-α. One of these hypotheses postulates that the normal stem cells might be suppressed to a point were they are unable to proliferate once the growth advantage of leukemic cells is controlled by IFN-α. It could be speculated that GM-CSF would then stimulate the normal residual stem cells to proliferate and constitute a larger proportion of hematopoietic cells. This hypothesis could be retained to explain the difference of Ph-negative hematopoietic cell reconstitution after transplantation between patients receiving GM-CSF and those not receiving it. Another hypothesis is that myeloid growth factors have a potent antileukemic effect against CML progenitors by inducing their terminal differentiation. Based on this, Gladstone et al40 have autografted high-risk CML patients using enriched normal progenitor autografts obtained by elutriation and GM-CSF incubation. Out of 10 patients, nine engrafted with 100% Ph-negative cells but relapsed cytogenetically, as we observed, at a median of 6 months. In our study, GM-CSF was stopped when a complete granulocytic recovery was obtained. The withdrawal could explain the lack of long-term maintenance of cytogenetic response observed after transplantation. Indeed, some authors have demonstrated that long term treatment combining GM-CSF and cytoreductive therapy was effective in prolonging a transient Ph-negative hematopoiesis after transplantation.41 Future goals could be holding the cytogenetic response obtained immediately after transplantation by maintenance therapy combining continuous IFN-α with discontinuous low doses of GM-CSF.
In conclusion, this study demonstrates that noninvasive hematopoietic stem-cell mobilization using the association of IFN-α and G-CSF is feasible at any time during CML progression, whatever the previous IFN-α therapy duration and the cytogenetic response premobilization. After reinfusion of these collected cells, we observed no engraftment trouble. However, the improved cytogenetic response obtained immediately after transplantation was not maintained in spite of post-transplantation IFN-α therapy requiring other prospective strategies.
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Michallet, M., Thiébaut, A., Philip, I. et al. Late autologous transplantation in chronic myelogenous leukemia with peripheral blood progenitor cells mobilized by G-CSF and interferon-α. Leukemia 14, 2064–2069 (2000) doi:10.1038/sj.leu.2401956
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