International Journal of Hematology

, Volume 88, Issue 3, pp 331–335

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

Authors

  • Makoto Yoshimitsu
    • Department of Hematology and ImmunologyKagoshima University Hospital
    • Department of Bioregulatory Medicine, Graduate School of MedicineEhime University
  • Atsuo Ozaki
    • Department of Hematology and ImmunologyKagoshima University Hospital
  • Heiichiro Hamada
    • Department of Hematology and ImmunologyKagoshima University Hospital
  • Kakushi Matsushita
    • Department of Hematology and ImmunologyKagoshima University Hospital
  • Naomichi Arima
    • Division of Host Response, Center for Chronic Viral Disease, Graduate School of Medical and Dental ScienceKagoshima University
  • Chuwa Tei
    • Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of MedicineKagoshima University
Case Report

DOI: 10.1007/s12185-008-0150-z

Cite this article as:
Yoshimitsu, M., Fujiwara, H., Ozaki, A. et al. Int J Hematol (2008) 88: 331. doi:10.1007/s12185-008-0150-z

Abstract

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.

Keywords

ImatinibDLIPh+ ALLRelapse post allo-HSCT

1 Introduction

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 [1]. Recently imatinib mesylate (imatinib) [2] 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 [35]. 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 [6]. 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.

2 Methods

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 [7]. 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

A 23-year-old man with Ph+ ALL was referred to our institute in December, 2004. He achieved hematological remission after induction chemotherapy containing imatinib according to the ALL202 protocol of the Japan Adult Leukemia Study Group [7]. Briefly, the patient received 60 mg/m2 of prednisolone (PSL) a day for the first 7 days, then imatinib was administered at a dose of 600 mg/day on day 15–70, in combination with 1,200 mg/m2 cyclophosphamide (CPA) on day eight, 60 mg/m2 daunorubicin on day 8–10, 1.3 mg/m2 vincristine on day 8, 15, 22, 29, 60 mg/m2 PSL on day 8–28. Intrathecal chemotherapy was administered with 15 mg of methotrexate (MTX), 40 mg of cytarabine (Ara-C) and 4 mg of dexamethasone on day 36. Consolidation therapy consisted of a course with high-dose MTX (1 g/m2 per day for 1 day) and high-dose Ara-C (4 g/m2 per day for 2 days) followed by 600 mg/day of imatinib alone for 28 days. After one course of consolidation therapy, the patient achieved a complete cytogenetic remission but not molecular remission. Following myeloablative conditioning with six of fractionated total body irradiation (12 Gy) and 60 mg/kg of CPA for 2 days, he underwent an allo-HSCT from his HLA-identical brother in June, 2005. Prophylaxis for acute graft-versus-host disease (GVHD) consisted of short-term MTX and cyclosporine A (CsA). No obvious acute GVHD was manifested after allo-HSCT. Serial assessments of m-bcr/abl by RQ-PCR after transplantation confirmed complete molecular remission. After 4.5 months of molecular remission, RQ-PCR revealed positive for m-bcr/abl (molecular relapse), in November, 2005. No point mutations associated with the resistance to imatinib (including the P-loop region), were detected in the bcr/abl gene [8]. CsA was discontinued and imatinib was restarted at a dose of 600 mg a day. Four days later, the patient received 5 × 107 cells/kg of CD3+ donor lymphocytes (Fig. 1). Two weeks later a bone marrow aspirate showed decreased levels of m-bcr/abl to below measurable range. With 4 weeks' interval, the second DLI was performed. The levels of m-bcr/abl remained below measurable range even after reduction of imatinib to 400 mg a day, and became undetectable on day 94 after the second DLI. At that time, without obvious manifestations of GVHD, he turned positive for anti-nuclear antibody (ANA), (a serological marker for GVHD). Confirming no development of treatment-required DLI-related GVHD, to consolidate molecular remission, we gave a third DLI on day 151 from relapse. At the time of this report, he is taking imatinib 400 mg/day and survives in complete molecular remission with full performance status 33 months after allo-HSCT (Table 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs12185-008-0150-z/MediaObjects/12185_2008_150_Fig1_HTML.gif
Fig. 1

Serial clinical events and follow-up of the case. SCT indicates stem cell transplantation, DLI donor lymphocyte infusion, RQ-PCR quantitative reverse transcriptase polymerase chain reaction

Table 1

Characteristics of patient

Case

 Presentation

  Diagnosis

B-precursor ALL

  White-cell count (×106/L)

11,700

  Hemoglobin (mg/dL)/Platelets (×109/L)

10.2/28.0

  Blasts (%)

98.6

  BCR–ABL

p190

  Initial treatment

ALL202U Ph+

 Pretransplantation characteristics

  Time from diagnosis to hematological remission (days)

36 days

  Blast phenotype

CD10+, CD19+, CD20+, CD22+,CD33+, CD34+, CD13+

CD2, CD3, CD4, CD5, CD7, CD8

  Disease status at transplantation

Hematological CR

  Time from diagnosis to transplantation (months)

7

  Charlson comorbidity index

0

  ABO blood type

Match

 Transplantation characteristics

  CD34+ cell dose (×106/kg)/CD3+ cell dose (×108/kg)

5.0/4.0

  Prophylaxis against graft-versus-host disease

Cyclosporin, MTX

  Post-transplantation graft-versus-host disease (grade)

None

 Post-transplantation relapse

  Time from transplantation to relapse (months)

4.5

  Relapse phase

Molecular relapse

  Starting imatinib dose (mg)

600

  Dose of donor-lymphocyte infusion (×107/kg CD3+ cells/kg)

5, 5, 10

  Time from treatment to molecular remission (days)

136

  Graft-versus-host disease (grade)

0

 Last follow-up

  Status

Alive in molecular remission

  Leukemia-free survival (months)

24

4 Discussion

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 [1]. 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 [6]. 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. [12] 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. [13] 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 [14], while the immune-mediated GvL brought by DLI itself can cure relapsed leukemia [15]. 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 [16]. 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. [13] 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 [17]. At that time, there were some reports describing the suppression of T-cell response by imatinib [1820]. 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.

Copyright information

© The Japanese Society of Hematology 2008