Pretransplant imatinib can improve the outcome of nonmyeloablative stem cell transplantation without increasing the morbidity in Philadelphia chromosome-positive chronic myeloid leukemia

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TO THE EDITOR

Chronic myeloid leukemia (CML) would appear to be the ideal disease for exploring nonmyeloablative stem cell transplantation (NST), at least in the early chronic phase (CP)1 (Deininger MWN et al. Bone Marrow Transplant 2002; 29: 31 (abstract)). However, NST in advanced phases will not routinely replace the conventional myeloablative regimen due to the higher relapse rate. Although imatinib, which is an inhibitor of BCR-ABL tyrosine kinase, is highly effective in Philadelphia (Ph) chromosome-positive CML,2 relapses during the imatinib treatment also have been observed in the accelerated phase (AP) and even in some patients with CP CML.3 Therefore, additional curative modalities will be needed in patients who have achieved the optimum responses after an imatinib treatment in advanced phases of CML. There have been a few case reports using imatinib for allogeneic transplantation.4, 5 So far, the precise impact of a long-term pretransplant treatment with imatinib on engraftment, the transplant-related morbidity and mortality (TRM), graft-versus-host disease (GVHD), relapse, and survival has not been reported.

To know the exact role of imatinib prior to NST, a total of 20 CML patients were evaluated. Of these, 10 patients (pre-NST imatinib group) were treated with imatinib and the disease phases at administration were three in CP and seven in AP. Imatinib was begun with oral doses of 400–600 mg daily for the pre-NST imatinib group and the doses were adjusted according to a previously published guideline.6 The imatinib treatment continued until complete cytogenetic response (CCR) or the major response for more than 6 months was achieved, and stopped on day −10 before starting the conditioning regimen. After a median imatinib treatment of 9.5 (range 6–12) months, nine achieved a CCR and one returned to CP at a transplant. The other 10 patients (no imatinib group) who showed CP at diagnosis were directly assigned to undergo a NST without using pretransplant imatinib.

Although the preparative regimens were varying, all 20 patients received fludarabine (Flu)-based regimens, and the cyclosporine (CSP) or the FK506 used for GVHD prophylaxis was tapered during or after the third month post-transplant according to the minimal residual disease (MRD) status and the evidence of GVHD. The median time to the last follow-up was 18 and 20 months in pre-NST imatinib and in the no imatinib group, respectively. Using conventional cytogenetics, nested reverse transcriptase polymerase chain reaction (RT-PCR), and quantitative real time RT-PCR (Q-RT-PCR) assays, as previously described,7 MRD was assessed from bone marrow samples in all cases at diagnosis, immediately before the transplant, and every 3 months after the transplant. The MRD was assessed more frequently at 1–2-month intervals when needed.

Other characteristics except the disease stages at diagnosis and pre-transplant were not significantly different between the two groups, and no differences in the engraftment and morbidity were observed between the two groups. In pre-NST imatinib group, one developed a cytogenetic relapse after transplant, and received imatinib. At present, all have maintained a CCR and are alive. In the no imatinib group, four developed a hematological relapse after transplant, and received imatinib. Two died from multi-organ failure and relapse. Overall, eight are alive including six in CCR (Table 1). In the pre-NST imatinib group, only one who was in CP at the transplant demonstrated a high transcript level 0.01 and five patients showed the transcript level 0.001 at 3 months. From 3 to 6 months, only two of nine MRD-assessable patients had a mild increase in the transcript level within 1 log. Overall, seven patients maintained a molecular remission (MR) according to both nested RT-PCR and Q-RT-PCR assays (Table 1). In the no imatinib group, although the transcript level increased only in one of the nine assessable patients during the early 3 months, four demonstrated a high transcript level 0.01 and seven patients showed the transcript level 0.001 at 3 months. An increasing transcript level was observed in six patients (n=9) between 3 and 6 months. Overall, two of the 10 patients sustained a MR (Table 1). Eventually, the MR rates were significantly different between the two groups (83.3 vs 40%, P=0.011).

Table 1 Characteristics and outcomes of CML patients undergoing NST

The previous study8 has shown that pretransplant chemotherapy leading to a return from blast crisis (BC) to a second CP is associated with a greatly improved transplant outcome. However, this is usually associated with significant morbidity and may result in serious complications, making the transplant impracticable. In contrast to chemotherapy and interferon, the use of imatinib prior to NST may potentially allow the disease to be controlled before the transplantation without an increase in the TRM. However, imatinib may also cause some suppression of the normal hematopoiesis via its inhibitory effect on colony formation via c-kit inhibition.2 Therefore, the first concern was whether pretransplant imatinib can influence the engraftment and early TRM. Although all the patients in pre-NST imatinib group received imatinib for an enough period of more than 6 months, all these patients were successfully engrafted. In addition, there were no significant differences in the period of cytopenia between the two groups. This is consistent with previously reported findings concerning the engraftment in CML patients receiving imatinib prior to transplantation4 as well as a conventional NST.

Despite the possible advantages of NST in the treatment of malignancies, GVHD is the main cause of TRM in NST. In our study, a lower frequency and lower intensity of the acute GVHD were observed in pre-NST imatinib group. Only 20% of patients in the pre-NST imatinib group had acute GVHD with a grade I intensity (vs 33% in no imatinib group). However, chronic GVHD (60 and 56% in the pre-NST imatinib and no imatinib groups, respectively) occurred with similar frequency in other conventional NST studies. Overall, the incidence of GVHD between our two groups was similar. There was a report6 showing that imatinib administered as a treatment for a post-transplant relapse is associated with the recurrence of severe GVHD. Of our patients, five patients were treated with imatinib for a post-transplant relapse, but no cases showed a recurrence of the GVHD during the imatinib treatment.

Some reports4, 5 using imatinib prior to transplantation have been published. However, most reports investigated a limited number of patients and mainly consisted of myeloablative regimens. In addition, imatinib was used only as a salvage therapy to conduct transplantation within a few weeks from the beginning of treatment, to avoid resistance in these studies. Therefore, no real conclusion as to the role of imatinib prior to the transplant could be made with these studies.

Here, we could develop a new strategy to effectively reduce the leukemia load prior to the transplant, and long-term use of imatinib might become a type of preparative regimen satisfying this purpose. Although Flu+cyclophosphamide preparative regimens with reduced intensity were used in four patients of pre-NST imatinib group, only one had a cytogenetic relapse after transplant, and now all the patients sustained a CCR, including seven MR. This result suggests that AP CML also can be a good candidate to perform this novel approach. As no fatal cases were observed and all patients have sustained the CCR in the pre-NST imatinib group, we can postulate that our approach was well tolerated by all the patients. The main question is how imatinib influences the transplant outcomes. As the MRD level in the pre-NST imatinib group at transplant was significantly lower than that of the no imatinib group (P=0.0001), and only one patient (10%) in the pre-NST imatinib group demonstrated a high level of normalized BCR-ABL transcripts 0.01 at 3 months post-transplant, compared to 44% (four out of nine) in the no imatinib group, we can speculate that a low MRD level induced by imatinib may contribute to the full development of the GVL effects. In our previous observations,7 all patients with a normalized BCR-ABL 0.01 eventually progressed to cytogenetic relapse without pre-emptive immunotherapy.

In conclusion, this study suggests that pre-transplant imatinib can lead to a durable engraftment and elimination of molecular evidence of the disease with minimum toxicity. As a small number of patients were involved in this study, prospective randomized trial with a larger number of patients would be required to confirm these clinical observations.

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Acknowledgements

This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (01-PJ10-PG6-01GN16-0005).

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Correspondence to S Lee.

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