Biology of Blood and Marrow Transplantation
Volume 16, Issue 3 , Pages 301-310, March 2010

Current Status and Perspectives of Tyrosine Kinase Inhibitor Treatment in the Posttransplant Period in Patients with Chronic Myelogenous Leukemia (CML)

  • Evgeny Klyuchnikov

      Affiliations

    • Interdisciplinary Clinic for Stem Cell Transplantation, University of Aachen, Germany
    • ,
  • Nicolaus Kröger

      Affiliations

    • Interdisciplinary Clinic for Stem Cell Transplantation, University of Aachen, Germany
    • ,
  • Tim H. Brummendorf

      Affiliations

    • Department of Hematology and Oncology, University of Aachen, Germany
    • ,
  • Bettina Wiedemann

      Affiliations

    • Interdisciplinary Clinic for Stem Cell Transplantation, University of Aachen, Germany
    • ,
  • Axel Rolf Zander

      Affiliations

    • Interdisciplinary Clinic for Stem Cell Transplantation, University of Aachen, Germany
    • ,
  • Ulrike Bacher

      Affiliations

    • Interdisciplinary Clinic for Stem Cell Transplantation, University of Aachen, Germany
    • Corresponding Author InformationCorrespondence and reprint requests: Ulrike Bacher, MD, Interdisciplinary Clinic for Stem Cell Transplantation, University Cancer Center Hamburg (UCCH), Martinistrasse 52, 20246 Hamburg, Germany.

Received 30 May 2009; accepted 31 August 2009. published online 23 September 2009.

Article Outline

Following the introduction of tyrosine kinase inhibitors (TKIs) in chronic myelogenous leukemia (CML), allogeneic stem cell transplantation (SCT) took a shift toward high-risk patients. Considering the high relapse rates posttransplant in these selected patients, several studies evaluated posttransplant use of the TKI imatinib. Although the number of studies are still limited, and data have to be confirmed by additional studies, safety of imatinib even within the first months after SCT seems to be acceptable. Imatinib was shown to be effective in patients with molecular or hematologic relapse of chronic or accelerated phase posttransplant (CP, AP), whereas outcomes in blast phase were more unfavorable. The compound further seemed beneficial for prophylactic use in patients who achieved complete remission posttransplant. The combination of imatinib with donor lymphocytes did not result in increased toxicity or graft-versus-host disease (GVHD). First studies suggest that second-generation TKIs such as dasatinib or nilotinib are manageable posttransplant with acceptable toxicity as well. In conclusion, TKIs of the first- and second-generation are promising options for the posttransplant period of patients with CML, but algorithms for dosage, intervals from SCT, duration of application, and the combination with donor lymphocytes still have to be developed.

Key Words: Allogeneic stem cell transplantation (SCT), Chronic myelogenous leukemia (CML), Tyrosine kinase inhibitors (TKIs), Imatinib, Dasatinib

 

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Introduction 

Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib (IM) as first-line strategy in chronic myelogenous leukemia (CML) 1, 2, 3, the rates of annual allogeneic stem cell transplantations (SCT) in this entity were soon dropping worldwide. A European Blood and Marrow Transplant (EBMT) study reported a decrease from 1396 in 1999 to a plateau of ∼800 annual transplantations in CML per year since 2004 [4]. However, this decrease was most pronounced in first chronic phase (CP), whereas allo-SCT still has an important role for the treatment of high-risk patients—either because of advanced disease such as accelerated (AP) or blast phase (BP), or because of failure of IM [5]. Thus, by now, >50% of transplantations in CML are performed in patients in advanced disease [6]. Considering the high relapse rates up to 30% to 40% in patients with AP or BP after SCT [4], posttransplant monitoring and prophylactic or therapeutic strategies in this setting gain more and more importance.

Whereas donor lymphocyte infusions (DLI) were previously the only therapeutic option, the availability of IM has broadened the spectrum of posttransplant strategies in case of relapse of CML 7, 8, 9, 10, 11. The largest study [9] included 128 patients, whereas others reported on cohorts up to the size of 15 to 30 patients 7, 8, 10, 11. The median intervals from SCT to the start of IM varied within these studies from 4 weeks [10] to 54 months [11]. Dosages of IM were also variable, ranging from 400 [9] to 1000 mg [7]. Further, 2 small series of patients with CML or Philadelphia-positive acute lymphoblastic leukemia (Phi+ ALL), who had been treated with dasatinib in the posttransplant period, have been reported. Thus, the introduction of second generation TKIs such as dasatinib and nilotinib12, 13 will further expand posttransplant strategies.

Although the number of reported cases with posttransplant TKI treatment are still limited, some preliminary conclusions can be drawn. This review focuses on the efficacy and safety of first- and second-generation TKIs in the posttransplant period in CML, and presents an overview on current strategies concerning indication, dosage, and intervals from SCT.

Efficacy of Posttransplant Imatinib 

Hematologic relapse 

Olavarria et al. [9] started IM in 128 patients with different stages of CML who had hematologic relapse posttransplant. Patients with relapse of CP received 400 mg daily, whereas those with advanced disease (AP/BP) were treated with 600 mg doses. This approach was highly effective in patients with relapse of CP, who had a 100% overall survival (OS) after 2 years. In those patients with relapse of AP, the 2-year OS was still favorable with 86%, whereas those in BP had a 12% 2-year OS only. In more detail, cytogenetic complete remission (CR) rates were 58% for CP, 48% for AP, and 22% for BP.

Kantarjian et al. [7] used IM doses mostly of 600 mg daily (3 patients received a 1000-mg dose) in 28 adult patients with CP (n = 5) or AP/BP (n = 23) with hematologic relapse. The overall hematologic and cytogenetic response rates were 74% and 58%, respectively. In patients with relapse of CP, a 100% hematologic CR rate was achieved, whereas the rate of hematologic CR was 83% in patients with AP and 43% in patients with BP. Cytogenetic response rates were 63% for CP or AP and 43% for BP.

These data demonstrate the efficacy of posttransplant IM for hematologic relapse of CP and AP, whereas alternative strategies are needed for those patients with relapse of BP.

Cytogenetic/molecular relapse 

Hess et al. [14] analyzed outcomes in 37 patients with cytogenetic or molecular relapse of CP. Patients received 400 mg of IM, and in case of failure to achieve a major molecular CR after 6 months of such therapy, the IM dose was increased to 600-800 mg daily. Within the initial 9-month period of study, 73% of the 15 patients with cytogenetic relapse achieved cytogenetic CR, in 32% of patients being accompanied by stable molecular remission. Those 18 patients with molecular relapse had better outcomes, as all achieved at least major molecular response, and 14 patients (78%) achieved molecular CR. Also, they achieved molecular CR after a median interval of 4 weeks in contrast to 16 weeks in those with cytogenetic relapse.

In contrast, Palandri et al. [11] observed no difference whether patients received IM at cytogenetic/molecular or hematologic relapse posttransplant in 16 patients with different phases of disease. Four of 5 patients with hematologic relapse achieved RT (reverse transcription)-polymerase chain reaction (PCR) negativity after a median of 7.5 months, which was comparable to the 82% rate of molecular CRs in those patients who received IM at cytogenetic/molecular relapse after a median treatment duration of 10.6 months. However, the small size of samples has to be considered. It seems worthwhile to explore the start of IM treatment in the posttransplant period already at molecular relapse in larger cohorts.

Prophylactic use 

Carpenter et al. [10] reported on the prophylactic use of IM in patients with CML and Phi+ ALL. This study included patients in CR as assessed by hematologic parameters, cytogenetics, or interphase fluorescein in situ hybridization (FISH). Adult patients received 400 mg daily, children had a 260 mg/m2 dose. Within a median follow-up of 1.4 years, 12 of 15 the Phi+ ALL patients and 5 of 7 the CML patients maintained major molecular CR as assessed by quantitative real-time PCR (qPCR), and there was a low hematologic relapse rate of 9% in the whole cohort [10].

Intervals from SCT to Start of Treatment 

The intervals between SCT and posttransplant IM administration were quite variable even within each study. This has to be seen on the background of the various comedications, unstable hematopoiesis, organ toxicity because of pretransplant conditioning, and finally infectious events, which makes a standardization of the start of TKIs in the posttransplant period difficult.

DeAngelo et al. [8] started IM with a median interval from SCT of 21 months for patients in CP and 41 months for those in AP/BP (range: 1-60 months). This time schedule was comparable to the study from Olavarria et al. [9], who started IM after a median interval of 14 months from SCT (range: 1-161 months). Considering the time of relapse manifestation, IM was started at a median interval of 5 months (range: 0-65 months). Longer intervals between SCT and IM administration were chosen by Palandri et al. [11] as the median interval to the start of IM was 54 months (range: 7-160 months) and by Kantarjian et al. [7] as patients received IM after a median of 41 months (range: 3-140 months) from allo-SCT.

For prevention of relapse, Carpenter et al. [10] started IM very early within the first month posttransplant: The median interval was 28 days from SCT only (21-39 days).

Tolerance of Posttransplant IM Treatment 

Posttransplant IM treatment was generally well tolerated. Thus, in the study by Olavarria et al. [9] only 6 of 128 patients (5%) developed severe pancytopenia when doses of 400-600 mg IM daily were applied over a median duration of 9 months (range: 2-34 months). In no case IM had to be interrupted. Kantarjian et al. [7] reported severe neutropenia in 43%, and severe thrombocytopenia in 27% of cases. Liver dysfunction was seen in 18%, fluid retention in 10% of patients. Despite using IM doses up to 1000 mg daily, the authors did not find any increase in adverse reactions. With respect to the elevation of liver enzymes, inhibition of CYP3A4 by concomitant antifungal triazole comedication may be relevant [10]. In the study of DeAngelo et al. [8], posttransplant IM was extremely well tolerated, and no patient had to discontinue therapy because of side effects. There was no grade III/IV nonhematologic toxicity, and only 1 patient required dose reduction from 600 to 400 mg because of hematologic toxicity. Palandri et al. [11] reported higher rates of severe complications, as 31% of patients developed grade III-neutropenia or thrombocytopenia, and 13% of patients showed musculoskeletal pain and periorbital edema.

Carpenter et al. [10] started preventive IM use within the first month after SCT in 22 patients with CML or Phi+ ALL. Most frequently, nausea, emesis, and elevation of liver enzymes were reported to be associated with IM prophylaxis. Adults tolerated 400 mg doses, children received 260 mg/m2. In general, the early start of posttransplant IM administration was well tolerated.

Hence, despite the different schedules regarding indication, start, dosage, and duration of treatment, most authors reported favorable tolerance of posttransplant IM and successful resolution of serious adverse events after dose reduction (Table 1). In all studies, IM discontinuation because of toxicity was rare and mostly temporary. However, close monitoring of peripheral blood (PB) counts is strongly recommended in patients receiving TKIs in the posttransplant period as to perform dose reduction in time. Also, clinical research should continue to evaluate the tolerance of TKIs posttransplant given the myelotoxic comedications and the unstable hematopoiesis in this specific situation.

Table 1. Posttransplant Use of First- or Second-Generation TKIs in Patients with BCR-ABL-Positive Diseases
ReferenceNo. of ptsCompoundIndication to posttranspl. TKIsMed. start of TKIs from SCT (months)Med. Treatment Duration (Months)Toxicity (Grade)Dose Red./ InterruptionAcute GVHD (Grade)Outcomes of {osttransp. TKI Treatment
HematologicHepaticOther
Carpenter et al. [10]22ImatinibProphylaxis28 days (range : 21-39 days)12
Neutro↓ (II-III): 2/22

Thrombo↓ (II-III): 2/22

6/22 (I-III)12/22 (I-III)13—CCgR: 13/15 ALL; 5/7 CML; PCR neg. : 12/15 ALL; 5/7 CML Relapse: 2/7 CML
Hess et al. [14]44ImatinibRelapse (CyR, MR)2 months8
Neutro↓ (III-IV): 6/44

Thrombo↓ (I-II): 2/44

n.a.20/44 (I-II)5—CCgR: 11/15 CMR: 23/37 MMR: 6/37 SMR: 8/37 Median time to CMR: 3.3 months
Kantarjian et al. [7]28ImatinibRelapse (HemR, CyR, MR)41 (range : 3-140)11
Neutro↓: 6/14

Thrombo ↓: 4/15

5/289/28 (III-IV)111/28 (II); 3/28 (III)CHR: 17/23 CCgR: 9/26 PCgR: 6/26 1-year OS: (n=20) 74%
DeAngelo et al. [8]15ImatinibRelapse (HemR, CyR)31 (range : 0.5-72)141/153/15—31 (II-IV)CHR: 11/15 CCgR: 11/15 PCR neg.: 7/15 1-year OS in CP: (n = 10) 100%; OS in AP/BP: 1/5 alive
Palandri et al. [11]16ImatinibRelapse (HemR, CyR, MR)54 (range: 7-160)31
Neutro↓ (III): 4/16

Thrombo↓ (III) : 1/16

—2/16 (II)7—CCgR: 14/16 at 4.6 months PCR neg.: 12/16 at 30 months
Olavarria et al. [9]128ImatinibRelapse (HemR)14 (range : 1-161)9Severe pancytopenia: 6/128n.a.n.a.6cGvHD re- exacer- bation: 3/27CHR: 71% CCgR: 42%; 2-year OS: Overall (n = 86) 65%; CP: (n = 51) 100%; AP: (n = 25) 86%; BP: (n = 10) 12%
Olavarria et al. [16]22ImatinibProphylaxis35 days12n.a.n.a.n.a.3—Relapse: 15/22 (68%) at a median of 6 months (2-18) from IM stop; 3-year-OS: (n = 19) 87%; mol. remission after DLI: 15/22 (68%)
Atallah et al. [12]11DasatinibRelapse (HemR)9 (range: 0.6-147)13Thrombo↓: 3/111/115/119n.a.Transitional CMR: 3/11 pts; 2/11 pts are alive with relapse
Klyuchnikov et al. [13]11
Dasatinib: n = 9;

Nilotinib: n = 2

Relapse (HemR, MR)12 (range: 2-40)8 (range: 1-19)Myelosup- pression: 4/11n1/113—4/9 pts had stable response (2 with extramedullary relapse of CML BP; 1 pt with MR; 1 pt with prophylactic use)

Med. indicates median; HemR, hematologic relapse; CyR, cytogenetic relapse; MR, molecular relapse; CHR, complete hematologic remission; CCgR, complete cytogenetic remission; OS, overall survival; CML, chronic myelogenous leukemia; CP, chronic phase, AP/BP, accelerated/blast phase; MMR, major molecular response; SMR, stable molecular response; n.a., not available; neg., negative; red., reduction.

Duration of Treatment 

According to the recent results of the STIM study (“Stop Imatinib Trial”), 47% and 61% of (nontransplanted) patients had lost molecular CR 9 months from discontinuation of IM with and without interferon (IFN)-α treatment, respectively. Therefore, the duration of IM therapy seems to be a sensible point, probably especially for those who underwent allo-SCT because of adverse risk profiles [15].

In most posttransplant studies, IM was continued for periods from 9 to 14 months 7, 8, 9, 11. Palandri et al. [11] continued IM for longer periods with a median treatment duration of 31 months. In total, 12 of 16 (75%) patients with either hematologic, cytogenetic, or molecular relapse of CP or AP/BP achieved molecular CR. This suggests that prolonged treatment with IM is effective and feasible in the posttransplant period and can be safely administered over longer periods.

Olavarria et al. [16] reported on a cohort of 22 patients who had all received reduced intensity conditioning (RIC) in newly diagnosed or late first CP. Most patients (82%) were minimal residual disease (MRD)-positive before SCT. Following SCT, only 1 of 22 patients (5%) achieved molecular CR, whereas 95% were still BCR-ABL-positive. IM was started on day +35 in all patients. When IM was stopped after 1 year of treatment, 95% of patients had achieved a 3-log reduction in BCR-ABL transcripts; being accompanied by molecular CR in 33% of those cases. However, several months after discontinuation of IM (median 6 months, range: 2-18 months), only 29% of patients maintained molecular CR or at least stable low-level molecular disease (BCR-ABL/ABL ratio: ≤0.02%), whereas 71% patients had molecular relapse. This demonstrates that interruption of posttransplant IM is associated with high risk for disease recurrence at least in patients who fail to achieve molecular negativity following SCT.

On the other hand, long-term application of IM has to be outbalanced with safety in the posttransplant period [14]. Moreover, it remains to be seen whether posttransplant IM alone is sufficient to guarantee continued molecular CR in patients with a residual leukemia cell load after SCT, or whether a combination with donor lymphocytes is required [17].

Immunomodulation by Posttransplant Imatinib 

IM was shown to have immunomodulating activities in several studies [18]: first, the compound can impair the differentiation of dendritic cells from either CD34+ peripheral blood progenitor cells (PBPCs) or monocytes as suggested by the in vitro studies of Appel et al. [19]. Moreover, these dendritic cells were unable to elicit primary or secondary T cell responses. Taieb et al. [20] confirmed these results in an animal model as feeding of mice with IM resulted in the inhibition of Flt3 ligand-induced expansion of dendritic cells and impaired the induction of a protective antitumor immunity. The in vivo results of Boissel et al. [21] in CML patients suggested that IM inhibits the normal development of dendritic cells.

In addition to the inhibition of monocyte and macrophage development [22], IM was shown to hamper T cell proliferation. An in vitro study from Cwynarsky et al. [23] demonstrated that IM inhibits the proliferation and activation of T cells at concentrations representative of the pharmacologic doses used therapeutically in vivo. This effect is reversible, antigen-presenting cells independent, and does not involve induction of apoptosis. Further, Leder et al. [24] demonstrated that IM inhibits antigen-specific IFN-gamma secretion of both CD4+ and CD8+ T-effector cells at therapeutically relevant concentrations, whereas T cells remain responsive and the effector T cells are modulated rather than suppressed. In a murine model, IM had immunosuppressive effects by inhibiting antigen presentation and T cell effector functions [25]. Therefore, the treatment of patients with higher doses of IM could result in a more profound suppression of CD8 T cells 26, 27. Moreover, treatment of patients with IM could influence the graft-versus-leukemia (GVL) effect of lymphocytes (including CD8+ T cells) in allo-SCT, and also lead to increased susceptibility to infections with viruses and other pathogens 14, 28, 29, 30, 31. The in vivo study from Sinai et al. [32] showed that IM diminishes the recall response of specific CD8+ T cells to pathogen exposure and could therefore affect the ability of CD8+ T cells to function optimally against relapsed tumors or other infections. On the other hand, in the study from Bocchia et al. 33, 34 in 16 CML patients who received prolonged treatment (>12 months) with imatinib after immunization with weakly immunogenic p210-derived peptide antigens as immunologic adjuvants, imatinib did not seem to impair specific antileukemic T cell immunity. At the present time it has not been documented whether the immunosuppression caused by posttransplant IM could increase the relapse risk in CML patients. Moreover, there was a trend to lower relapse rates patients who received either pre- or posttransplant IM compared with those who did not (13% versus 35%; P = .2), respectively [35].

It remains important to evaluate whether posttransplant IM modifies the probability of acute or chronic graft-versus-host disease (aGVHD, cGVHD). A recent report suggested that IM inhibits (CD4+CD25+) regulatory T cells, therefore reducing peripheral immune tolerance [36]. However, Olavarria et al. [9] reported no case of de novo GVHD in a total of 30 patients with IM in the posttransplant period. Reactivation of aGVHD or cGVHD was observed in 3 patients, but probably without any association to TKIs. Other series either had no case of de novo GVHD or saw no exacerbation of already existing disease in stem cell recipients under IM 7, 8, 10, 11. In some cases, successful use of IM for refractory sclerodermous cGVHD has been reported [37]. To our knowledge, no studies so far compared the frequencies of aGVHD or cGVHD in the content of posttransplant IM. Concerning calcineurin inhibitor serum levels, these seem not be affected by IM as being demonstrated in 19 stem cell recipients under cyclosporine or tacrolimus regimens [10].

Second-Generation TKIs in the Posttransplant Period 

Resistance against IM is categorized in BCR-ABL-dependent or BCR-ABL-independent mechanisms. BCR-ABL-dependent mechanisms are thought to be the most common reason for the development of acquired IM resistance and are mostly associated to point mutations in the ABL kinase domain [38]. Mutations conferring IM resistance are associated with advanced disease, presence of cytogenetic clonal evolution, or failure to achieve a cytogenetic CR after 12 months of IM 39, 40. Whereas IM-resistance conferring mutations were described in <15% of patients in CP, they were found in 60% of patients in AP and 90% of those in BP within 3 years of therapy [41]. Therefore, patients who are selected for allo-SCT will frequently have a history of IM resistance. This emphasizes the need for alternative strategies for part of CML patients in the posttransplant period.

With respect to second-generation TKIs, the multikinase inhibitor dasatinib has been approved for the treatment of IM-resistant and -intolerant patients across all phases of CML and Phi+ ALL [42]. Dasatinib was shown to confer higher in vitro activity against native BCR-ABL and to be active against all IM-resistant BCR-ABL mutations with the exception of T315I [43]. Nilotinib was recently approved by the FDA for patients with CP or AP CML being resistant to or intolerant of IM or other prior therapy, and is also effective against all IM-resistant ABL kinase mutations except T315I [44]. Thus, there seems to be no adequate solution for patients with a T315I mutation. In this setting the development of new TKIs appears to be crucial [45].

So far, reports describing the role of second-generation TKIs as an early posttransplantation strategy are very limited. In an own series, 9 patients with advanced phases of CML received dasatinib in the posttransplant period [13]. Interruption of dasatinib was necessary in 1 case only (13%) because of thrombocytopenia-related gastrointestinal bleeding. Atallah et al. [12] analyzed outcomes in another 11 stem cell recipients with CML or Phi+ ALL, who received treatment with dasatinib and reported as well favorable tolerance of the compound in the posttransplant period. Although there were rather high rates of gastrointestinal (GI) bleeding (27%), pulmonary complications (18% of patients), or liver toxicity (being seen in 9%), side effects were well manageable in most cases by dose reduction or interruption of treatment.

Considering the efficacy of second-generation TKIs, the number of patients receiving these compounds in the posttransplant period is too limited for definite conclusions. Results have to be seen on the background of adverse risk profiles of patients being so far reported. Atallah et al. [12] achieved transient major molecular CR in 3 of 11 patients with chronic or advanced phase of CML or with Phi+ ALL. In an own series, stable response to posttransplant dasatinib was seen in 4 of 9 CML patients who all had a history of AP/BP or extramedullary disease [13].

In contrast to IM, which appears to be unable to penetrate the extramedullary tissue [46] or the central nervous system 47, 48, dasatinib may be useful for posttransplant extramedullary relapse of CML [49]. In the conservative treatment setting, response to dasatinib was reported in 79% of patients with CNS involvement and IM resistant Phi+ disorders [50].

In conclusion, first reports suggest that dasatinib can be administered with acceptable tolerance in the posttransplant period. Considering the limited amount of data, second-generation TKIs should be further evaluated for use in the posttransplant period in patients with a history of IM resistance/intolerance or advanced stages of CML.

Monitoring Strategies during Posttransplant TKI Treatment 

The use of diagnostic methods has not been standardized for the posttransplant period of CML in contrast to the monitoring of nontransplanted patients under IM treatment 51, 52, 53. With quantitative real-time PCR, a highly sensitive tool is available for the determination of the molecular response, and criteria for the definition of molecular and cytogenetic response to IM were internationally standardized 51, 52, 53, 54. Within the conservative therapy setting, karyotyping was suggested to be repeated at least every 6 months until cytogenetic CR has been achieved, then every 12 months. Quantitative PCR was proposed to be performed every 3 months, even after achievement of molecular negativity [53].

In contrast, it is still difficult to determine the meaning of positive results in the posttransplant period. Kaeda et al. [55] performed serial BCR-ABL measurement in 243 CML patients to define the meaning of low BCR-ABL transcript levels frequently being identified in the posttransplant period in patients with CML. The authors subdivided patients according to their posttransplant BCR-ABL expression status in the following categories: “persistently negative”; “fluctuating positive, low level” (>1 positive result but never >2 consecutive positive results); “persistently positive, low level” (persisting BCR-ABL/ABL transcripts ≤0.02%, but never ≥3 consecutive positive results), and “molecular relapse” (3 positive results with a BCR-ABL/ABL ratio ≥0.02% or 2 results >0.05% over ≥4 weeks). In this series, only patients who fulfilled the criteria of molecular relapse were likely to progress, whereas those who had fluctuating low BCR-ABL levels had no increased relapse risk [55].

Combination of TKIs with Adoptive Immunotherapy 

Since being first reported in 1990, DLIs were mainstay of treatment for relapsing CML 56, 57 as stable responses were achieved in 60%–70% of patients with recurrence of CP 57, 58, 59, 60, whereas durable CRs were less frequent in patients relapsing into AP/BP.

There are few reports regarding the combination of IM with DLI. In the study from Kantarjian et al. [7], DLIs were given to 13 of 28 patients with relapse of advanced CML. The median interval between DLI and IM was 4 months (range: 3-29 months). Although this regimen was well tolerated, there were no differences in CR rates compared to the cohort of 15 patients who received no DLI. DeAngelo et al. [8] administered DLI >12 months before start of posttransplant IM in 4 of 15 patients with different phases of CML. There were no signs of increased toxicity of this combined approach, and 2 patients achieved a transient cytogenetic CR. Most authors reported the use of DLI in IM-treated patients with intervals of 4 to 12 months from stop of posttransplant IM treatment 7, 8, 11.

Weisser et al. [61] compared use of IM and DLI in CML relapse. The majority of patients from the 2 groups were in cytogenetic relapse (n = 23), whereas 8 patients were in hematologic relapse. IM was administered at a dose of 400-800 mg/day depending on response. There was a significantly lower relapse rate (14% versus 60%) and improved disease-free survival (DFS) in the DLI compared to the IM group. Savani et al. [17] performed comparison of 3 groups of patients with hematologic or molecular relapse of CML, who received either IM, DLI, or a combination of both in concurrent or sequential regimens. DLIs were given in incremental doses from 1 × 107 to 10 × 107 CD3+ cells/kg every 3 months or faster in case of progression. The authors observed a beneficial effect of the DLI/IM combination compared to the use of either agent alone: with the combination, patients were able to stop IM without recurrence of molecular disease and had a superior overall (100%, 89%, and 54% for IM/DLI, IM, and DLI, respectively; P = .02) and DFS after treatment (100%, 54%, and 43% for IM/DLI, IM, and DLI; P = .03). It was also remarkable that molecular CR was sooner achieved in patients receiving the DLI/IM combination compared to DLI or IM alone (90%, 7.7%, and 11% at 3 months from start of treatment). Considering AP CML, all 4 patients achieved molecular remission and are currently disease free after follow-ups of 8-42 months.

There are abundant data indicating that IM can reduce the disease bulk in CML, but little evidence that leukemic progenitors are permanently eliminated, because disease recurrence typically follows withdrawal of IM. In contrast, DLI is believed to exert an immune-mediated GVL effect [62], which can permanently eliminate residual disease. The combination of DLI and IM is therefore logical: IM may reduce disease burden readily to levels below molecular detection, but alone it is incapable of preventing recurrence. However, further prospective studies are required to evaluate a benefit of such combination.

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Conclusions 

Although the number of studies and the number of investigated patients concerning the posttransplant use of TKIs are limited 7, 8, 9, 11, some conclusions can already be drawn.

The application of either first- or second-generation TKIs showed adequate efficacy and acceptable tolerance in patients with CML after allo-SCT 9, 12, 13. There seems to be a tendency for better outcome in case of cytogenetic and molecular relapses when compared to hematologic relapse [14]. Furthermore, use of these compounds as preventive strategy in either all or selected groups of patients in the posttransplant period seems feasible [10]. Such strategy could also contribute to an appropriate timing for DLI and other immunotherapeutic interventions [16].

The time point of start of TKI treatment does not seem to be very critical. Early administration of imatinib even within the first months after allo-SCT seems to be feasible [10]. Although in some studies IM dosages were higher than recommended for standard regimens, adverse event rates were not increased [7]. Moreover, posttransplant TKI treatment seemed to be feasible despite the different comedications, which are standard in the posttransplant period. Concerning the duration of posttransplant TKIs therapy, it is important to note, that long-term application (>1 year) should be more preferable when compared to short-term application (<1 year) [16]. It is not clear, whether life-long therapy duration would be associated with better outcomes.

However, it should be mentioned again that additional data will be needed to evaluate the efficacy and tolerance of posttransplant imatinib for patients with CML considering the limited number of studies and the limited follow-up period since the introduction of imatinib in prophylaxis and treatment of stem cell recipients with CML. Another important issue is the apparent immunomodulating potential of imatinib. However, the clinical impact of these immunomodulatory properties in the posttransplant periodremains unclear 24, 25, 36. As pretransplant strategy, IM was associated to a reduction of cGVHD rates. Whether the posttransplant application of IM has the same effect, is uncertain 63, 64.

Further, it has to be seen that many patients being selected for allo-SCT today have had a history of resistance to imatinib. Thus, the most appropriate strategies for these patients are still difficult to define. One option might be represented by a second generation of TKIs. However, at present times, there are no large studies, although existing data suggests that these compounds might represent a therapeutic alternative for patients with IM failure or extramedullary relapses 46, 47, 48, 49. Concerning patients with resistance to imatinib and second-generation TKIs, for example, because of the T315I mutation, novel TKIs should be explored for use in the posttransplant period. Small molecule inhibitors simultaneously targeting Aurora kinases and BCR-ABL kinases might represent a promising approach [65].

The combination of IM with DLI seems to be feasible and well tolerated, but whether this combination is more efficient than IM alone remains to be further clarified. Regarding the relapse rate, there is a tendency to decreased relapse incidence in case of using IM together with DLI 17, 61. Nevertheless, the question whether this approach is associated with improved survival rates when compared to IM alone remains open at this time, which applies as well to the best appropriate combination strategies of posttransplant TKIs and DLIs. Thus, a standardization of the posttransplant application of TKIs—regarding intervals from SCT, dosages, treatment duration, and the combination with DLIs—is urgently needed. Multicenter studies should focus on this aspect aiming to improve outcomes of the high risk patients with CML being selected for allo-SCT.

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Acknowledgments 

The authors would like to thank Adelbert Bacher (Technical University of Munich, Germany) for valuable contributions to the design of this review.

Financial disclosure: The authors have nothing to disclose.

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 Financial disclosure: See Acknowledgments on page 308.

PII: S1083-8791(09)00400-5

doi:10.1016/j.bbmt.2009.08.019

Biology of Blood and Marrow Transplantation
Volume 16, Issue 3 , Pages 301-310, March 2010

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