The first 2 authors contributed equally.
Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis
Version of Record online: 5 MAR 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 8, pages 1543–1549, 15 April 2007
How to Cite
Fruehauf, S., Topaly, J., Buss, E. C., Fischer, T., Ottmann, O. G., Emmerich, B., Müller, M. C., Schuld, P., Balleisen, L., Hehlmann, R., Ho, A. D. and Hochhaus, A. (2007), Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer, 109: 1543–1549. doi: 10.1002/cncr.22535
- Issue online: 4 APR 2007
- Version of Record online: 5 MAR 2007
- Manuscript Accepted: 18 DEC 2006
- Manuscript Revised: 13 DEC 2006
- Manuscript Received: 6 NOV 2006
- Suddeutsche Hamoblastosegesellschaft (SHG)
- Competence Network ‘Acute and chronic leukemais,’ sponsored by the German Bundesministerium fur Bildung und Forschung (Projekttrager Gesundheitsforschung: DLR e.V.-01 GI9980/6)
- European LeukemiaNet within the 6th Framework program of the European Commission
- myeloid blast crisis;
- allogeneic transplantation
Despite advances in drug therapy and allogeneic stem cell transplantation (allo-SCT), the prognosis of patients with chronic myeloid leukemia (CML) in blast crisis remains poor. Imatinib has demonstrated synergistic effects in vitro with mitoxantrone, etoposide, and cytarabine.
A Phase I/II trial was performed in patients with CML myeloid blast crisis. Patients were treated with imatinib + mitoxantrone/etoposide in four cohorts: mitoxantrone 10 mg/m2/day and etoposide 100 mg/m2/day for 2 or 3 consecutive days and imatinib 600 mg/day from Day 15 (cohorts 1 and 2) or from Day 1 (cohorts 3 and 4). After hematologic reconstitution after the cytopenic phase, cytarabine was given at a dose of 10 mg/m2/day in addition to imatinib as maintenance treatment.
A total of 16 patients were available for analysis, median age 59 years (range, 37–74). All patients who received more intensive induction treatment (cohorts 3 and 4, n = 7) achieved a hematologic response (HR). In contrast, HR was achieved in only 6 of 9 patients treated in cohorts 1 and 2. The induction treatment was well tolerated. Six patients who achieved HR received an allo-SCT with myeloablative conditioning. The median survival in the transplant group was 16.2 months vs 4.7 months in the group with conventional treatment only (P = .067).
The combination of mitoxantrone/etoposide and imatinib is well tolerated, with mild nonhematologic toxicity even in older patients. Eligible patients benefit from allo-SCT after response to the induction treatment. Cancer 2007. © 2007 American Cancer Society.
Blast crisis is the terminal phase of chronic myeloid leukemia (CML), a clonal neoplastic disorder of the hematopoietic stem cell. The hallmark of CML is the Philadelphia (Ph) chromosome, an abnormality of chromosome 22, that results from a reciprocal translocation t(9;22)(q34;q11) and leads to the expression of the BCR-ABL fusion protein with constitutively deregulated tyrosine kinase activity.
Blast crisis is traditionally defined as the presence of 30% or more blasts in peripheral blood or bone marrow or extramedullary infiltrates of leukemic cells (other than the spleen or liver). This definition is still commonly used in major clinical trials,1 although according to the latest WHO classification the blast count defining blast crisis is 20% or more.2 In the majority of cases the blasts are of myeloid or undifferentiated origin. In about one-third of cases the blasts originate from lymphoid lineages (predominantly B-cell lineage). In most patients blast crisis is preceded by a chronic phase and a transitional stage, termed accelerated phase.
There is no standard therapy for blast crisis. The median survival in lymphoid blast crisis after treatment with regimens for acute lymphoblastic leukemia ranges from 9 to 12 months.3 The outcome of myeloid blast crisis treated with cytarabine-based regimens for acute myeloid leukemia is reported to be even worse, with a median survival of 3 to 5 months.4 The only curative treatment option for myeloid blast crisis is allo-SCT. However, cures are rare, with less than 10% of patients achieving a durable remission. Pretransplantation induction therapy leading to a remission of blast crisis or return to chronic phase is associated with improved transplantation outcome.5
Imatinib is a rationally designed selective inhibitor of the BCR-ABL tyrosine kinase. In a Phase II trial monotherapy with imatinib induced a hematologic response (HR) in about 50% of patients with myeloid blast crisis and showed a favorable safety profile. The most common complications leading to discontinuation of treatment (about 5% of treated patients) are cytopenia, exanthemas, or gastrointestinal reactions.6
The combination of imatinib with mitoxantrone, etoposide, or cytarabine was shown to be additive to highly synergistic in BCR-ABL-positive leukemias in preclinical studies by several investigators, including our group.7, 8 A combination of chemotherapy with imatinib is expected to result in a better leukemia load reduction and may be a strategy to delay or offset clonal selection of resistant leukemia cells. We initiated a Phase I/II trial for patients with CML myeloid blast crisis to investigate the safety and efficacy of an imatinib-based combination treatment regimen. Patients who responded to induction treatment and who had a matched donor received an allo-SCT.
MATERIALS AND METHODS
Male and female patients at least 18 years of age were eligible for participation in this study if they had BCR-ABL-positive CML myeloid blast crisis and had given written informed consent to participate in the trial before study entry. The study was approved in all participating centers by local ethics committees and was performed in accordance with the Declaration of Helsinki. 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 cytometry9 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.10
The patients were required to be free of marked liver or kidney disease as indicated by levels of serum aspartate aminotransferase, alanine aminotransferase, and bilirubin not higher than 3 times the upper limit of normal, and serum creatinine levels not higher than twice the upper limit of normal. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower and were excluded from the trial if they had any serious concomitant medical condition. Prior treatment for blast phase of CML was allowed. Patient characteristics are given in Table 1.
|ID||Age/Sex||Treatment for CP/AP||Time to BC,* mo||Cytogenetics in blast crisis||HR||BCR-ABL mutations||Cohort||Time to allo-SCT,† mo||Survival,‡ mo||Cause of death|
|01-4||60M||IFN||46||46,XY, t(9;22)||Yes||No||1||No||50, alive|
|01-5||72F||HU, IFN||89||46,XX, t(9;22)||Yes||H396R, E459K||4||No||15||DOD|
|01-6||74M||Bu, HU||65||46,XY, t(9;22)||Yes||No||2||No||18||DOD|
|01-7||62F||HU, IFN, IM||31||47,XX,+8, t(9;22) , 47,idem,add(2),del(3) ,47,idem,add(2),del(3),der(4)add(4)  47,idem add(1),add(2),del(3) ||Yes||G250E, F359V||4||No||5||DOD|
|01-8||75M||HU||14||46,XY, t(9;22), ins(13;7)||Yes||No||4||No||2||Septicemia|
|01-9||43M||HU||1||47,XY,+8, t(9;22)||Yes||No||3||7||30, alive|
|01-10||37F||IM||4||46,XX, t(9;22)||Yes||Not done||4||7||16, alive|
|02-1||64M||Not known.||172||45,XY,der(2)t(2;7),der(5)t(5;17), der(7)t(2;7),t(9;22),der(9)t(2;9),-1747,idem,+8,+8 ||No||No||1||No||2||DOD|
|02-2||60M||Not known.||9||not available||Yes||No||1||4||16||GVHD|
|03-1||42M||IFN, Ara-C||9||46,XY,t(9;22;15;13) 48,XY,idem,+21,+Ph ||Yes||No||1||2||4||DOD|
|03-2||59F||HU, IFN||63||46,XX,t(4;9;22) 45,XX,der(4)t(4;9;22),-9,add(22) ||Yes||Y253H, E255V||1||No||7||DOD|
|03-3||55F||IFN, ASCT||110||43-48,XX,der(3),+der(3),-6,del(8), t(9;22),-10,add(12),-16,-17,+Ph,+3m(D,E,F)||No||Not done||1||No||1||DOD|
|03-4||46F||IFN+HU||114||46,XX,t(2;8),t(9;22),der(14) 48,idem,+8,+Ph 46,XX ||No||Not done||1||No||0||DOD|
|04-2||54F||No treatment||1||Not available||Yes||Not done||4||3||31, alive|
|06-1||65F||Not known||22||Not available||Yes||No||1||No||5||Hemorrhage|
|07-1||53M||Not known||13||Not available||Yes||No||3||2||16||Septicemia|
Patients were treated in four cohorts: cohort 1, mitoxantrone and etoposide on Days 1-2, imatinib from Day 15; cohort 2, mitoxantrone and etoposide on Days 1-3, imatinib from Day 15; cohort 3, mitoxantrone and etoposide on Days 1-2, imatinib from Day 1; cohort 4, mitoxantrone and etoposide on Days 1-3, imatinib from Day 1.
Drug dosages were mitoxantrone 10 mg/m2 intravenous daily, etoposide 100 mg/m2 intravenous daily, and imatinib 600 mg orally daily. After recovery of neutrophil (absolute neutrophil count [ANC] >1.5 × 109/L) and platelet counts (>100 × 109/L) and achievement of a hematologic remission a maintenance treatment with cytarabine 10 mg/m2 subcutaneously daily was initiated. Imatinib was administered continuously and throughout the cytopenic phase.
Patients were evaluated for hematologic and cytogenetic response and recurrence at specified intervals. Peripheral blood samples were obtained and analyzed at baseline, at least 3 times a week in the first 3 weeks, then at least weekly for the next 3 months and every 4 weeks thereafter.
Bone marrow aspirates for morphologic and cytogenetic evaluation were done at screening and after hematologic recovery or in case of prolonged cytopenia on Day 28. Consecutive aspirates were done at weeks 8 and 12 and every 3 months thereafter.
Hematologic and nonhematologic toxicities were assessed according to National Cancer Institute (NCI), National Institutes of Health (NIH) common toxicity criteria (CTC). The duration of grade 3–4 cytopenia, the number of transfused red cell and platelet concentrates, neutropenic fever, and the duration of intravenous antibiotic and antifungal treatment were documented.
Complete HR was defined as normalization of peripheral blood counts and differentials (ANC >1.0 × 109/L, white blood cell [WBC] of 2.0 to 10.0 × 109/L, and platelet counts of >100 × 109/L) with ≤5% blasts in bone marrow smears for at least 4 weeks, no palpable splenomegaly, with no evidence of extramedullar involvement.
Cytogenetic response was based on the prevalence of Ph-positive metaphases among at least 20 metaphases investigated in each bone marrow sample and was defined as complete (0% Ph-positive metaphases), partial (1%–35%), minor (36%-65%), minimal (66%–95%), or none (>95%).11
Quantitative real-time polymerase chain reaction (RQ-PCR) for BCR-ABL mRNA transcripts was performed in 9 of 16 patients. Real-time PCR was carried out using the LightCycler technology (Roche Diagnostics, Mannheim, Germany) as described.12 The numbers of total ABL transcripts were determined as internal standards in all samples in order to adjust for different qualities of RNA and cDNA and to exclude negative results derived from samples of poor quality. The final results were calculated as the ratios BCR-ABL/ABL and expressed as percentages.
Overall survival was calculated from the time of the start of the study treatment to the date of death. Survival was censored at the last recorded contact or evaluation for patients alive at the time of analysis.
The study was designed to investigate the safety of the combination treatment regimen in an intensity-escalation setting. Safety results are reported for all enrolled patients who received the study medication. Duration of severe leukopenia (WBC <1 × 109/L), antibiotic treatment, and the number of transfused packed red cells and platelet concentrates were used as primary endpoints for toxicity. The differences in toxicity profiles depending on treatment group were assessed for statistical significance using a Studentt-test.
In a second step the efficacy of the study treatment was assessed. Survival was computed using standard Kaplan-Meier methods with SPSS software v. 13 (Munich, Germany). The association of treatment modalities with survival was assessed using the log-rank test. P ≤ .05 was considered statistically significant.
Patients and Treatment
Eighteen patients were included in the study. For 1 patient no follow-up data are available. The diagnosis of myeloid blast crisis of another patient was later revised as lymphatic blast crisis and this patient was therefore excluded from further analysis. Data from 16 patients could be evaluated, 8 men and 8 women. Eight patients were treated in cohort 1, 1 patient in cohort 2, 2 patients in cohort 3, and 5 patients in cohort 4. The overall median age was 60 years (range, 37–75). At diagnosis of blast crisis the median age of the patients treated in cohorts 1 and 2 (n = 9) was close to the median age of the patients in cohorts 3 and 4 (n = 7): 60 years (range, 43–75) vs 60 years (range, 37–75).
The median time from diagnosis of CML to inclusion into the study was 5 months (range, 1–23.6 months). Five patients had received prior treatment for blast crisis, consisting of cytarabine-based chemotherapy. One patient was previously treated with imatinib for chronic phase disease.
Six patients (2 patients in each of cohorts 1, 3, and 4) received allo-SCT after achieving HR with or without platelet recovery >100 × 109/L, at a median of study treatment duration of 111.5 days (range, 64–214). The median age of the patients who received allo-SCT was 48.4 years (range, 37–54), the median age of the remaining patients was 62 years (range, 46–75), P = .02.
The induction treatment with mitoxantrone and etoposide in combination with imatinib was well tolerated by most patients. During the cytopenic phase the patients required a median of 5 (range, 2–18) red blood cell concentrates, a median of 3.5 (range, 1–8) platelet concentrates, and therapeutic antibiotic treatment for a median of 10 (range, 0–38) days. Of note, CTC grade 3 or 4 mucositis did not occur. Patients who received imatinib on Day 1 (cohorts 3 and 4) had a significantly longer duration of severe leukopenia (WBC <1/nL): median of 19 days (range, 0–23) vs 2 days (range, 0–14), P = .015. Interestingly, neutropenic fever and the duration of antibiotic treatment were not increased in cohorts 3 and 4. Two treatment-related deaths occurred, 1 due to severe pneumonia (cohort 4) and another due to an intracranial hemorrhage during the cytopenic phase (cohort 1). The treatment-related mortality (TRM) rate of 12.5% (2 of 16 patients) observed in this study is similar to TRM rates observed with intensive chemotherapy alone reported by others.4
The median overall survival was 6.4 months (Fig. 1), which is similar to the results reported for imatinib alone in myeloid blast crisis.1 HR with normalization of WBC count and differentials and reduction of bone marrow blasts to <5%, was observed in 6 of 9 patients (67%) in cohorts 1 and 2 and in 7 of 7 (100%) patients in cohorts 3 and 4, indicating a higher efficacy of the more intensive treatment regimen. Two of 9 patients in cohorts 1 and 2 and 4 of 7 patients in cohorts 3 and 4 could be allogeneically transplanted later.
Out of 10 patients who received no allo-SCT, 1 is still alive and in a complete cytogenetic remission 48.5 months after study entry (cohort 1). In this patient a molecular remission was achieved after 3 months of study treatment and was sustained until the timepoint of the most recent PCR examination at low levels of residual disease (Month 45, ratio BCR-ABL/ABL 0.0062%). The treatment-related causes of death in 2 patients were mentioned above. Seven patients died of progressive disease: 4 patients in cohort 1, 1 patient each in cohorts 2, 3, and 4. A comparison of the overall survival of patients in the different treatment intensity cohorts who did not receive an allo-SCT did not reveal an overall survival advantage in cohorts 3 and 4 despite a better initial response: median survival 4.7 months (range, 2–14) in cohorts 3 and 4 and 4.7 months (range, 0–50) in cohorts 1 and 2.
Three of the 6 transplanted patients are still alive and in complete cytogenetic remission at 16, 30, and 31 months after study entry (9, 23, and 28 months after allo-SCT, respectively). The 6 transplanted patients were distributed equally in cohorts 1, 3, and 4. Two patients who were in complete molecular remission died because of transplant-related complications (infection and graft-vs-host disease [GVHD], 11 and 12 months after allo-SCT, respectively). One patient who never achieved a molecular response succumbed to recurrence 1.5 months after transplantation. Of the 3 patients still alive, 2 patients were treated in cohort 4 and 1 in cohort 3.
For 2 of 3 patients still alive the molecular response data are available. They achieved a complete molecular response that was sustained at Months 24 and 27 (timepoint of the most recent PCR examination).
The median survival of the transplanted patients was 15.7 months (range, 4–31) as compared with 4.7 months (range, 0–49) in the group that received conventional treatment alone, P = .067 (log-rank test; Fig. 2).
The combination of mitoxantrone/etoposide and imatinib is well tolerated even in older patients with generally mild nonhematologic toxicity. The hematologic toxicity was difficult to assess because of different levels of pretreatment myelosuppression. More aggressive treatment (cohorts 3 and 4) was associated with longer duration of cytopenia. Interestingly, no increase in infectious complications could be observed. Of the 16 evaluable patients, 2 (12.5%) died because of myelosuppression-associated complications after the induction treatment, which is comparable with induction mortality rates reported in the literature for patients with myeloid blast crisis treated with chemotherapy alone.1, 4 All patients who received the more intensive induction treatment (cohorts 3 and 4, n = 7) achieved an HR. In contrast, HR was achieved in only 6 of 9 patients treated in cohorts 1 and 2. Aggressive combination induction treatment is important to achieve effective reduction of the malignant clone and to assure a better outcome after allo-SCT. Three of 6 (50%) transplanted patients are still in complete cytogenetic remission about 16 to 31 months after initiation of study treatment (9 to 28 months after transplantation) and have a sustained complete molecular response. In our trial, patients who received more aggressive treatment including allo-SCT had a longer survival.
Our trial was initiated several years ago when imatinib did not have approval for general clinical use; therefore, the majority of patients who entered our trial were imatinib-naive. However, 2 patients had documented prior imatinib treatment for CML chronic or accelerated phase. Both of these patients responded to the imatinib-based combination treatment. However, 1 patient experienced recurrence and died 5 months later of disease progression in spite of second-line chemotherapy. Another patient remained in remission and received an allogeneic transplant 7 months after entering the study. This patient is still alive. Because most patients nowadays receive imatinib treatment for chronic phase, the response to imatinib-based combination treatment in blast crisis may differ from the response rates observed in our study. In cases of partial resistance to imatinib, combination treatment including imatinib is feasible because synergistic effects take place.13, 14 In our opinion, the data presented here support the recommendation for imatinib-based induction treatment in patients diagnosed with CML in myeloid blast crisis.
Because mutations of the BCR-ABL tyrosine kinase domain are a common cause for imatinib resistance and disease progression, induction treatment of blast crisis based on combinations with newer, more potent tyrosine kinase inhibitors such as nilotinib,15 dasatinib,16 and others17 is warranted.
New concepts are also needed for initially responding patients without a suitable donor. Here a consolidation with myeloablative high-dose chemotherapy followed by autologous stem cell transplantation is a feasible approach. Clinical trials are needed to evaluate this concept.
We thank the medical staff at the participating centers and Elke Brants, Heidelberg, for assistance in collecting the data. We thank Marlies Stutzle-Schnetz, Heidelberg, for help in preparation of the article and Dr. Heather G. Jorgensen, Glasgow, for reading the article and for valuable advice.
- 2JaffeES, HarrisNL, SteinH, VardimanJW (eds.). World Health Organization classification of tumors. Pathology and genetics of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001.
- 5Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation. Bone Marrow Transplant. 1993; 2: 509–516., , , et al.
- 9Combination of imatinib and established antileukemic treatment modalities for otherwise refractory BCR-ABL positive lymphoblastic leukemia. Haematologica. 2002; 7: ECR38., , , et al.
- 11Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Philadelphia chromosome-positive patients. Ann Intern Med. 1991; 14: 532– 538., , , ,
- 14Combination treatment of imatinib-sensitive and -resistant BCR-ABL-positive CML cells with imatinib and farnesyltransferase inhibitors. Anticancer Res. 2006; 6: 2169–2177., , ,