Case of a patient with Philadelphia-chromosome-positive acute lymphoblastic leukemia relapsed after myeloablative allogeneic hematopoietic stem cell transplantation treated successfully with imatinib and sequential donor lymphocyte infusions
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- Yoshimitsu, M., Fujiwara, H., Ozaki, A. et al. Int J Hematol (2008) 88: 331. doi:10.1007/s12185-008-0150-z
A 23-year-old man with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) underwent myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his HLA-identical brother in first hematological remission following induction chemotherapy which included imatinib. He had no acute graft-versus-host disease (GVHD), and 4.5 months after HSCT, he had a molecular relapse (180,000 copies/μg RNA of minor bcr/abl transcripts (m-bcr/abl) without mutation in 22 sites including the p-loop region). Following discontinuation of cyclosporine A, imatinib (600 mg daily) was restarted and 4 days later donor lymphocyte infusion (DLI) (5 × 107/kg of CD3+ cells) was given. In 2 weeks, the marrow m-bcr/abl became undetectable. He received two further DLIs and imatinib was continued at a reduced dose of 400 mg a day. At the time of this report, he remains in complete hematological remission more than 33 months after allo-HSCT and persists in the second molecular remission for longer than 24 months. During this clinical course, he became positive for anti-nuclear antibody after second DLI, without any other manifestations of GVHD. The standard treatment for Ph+ ALL relapsing after allo-HSCT still remains to be established. Imatinib in combination with DLI for early molecular relapse may be a promising option.
KeywordsImatinibDLIPh+ ALLRelapse post allo-HSCT
To date, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment modality for Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), but relapse after allo-HSCT still remains one of the major causes of treatment failure . Recently imatinib mesylate (imatinib)  has been shown to have a pronounced brief antileukemic activity in patients with relapsing Ph+ ALL after allo-HSCT; however, sustained molecular remission is uncommon [3–5]. While several reports have shown that donor lymphocyte infusion (DLI) can control relapsed acute leukemia after allo-HSCT, through a graft-versus-leukemia (GVL) effect, the usefulness of DLI for relapsed Ph+ ALL is still debated and complete eradication of leukemic cells is rarely observed . Here, we report the successful outcome in a patient who was given imatinib combined with sequential and multiple courses of DLI as a salvage treatment for the molecular relapse state of Ph+ ALL after allo-HSCT.
The copy number of minor bcr/abl transcripts (m-bcr/abl) was measured using multiplex real-time quantitative RT-PCR (RQ-PCR) assay as described previously . The detection threshold of RQ-PCR in this study is 50 copies/1 μg RNA, which corresponds to a sensitivity of 10−5. Levels below the threshold were defined as “undetectable” and “below measurable range”.
3 Case report
Characteristics of patient
White-cell count (×106/L)
Hemoglobin (mg/dL)/Platelets (×109/L)
Time from diagnosis to hematological remission (days)
CD10+, CD19+, CD20+, CD22+,CD33+, CD34+, CD13+
CD2−, CD3−, CD4−, CD5−, CD7−, CD8−
Disease status at transplantation
Time from diagnosis to transplantation (months)
Charlson comorbidity index
ABO blood type
CD34+ cell dose (×106/kg)/CD3+ cell dose (×108/kg)
Prophylaxis against graft-versus-host disease
Post-transplantation graft-versus-host disease (grade)
Time from transplantation to relapse (months)
Starting imatinib dose (mg)
Dose of donor-lymphocyte infusion (×107/kg CD3+ cells/kg)
5, 5, 10
Time from treatment to molecular remission (days)
Graft-versus-host disease (grade)
Alive in molecular remission
Leukemia-free survival (months)
Allo-HSCT is the only curative treatment modality for patients with Ph+ ALL, so the prognosis of relapsed Ph+ ALL after allo-HSCT is very poor . Contrary to the great success of imatinib in the treatment for chronic myelogenous leukemia (CML) [9, 10], imatinib alone is less effective for Ph+ ALL because of rapid acquisition of drug resistance. On the other hand, DLI alone for relapsed Ph+ ALL after allo-HSCT also rarely achieves sustained remission . Recently, highly effective induction treatment comprising imatinib with conventional chemotherapy has been reported [7, 11]; nevertheless its long-term outcome without allo-HSCT remains to be elucidated.
Our patient once achieved molecular remission soon after allo-HSCT. Following the report of Wassmann et al.  that imatinib mono therapy was effective to treat minimal residual disease (MRD) of Ph+ ALL after allo-HSCT, and in order not to miss the early stage of relapse of Ph+ ALL of which disease burden is within the level of MRD, the amount of m-bcr/abl in bone marrow aspirates were serially monitored by RQ-PCR every 4–6 weeks after allo-HSCT. Then the molecular relapsed disease was detected on day 137 after transplantation. Wassmann et al. also observed that the relapse with higher tumor load tended to show the poor prognosis (none of five patients with higher tumor load obtained molecular CR after re-initiation of imatinib treatment) in the same report. As the presented case relapsed with relatively higher tumor load, we assumed that the disease was less likely to be controlled by imatinib mono therapy, which prompted us to choose the rapid discontinuation of immunosuppressant, and re-administration of imatinib followed by sequential DLI. The patient achieved the more reduced leukemia burden from molecular relapsed disease to below the detection level of m-bcr/abl transcript in 2 weeks.
Although the efficacy of the combination of DLI and imatinib for the treatment of relapsed Ph+ ALL after allo-HSCT remains to be determined, Savani et al.  have reported favorable outcome for the relapsed Ph+ ALL and CML after allo-HSCT by discontinuation of immunosuppressant, and resumed administration of imatinib in combination with DLI. Our patient also showed that the similar combination treatment could effectively control molecular relapsed disease and induce durable molecular remission again.
It has been already demonstrated that imatinib cannot eradicate the leukemic progenitors , while the immune-mediated GvL brought by DLI itself can cure relapsed leukemia . Thus, the combination treatment of imatinib and DLI for relapsed Ph+ ALL after allo-HSCT seems a rational option. Furthermore, a recent report has described that imatinib can amplify the leukemia-reactive immune response in vivo . This effect must be rationally augmented by concurrent DLI. As for the synergistic effect of imatinib and DLI for relapsed CML after allo-HSCT, Savani et al.  have evaluated in detail. They described that imatinib could provide the rapid reduction of relapsed leukemia burden, and DLI could support to sustain the durable remission. The latter observation may answer the question of whether we can stop imatinib in this setting, especially in a patient who achieved the second molecular remission, and the former suggests that we can avoid the dose-escalating multiple DLI, which usually requires longer time to control the leukemia mass burden, and potentially comprise the risk of severe DLI-related GVHD. In our case, without any treatment-required DLI-related GVHD, we gave three courses of DLI in total. As for DLI-provided GvL effect against relapsed leukemia, the close correlation between GvL and the development of some DLI-related GVHD is known . At that time, there were some reports describing the suppression of T-cell response by imatinib [18–20]. In the present case, we thought that imatinib might have suppressed the development of symptomatic GVHD after two courses of DLI, even concurrent with the discontinuation of CsA. At the same time, we were afraid that imatinib might also suppress GvL effect brought by DLI to some extent. Thus, we expected that no severe GVHD might occur, as long as we would not rapidly decline imatinib, and decided to undergo third DLI to potentiate GvL. Describing as above, we believe that the achievement of durable second molecular remission in this patient is provided not only by continuous imatinib, but also by the combination with sequential and multiple DLIs, just with the marginal allo-response (positivity for ANA) following DLIs.
In an interim conclusion, our case report suggests that imatinib combined with sequential DLI may be a promising option for the treatment of relapsed Ph+ ALL after allo-HSCT. This is a single case report; further well-designed and randomized studies in large number of cases are needed to evaluate this strategy and to answer the remaining questions: how many numbers of DLI are required, whether we can stop imatinib in patients with second molecular remission, and so on.