Annals of Hematology

, Volume 89, Issue 11, pp 1099–1105

Standard-dose imatinib plus low-dose homoharringtonine and granulocyte colony-stimulating factor is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis who have failed prior single-agent therapy with imatinib

Authors

  • Baijun Fang
    • Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital, Zhengzhou Medical SchoolZhengzhou University
  • Ning Li
    • Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital, Zhengzhou Medical SchoolZhengzhou University
    • Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital, Zhengzhou Medical SchoolZhengzhou University
  • Qin Han
    • Institute of Haematology and Blood Diseases Hospital, Center of Excellence in Tissue EngineeringChinese Academy of Medical Sciences and Peking Union Medical College
  • Robert Chunhua Zhao
    • Institute of Haematology and Blood Diseases Hospital, Center of Excellence in Tissue EngineeringChinese Academy of Medical Sciences and Peking Union Medical College
Original Article

DOI: 10.1007/s00277-010-0991-4

Cite this article as:
Fang, B., Li, N., Song, Y. et al. Ann Hematol (2010) 89: 1099. doi:10.1007/s00277-010-0991-4
  • 140 Views

Abstract

We investigated the efficacy of the induction therapy involving granulocyte colony-stimulating factor (G-CSF) and low-dose homoharringtonine as well as standard-dose imatinib, which we called the G-CSF + homoharringtonine + imatinib (GHI) regimen, in patients with chronic myelogenous leukemia (CML) in blast crisis who have failed prior single-agent therapy with imatinib. Twelve patients were enrolled. The GHI regimen consisted in a unique induction course where imatinib was administered at 400 mg day−1 until remission, together with homoharringtonine (1 mg/m2 s.c. twice daily for 14 days every 28 days), and G-CSF, which was administered 1 day before chemotherapy (5 µg/kg s.c. daily). Patients who failed to obtain at least a partial hematologic response (PHR) after three courses were taken off study. Patients who responded to induction treatment and who had a matched donor received allogeneic hematopoietic stem cell transplantation (allo-HSCT). The results demonstrates that the GHI regimen re-induce hematologic responses or improve the cytogenetic responses in all evaluable patients. Furthermore, eligible patients have benefited from allo-HSCT after response to this induction treatment. We conclude that the GHI regimen may overcome disease-poor response to conventional doses of imatinib and this approach deserves further evaluation as frontline therapy for newly diagnosed CML.

Keywords

Chronic myelogenous leukemiaBlast crisisGranulocyte colony-stimulating factorHomoharringtonineImatinibResistant

Introduction

There is no standard therapy for blast crisis of chronic myeloid leukemia (CML). The median survival in myeloid blast crisis after treatment with regimens for acute myeloid leukemia ranges from 3 to 5 months [1]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the first-line approach for patients with CML in blast crisis. Since the outcome of allo-HSCT is better in patients in the first chronic phase or in blast crisis who are first returned to the chronic phase of CML than in patients who undergo transplantation during blast crisis [2], the reduction in the proportion of blasts in the marrow of patients with blast crisis suggests that imatinib (Glivec or Gleevec, Novartis Pharmaceuticals, Basel, Switzerland) may be a useful bridge to transplantation [3]. However, resistance to imatinib is increasingly recognized as a clinical problem, particularly in blast crisis, where it is nearly universal.

ABL kinase domain mutations have been reported in 30-50% of patients with CML who fail single-agent imatinib therapy [4, 5]. Although in some cases, the expansion of some mutant clones may simply be due to selective imatinib pressure and therefore may not have clinical significance, some ABL kinase mutations have been associated with tyrosine kinase inhibitor resistance and aggressive clinical behavior. In the latter setting, the use of agents whose mechanism of action is independent of the configuration of the ABL kinase such as homoharringtonine (HHT) is particularly appealing [6]. Moreover, a phase I/II trial has shown that HHT and imatinib have synergistic in vivo; the addition of HHT should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease [7].

Primitive quiescent CML cells are biologically resistant to imatinib [8], and the study has suggested that granulocyte colony-stimulating factor (G-CSF) in combination with imatinib may offer a novel strategy for improving responses in patients with CML by enhancing the elimination of imatinib-resistant CML stem cells [9].

In addition, the combination chemotherapy with low-dose cytarabine, HHT, and G-CSF priming has been suggested to be effective in remission induction for refractory and relapsed AML patients and well tolerated in maintenance therapy [10].

Inspired by the aforementioned observations, we developed another new therapy for patients with CML in myeloid blast crisis who have failed prior single-agent therapy with imatinib. This therapy combines G-CSF priming and low-dose HHT as well as standard-dose imatinib, which we called the GHI regimen.

Patients and methods

Patients

A total of 12 patients were registered in this study between April 2005 and February 2008 (Table 1). The study was approved by the Institutional Review Board at all participating institutions, and all patients signed an informed consent according to institutional guidelines. Patients entered into the study were required to have a diagnosis of Philadelphia chromosome (Ph)-positive CML in myeloid blast crisis and to have evidence of resistance to imatinib (400 or 600 mg day−1). CML blast crisis was defined as at least 30% blasts in the bone marrow or peripheral blood or extramedullary blast infiltration. The presence of a myeloid phenotype had to be confirmed by flow cytometry [11] and cytochemistry required positivity for standard myeloid markers and myeloperoxidase. To differentiate myeloid blast crisis from biphenotypic leukemia or lymphoid blast crisis, the European Group for the Immunological Characterization of Leukemia scoring system was used [12]. Resistance to imatinib was defined by appearance of blastic phase features while on imatinib therapy. Other eligibility criteria included age ≥18 years, bilirubin <1.5× upper limit of normal value, serum creatinine <2.0 mg/dl, aspartate aminotransferase <3.0× upper limit of normal value, left ventricular ejection fraction >40%, and pulmonary function forced expiratory volume at 1 s >50% is predicted. Pregnancy and active infection were exclusion criteria.
Table 1

Patients’ characteristics

Patient

Age (sex)

Peripheral blasts + promyelocytes (%)

Marrow blasts + promyelocytes (%)

% Ph at the onset of the GHI regimen

Cytogenetics at the onset of the GHI regimen

BCR-ABL mutations

The best response to imatinib preceding the GHI regimen

1

33 (F)

41

59

100

Ph

No

CHR + PCR

2

18 (M)

53

70

100

inv (3) (q21; q26)

No

CHR + CCR

3

28 (F)

71

65

100

+8,+Ph

M244V

PHR + MCR

4

34 (M)

39

54

100

+Ph

No

CHR + PCR

5

36 (F)

47

61

100

+8, +Ph

No

CHR + PCR

6

44 (M)

49

64

100

+8,+Ph

No

CHR + PCR

7

51(M)

57

72

100

+Ph

No

CHR + PCR

8

48 (M)

52

73

100

+8, +Ph

No

CHR + PCR

9

30 (M)

48

60

100

+Ph

M244V

PHR + MCR

10

31 (F)

47

58

100

Ph

No

PHR + PCR

11

19 (M)

58

64

100

inv (3) (q21; q26)

No

PHR + PCR

12

23 (M)

39

57

100

Ph

No

PHR + MCR

M male, F female, CHR complete hematologic response, PCR partial cytogenetic responses, CCR complete cytogenetic responses, PHR partial hematologic response, MCR minor cytogenetic response, Ph Philadelphia chromosome

Treatment schedule

The GHI regimen consisted in a unique induction course where imatinib was administered at 400 mg day−1 (imatinib treatment was interrupted or reduced from 400 to 300 mg day−1 in case of grade 3–4 nonhematological toxicity according to National Cancer Institute/National Institutes of Health Common Toxicity Criteria) until remission, together with HHT (Xichuan Pharmaceuticals, Nanyang, China; 1 mg/m2 s.c. twice daily for 14 days every 28 days), and G-CSF (Filgrastim; Amgen, Thousand Oaks, CA, USA), which was administered 1 day before chemotherapy (5 µg/kg s.c. daily). The administration of G-CSF was postponed or interrupted in the event of leukocytosis (leukocytes ≥ 30 × 109/l) until the white cell count fell <20 × 109/l. Patients who failed to obtain at least a partial hematologic response (PHR) after three courses were taken off study. Those who obtained at least a PHR but developed grade III or IV nonhematologic toxicity continued to receive HHT s.c. for 10 days every 28 days. The use of hydroxyurea and anagrelide was temporarily allowed for patients with leukocytosis ≥ 30 × 109/l or thrombocytosis ≥ 700 × 109/l. The management of tumor lysis syndrome was performed under the guidelines of each participating center. Patients who responded to induction treatment and who had a matched donor received an allo-HSCT.

Evaluation

Response criteria were as previously described [13]. A complete hematologic response (CHR) required disappearance of all signs and symptoms related to disease, normalization of peripheral counts (absolute neutrophil count ≥1.0 × 109/l, platelet count ≥100 × 109/l), and a normal bone marrow morphology with ≤ 5% marrow blasts. A PHR was similar to CHR except for persistence of peripheral immature cells or persistence but more than 50% improvement in splenomegaly or leukocytosis. Cytogenetic responses were defined as follows: complete, 0% Ph-positive metaphases; partial, 1-35% Ph-positive metaphases; minor, 36-90% Ph-positive metaphases. A major cytogenetic response included complete and partial cytogenetic responses.

Results

Patient characteristics

The clinical characteristics of patients entered into our study are summarized in Table 1. The median age of the patients was 32 years (range, 18–51 years) and the median time from the diagnosis of CML to therapy with the GHI regimen was 3.5 years (range, 1.8–5.4 years). The median duration of therapy with imatinib was 1.5 years (range, 0.9–2.6 years). In addition to imatinib, all patients had received prior therapy with interferon-α and cytosine arabinoside. Seven patients had received additional therapies including homoharringtonin (patients 3 and 9), all-trans retinoic acid (patients 2, 3, 4, and 9), and mitoxantrone (patients 1, 7, and 12). All patients had failed therapy with imatinib. Among the patients who had failed therapy with imatinib, the best response to imatinib was a complete cytogenetic response (CCR) in one patient (patient 2), a partial cytogenetic response (PCR) in eight patient (patients 1, 4, 5, 6, 7, 8, 10, and 11), minor cytogenetic response (MCR) in three patients (patients 3, 9, and 12), and a CHR in seven patients (patients 1, 2, 4, 5, 6, 7, and 8). Before the initiation of the GHI regimen, patients had been taken off imatinib for a median of 14 days (range, 6–29 days). At the time of the new induction therapy with the GHI regimen, all the patients were in blastic phase of CML. Nine patients had clonal evolution at the start of therapy with the GHI regimen: three (patients 4, 7, and 9) double Ph, four (patients 3, 5, 6, and 8) double Ph and +8, and two (patients 2 and 11) inv (3) (q21; q26). Two patients (patients 3 and 9) had the same BCR-ABL kinase domain mutation (M244V), which has been associated with resistance to imatinib [4, 14].

Response

One patient (patient 1) was not assessable because of early death during the first course of induction. Table 2 shows the features of the 11 evaluable patients’ responses to the GHI regimen.
Table 2

Response to the GHI regimen following resistance to standard-dose imatinib

Patient

Hematologic response

Cytogenic response

Number of cycles to get optimal response

Time to HSCT (days)

HSCT

Survival after HSCT (months)

Cause of death

CHR

PHR

CCR

PCR

1a

NA

NA

NA

NA

     

2b

+

+

3

    

3

+

 

+

 

2

43

Allo/MUD

Alive (25)

 

4

+

 

+

2

28

Allo/MUD

Alive (21)

 

5

+

 

+

2

38

Allo/MUD

Alive (13)

 

6

+

 

+

3

30

Allo/MUD

Alive (12)

 

7

+

 

+

 

2

10

nAllo/G

Alive (5)

 

8

+

+

3

12

nAllo/G

Death (2)

GVHD

9

+

 

+

3

36

Allo/MUD

Alive (13)

 

10b

+

+

3

    

11c

+

 

+

 

2

    

12

+

+

3

15

nAllo/G

Death (3.8)

Infection

CHR complete hematologic response, PHR partial hematologic response, CCR complete cytogenetic response, PCR partial cytogenetic response, NA not assessable, HSCT hematopoietic stem cell transplantation, Allo myeloablative allogenic HSCT, MUD matched unrelated donor, nAllo non myeloablative allogenic HSCT, G genoidentical, GVHD graft-versus-host disease

aThis patient was not assessable because of early death during the first course of induction

bThese patients gave up therapy and died of disease about 1-3 months later

cThis patient in CCR after induction with the GHI regimen received conventional chemotherapy and died five months later because of relapse

After two to three courses of GHI regimen, 11 patients improved peripheral blood (PB) blast counts, with a reduction greater than 50% in seven (patients 3, 4, 5, 6, 7, 9, and 11) of them, and these seven patients maintained their WBC counts within a normal range. Five patients (patients 3, 4, 5, 7, and 11) improved PB basophil counts, four (patients 3, 4, 7, and 11) of them achieving reductions greater than 50%. Also, in three (patients 3, 7, and 11) of these five patients, blasts disappeared from the PB.

Among eight evaluable patients who had lost their CCR (n = 1) or PCR (n = 7), eight (100%) achieved a major cytogenetic response (complete, three; partial, five). Among three evaluable patients who had lost of a MCR, one achieved a CCR and two a PCR. Among six evaluable patients who had lost their CHR, four (66.7%) achieved a CHR again, and all of them had a major cytogenetic response (complete, one; partial, five). Among five evaluable patients who had lost their PHR, five (100%) achieved a hematologic response (complete, three; partial, two), and all of them had a major cytogenetic response (complete, two; partial, three).

Thus, among 11 evaluable patients treated for CML in myeloid blast crisis not responding to standard-dose imatinib, seven (64%) of the 11 evaluable patients achieved a CHR and four (36%) got a PHR, for an overall hematologic response rate of 100%. Complete cytogenetic responses were observed in three patients (27%), and partial cytogenetic responses were seen in eight patients (73%) for an overall major cytogenetic response rate of 100%.

Two patients (patients 3 and 9) with BCR-ABL mutation (M244V) who had lost their MCR got a major cytogenetic response (complete, one; partial, one) on the GHI regimen, and the mutation disappeared; while the clonal evolution (double Ph) in patient 9 before study entry was still detectable. Patient 3 achieved CCR on the GHI regimen; her marrow metaphases contained neither Ph chromosome nor trisomy 8. Patients 7 and 11 achieved CCR; the originally present clonal evolution [double Ph or inv (3) (q21; q26)] before study entry was undetectable. In addition, the clonal evolution (trisomy 8) in patient 5 at the start of therapy with the GHI regimen disappeared after she achieved CHR. In the other patients (patients 2, 4, 6, and 8), the originally present clonal evolution before study entry was still detectable on the GHI regimen.

After induction with the GHI regimen, eight patients in CHR or PHR received allo-HSCT (Table 2). The median interval was 29 days (10–43 days) post-CHR or PHR. After a median follow-up of 12 months (2–25 months), 75% (6/8) of patients remain alive including five (patients 3, 4, 5, 6, and 7) with persistent CHR and one (patient 9) that have lost a status of CHR. One patient (patient 8) died on day +62 after allo-HSCT because of graft-versus-host disease. Another patient (patient 12) died of an invasive fungal infection at day 114 after allo-HSCT. One patient (patient 11) in CHR chose conventional chemotherapy and died 5 months later because of relapse; two patients (patients 2 and 10) gave up therapy and died about 1-3 months later after stopping treatment with the GHI regimen.

Toxicity

The most frequent grade 1-2 nonhematologic toxicities experienced in the study were nausea (n = 6), fatigue (n = 8), hypokalemia (n = 3), edema (n = 3), and diarrhea (n = 2). In the majority of cases, these side effects were mild and did not prevent the administration of homoharringtonin. Grade 3-4 nonhematologic side effects consisted of myalgias (n = 1) and fatigue (n = 2). All patients had reactions at the site of injection (grade I), which needed 3-7 days to resolve. Grade 3-4 anemia, neutropenia, and thrombocytopenia were recorded in eight, two, and four patients, respectively. No bleeding episodes occurred. Two patients were hospitalized for neutropenic fever. No patient discontinued therapy because of toxicity and there were no treatment-related deaths.

Discussion

Overcoming resistance to imatinib mesylate therapy in CML can be achieved through strategies. The first approach used to overcome resistance to imatinib was to increase the dose of imatinib [1517]. More recently, Cortes and his colleagues’ data suggest that imatinib dose escalation is well tolerated and may be effective in overcoming resistance to standard-dose imatinib, inducing long-lasting cytogenetic responses in some patients with imatinib resistance, particularly those with cytogenetic relapse and less disease burden. In addition, more potent tyrosine kinase inhibitors such as nilotinib, dasatinib, and bosutinib have shown to be effective in this setting. But these strategies are not practical just because most CML patients in China cannot afford it.

HHT is an ester of the alkaloid cephalotaxine isolated from the Cephalotaxus species, an evergreen tree ubiquitous to China, which induces responses alone or in combination in various phases of CML. O'Brien et al. [18] reported cytogenetic responses in 31% of 71 patients with CML in late chronic phase treated with HHT as a constant intravenous infusion at an initial dose of 2.5 mg/m2 day−1 for 14 consecutive days. The same research group also reported cytogenetic responses in 66% of 47 patients in chronic phase using HHT at a dose of 2.5 mg/m2 day−1 by constant infusion over 5 days in combination with interferon-alpha (intended dose 5 MU/m2 day−1) [19].

With the introduction of imatinib the focus for HHT development has shifted to investigate its potential to overcome resistance to imatinib. Recently, HHT has been shown to have a synergistic or additive effect with imatinib in vitro against imatinib-resistant cell lines and against cells from patients with CML in blastic phase [20, 21]. In addition, clinical studies have shown that subcutaneous HHT is well tolerated and have clinical activity in patients with CML after imatinib failure [6].

CML is a clonal disease of hemopoietic stem cell origin. Imatinib induces rapid hematologic and complete cytogenetic response in most chronic phase CML patients but rarely eradicates the BCR-ABL+ clone [22, 23]. The persistence in most imatinib-treated patients of a small but molecularly detectable population of leukemic cells is of concern as they represent a potential reservoir from which mutant imatinib-resistant CML cells may emerge [24]. Moreover, it is likely that the imatinib treatment of patients is less effective on the most primitive, quiescent leukemic cells that display stem cell properties in immunodeficient mice. This inference is based on in vitro studies showing the quiescent CD34+ CML cells are relatively resistant to imatinib at concentrations at least double those achievable in vivo [8]. In vitro studies have further shown that imatinib exerts an antiproliferative effect on these primitive quiescent CML cells that reduces their rate of elimination [8, 25]. In addition, several recent case reports indicate that even patients who have achieved a molecular remission on imatinib may relapse rapidly after imatinib is discontinued but remain responsive to retreatment with imatinib, consistent with a more resistant leukemic stem cell compartment [26, 27].

Previous in vitro studies have shown that intermittent exposure to G-CSF can enhance the effect of imatinib on CML cells by specifically targeting the primitive quiescent leukemic elements [9]. In addition, G-CSF has been safely and successfully used for peripheral blood stem cell mobilization in healthy donors and in CML patients treated with imatinib with no significant increase in BCR-ABL transcript levels by quantitative reverse transcription-PCR [28, 29]. G-CSF is currently being used in patients with CML to overcome imatinib-induced neutropenia as myelosuppression [30, 31]. In this setting, it has been postulated that the improved cytogenetic responses observed result from an increased exposure to imatinib [32, 33]. However, another effect of pharmacologic doses of G-CSF given to CML patients might be to stimulate the entry of their quiescent CML stem cells into cycle and, hence, increase the sensitivity of these cells to imatinib [9, 34, 35].

The present analysis demonstrates that the GHI regimen re-induce hematologic responses or improve the cytogenetic responses in all evaluable patients with CML in blast crisis who have failed prior single-agent therapy with standard-doses imatinib. Furthermore, eligible patients have benefited from allo-HSCT after response to this induction treatment. However, the mechanism of resistance to standard dose was not evaluated in this study. This could be an important factor in determining which patients might respond to the GHI regimen, and this should be addressed in future studies.

In our opinion, a consolidation with the GHI regimen followed by allo-HSCT may be a feasible approach for patients with chronic myeloid leukemia in myeloid blast crisis who have failed prior single-agent therapy with imatinib. Clinical trials are needed to evaluate this concept.

Acknowledgments

The authors would like to thank all patients for their cooperation.

Copyright information

© Springer-Verlag 2010