- Email: [email protected]
Prognostic Factors, Response to Treatment, and Survival in Patients With Chronic Myeloid Leukemia in Blast Phase: A Single-Institution Survey
Original Study
Prognostic Factors, Response to Treatment, and Survival in Patients With Chronic Myeloid Leukemia in Blast Phase: A Single-Institution Survey Fernando Pérez-Jacobo, Elena Tuna-Aguilar, Roberta Demichelis-Gómez, Erick Crespo-Solís, Ubaldo Valencia-Rocha, Álvaro Aguayo, Xavier López-Karpovitch Abstract We retrospectively analyzed data from 51 patients with chronic myeloid leukemia in blast phase (BP) at a single institution. Disease characteristics and prognostic factors are described. Lymphoid BP and use of tyrosine kinase inhibitors were independent prognostic factors for response. Age, hemoglobin level, and chromosomal aberrations were identified as prognostic factors for overall survival. Introduction: Data from 51 patients (23 women) with chronic myeloid leukemia (CML) in blast phase (BP) were analyzed in order to identify prognostic factors for complete hematologic response (CHR) and survival. Patients and Methods: Forty-four patients experienced disease progression from chronic or accelerated phase, and 7 cases presented as CML-BP. Thirteen patients (25.5%) had extramedullary involvement at diagnosis, and 71% were myeloid BP. Clonal evolution was identified in 53% of the cases, and the abnormalities most frequently observed were isochromosome (17q), double Philadelphia chromosome, and trisomy 8. Forty-five patients received treatment: 60% chemotherapy (CT) alone and 40% CT plus tyrosine kinase inhibitors (TKI) or TKI alone; 42% of them experienced CHR. Results: Median overall survival (OS) in patients whose disease responded to treatment was 7 months (95% confidence interval, 1.7-6.2 months), with a median disease-free survival of 5 months (95% confidence interval, 2.85.8 months). One out of 3 patients who underwent hematopoietic stem-cell transplantation remains alive. Multivariate analysis revealed that lymphoid BP and TKI therapy had a statistically significant positive impact as prognostic factors for CHR. In the multivariate analysis, age > 60 years, hemoglobin < 10 g/dL, and complex karyotype were statistically significant negative prognostic factors for OS. There was no statistical significant difference in OS between patients who received only CT (1988-2002) with those treated with CT plus TKI (2003-2013). Conclusion: This is the first study in Mexico to report prognostic factors associated with CHR and OS in patients with CML-BP. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Characteristics, Chronic myeloid leukemia blast phase (CML-BP), Cytogenetic, Immunophenotype, Treatment
Introduction Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of 1 or 2 cases per 100,000 adults.1,2 The hallmark of the disease is a balanced translocation Chronic Leukemia Clinic, Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, México Submitted: Jul 9, 2015; Revised: Sep 15, 2015; Accepted: Sep 21, 2015 Address for correspondence: Xavier López-Karpovitch, MD, Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Tlalpan 14000, México, DF E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.09.007
involving chromosome 9 and chromosome 22, known as the Philadelphia chromosome (Ph).3 The resulting oncoprotein, termed BCRABL, promotes growth and replication driving leukemogenesis.2,4-8 At diagnosis, approximately 90% of CML patients present in chronic phase. As the disease progresses, it may follow a biphasic or triphasic course evolving through an accelerated phase and/or blast phase (BP), in which hematopoietic differentiation has become arrested and immature blasts accumulate in the bone marrow (BM) and spill into the peripheral blood.8-10 The mechanisms for progression to BP are varied and not entirely understood. These include differentiation arrest, genomic instability, telomere shortening, alterations in apoptotic signals, and loss
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-1
Prognostic Factors for Survival in CML-BP of tumor-suppressor functions, which leads to clonal evolution.8 This is evidenced as nonrandom additional cytogenetic aberrations (ACA)11-13 and molecular alterations including mutations in the BCR-ABL tyrosine kinase domain, p53, RUNX1, and IKZF1, among others.11,14,15 CML-BP is highly refractory to treatment. Multiple induction CT regimens have been evaluated with response rates of approximately 30%.16-20 Among those with response, median overall survival (OS) is approximately 3.5 to 19 months.16 Introduction of tyrosine kinase inhibitors (TKI) to the treatment of CML in chronic phase has greatly improved outcomes.21 In previously untreated CML-BP patients, complete hematologic and cytogenetic responses (CyR) are achieved with imatinib alone in about 50% and 15%, respectively, with a 12month OS of approximately 20% to 30%.22-25 Hematologic response rates for second-generation TKI range between 55% and 65%, and CyR are observed in 40% to 55% of cases. Despite this, responses are short, with median OS between 5.3 and 11.8 months.16,26,27 Allogeneic hematopoietic stem-cell transplantation (HSCT) is recommended in patients who experience complete hematologic response (CHR). However, the long-term survival rate is low—nearly 20%.28,29 Studies depicting CML-BP characteristics are scant,30-34 and to our knowledge there are no previous reports regarding the clinical characteristics and outcome of this entity in the Mexican population. Thus, the aim of this study was to retrospectively analyze our experience in patients with CML-BP and describe their clinical, cytogenetic, and immunophenotypic characteristics as well as their prognostic features and outcomes.
Patients and Methods
2
-
We retrospectively analyzed the characteristics of 51 patients with CML-BP diagnosed and treated at our institution between 1988 and 2013. All patients fulfilled World Health Organization 2008 criteria for CML-BP.1 Patients were evaluated with complete blood counts, BM aspiration and biopsy, blast immunophenotyping by flow cytometry, and conventional cytogenetics. Fluorescence in-situ hybridization (FISH) analysis started in 1999. CHR was defined as an absolute neutrophil count 1 109/L, platelet count 100 109/L, 5% marrow blasts with absence of blasts in peripheral blood and no evidence of extramedullary disease, lasting for at least 4 weeks.35 Relapse was defined as reappearance of blasts in peripheral blood or 5% of blasts in BM or extramedullary disease in those patients who previously had experienced CHR. Patients who died within 4 weeks from the beginning of therapy were considered as early deaths. CyR in patients who received TKI were determined by the percentage of Ph-positive cells in at least 20 analyzable BM metaphases. Depending on the percentage of Ph-positive cells, CyR was classified, according to the European LeukemiaNet recommendations,36 as complete (0), partial (1%-35%), major (0%-35%), minor (36%-65%), minimal (66%-95%), or none (96%-100%). The presence of ACA in Ph-positive clones at diagnosis was reported following the International System for Human Cytogenetic Nomenclature (ISCN) 2009.11-13 OS was calculated from the date of CML-BP diagnosis to the date of death from any cause or loss during follow-up. Disease-free survival (DFS) was calculated from the date of documented CHR to the date of relapse.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
Numerical variables were described in terms of mean standard deviation or median and range; categorical variables were described in frequencies and proportions. In order to compare categorical or
Table 1 Characteristics of Patients With CML in BP Characteristic Gender, n (%) CML phase at initial diagnosis, n (%)
Treatment previous to progression, n (%)
Complete hematologic response to previous treatment, n (%)
Cytogenetic response in TKI-treated cases, n (%)
Blast cell lineage, n (%)
Extramedullary disease, n (%)
Available karyotype at BP diagnosis Complex karyotype, n (%) ACA, n (%)
Hemoglobin count, g/dL, median (range) WBC count, 109/L, median (range) Platelet count 109/L, median (range) Treatment, n (%)
Variable
Value
Male Female Chronic
28 (54.9) 23 (45.1) 35 (68.6)
Accelerated Blast Total
9 (17.6) 7 (13.7) 44 (86.3)
Busulfan Imatinib Hydroxyurea Interferon-a Total
15 12 10 7 31
(29.4) (23.5) (22.7) (13.7) (60.8)
Other therapies Treated with TKI Total
22 (43.1) 9 (17.7) 12 (23.5)
Complete CyR Partial CyR Minor CyR No response Not available Myeloid Lymphoid Mixed phenotype Total Central nervous system Skin Bones Ganglion Intestinal
3 3 3 2 1 36 12 3 13 6
(25) (25) (25) (16.7) (8.3) (70.6) (23.5) (5.9) (25.5) (46.1)
3 2 1 1 36
(23.1) (15.4) (7.7) (7.7) (70.5)
8 19 12 7 8.8
(22.2) (53) (63) (37) (4.4-15.2)
Total Major route ACAs Other ACAs
36 (1.9-648) 68 (6-1060) CT CT þ TKI TKI alone Supportive care
27 16 2 6
(52.9) (31.4) (3.92) (11.7)
Abbreviations: ACA ¼ additional cytogenetic alterations; BP ¼ blast phase; CML ¼ chronic myeloid leukemia; CT ¼ chemotherapy; CyR ¼ cytogenetic response; TKI ¼ tyrosine kinase inhibitors; WBC ¼ white blood cell count.
Fernando Pérez-Jacobo et al continuous variables, the c2 test and Student’s t test were used, respectively. Survival curves were estimated by the Kaplan-Meier method and were compared by the log rank test. Risk factors related to CHR and OS were identified through univariate and multivariate analysis by means of the binary logistic regression model and the Cox proportional hazard regression model, respectively. A P value of .05 was considered statistically significant. Data were analyzed by SPSS 21 (IBM, Armonk, NY).
Results At diagnosis, the median age of the 51 patients with CML-BP was 41 years (range, 13-75 years), 54.9% were men, and 86.3% experienced disease progression from chronic phase or accelerated phase. The median time to progression to BP was 22 months (range, 1-124 months). The demographical, clinical, and laboratory characteristics of the 51 patients analyzed are detailed in Table 1. Immunophenotype analysis of blast cells in BM and peripheral blood specimens showed 36 cases (70.6%) of myeloid BP, 12 (23.5%) lymphoid BP, and 3 (5.9%) mixed phenotype BP. Patients with lymphoid BP presented with a higher BM blast cell count compared to those who had myeloid BP (mean 61% vs. 31%, P ¼ .002) and a lower platelet count (mean 36 109/L vs. 191 109/L, P ¼ .004) (Table 2). In patients classified as myeloid BP, overall antigen expression was as follows: CD13, 85%; CD15, 41%; CD33, 71%; CD117, 40% and myeloperoxidase, 72%. Seven patients (19.4%) expressed megakaryocyte-associated antigens. In 6 patients (16.7%), myeloblasts and monoblasts were demonstrated in the BM aspirate and expressed CD11b and CD64. One case (2.8%) was classified as erythroleukemia on the basis of expression of glycophorin and CD71 (transferrin receptor). Finally, 2 cases (5.5%) presented as isolated biopsy-confirmed myeloid sarcoma. In lymphoid BP cases, 16% depicted early precursor B-cell immunophenotype and 84% precursor B-cell immunophenotype.
Overall expression of B-celleassociated antigens was as follows: CD10, 75%; CD19, 83%; CD20, 41%; and CD22, 67%. Two cases were classified as B-cell lymphoid/myeloid lineage. In both cases, blast cells expressed CD13, CD117, myeloperoxidase, CD19, and CD79a. One case was classified as an uncommon case of mixed lymphoid B/T phenotype on the basis of expression of B-cell markers CD10, CD19, and CD22 and T-cell markers CD5 and CD7 (data not shown). At the time of CML-BP diagnosis, the karyotype was available in 36 patients. ACA were identified in 19 cases (53%); 63% had major-route ACA and 37% other ACA. The most common majorroute ACA was i(17q), present in 6 patients (50%), and trisomy 8 as well as double Ph, present in 25% of cases. Complex karyotype was found in 8 cases (22%), often associated with a major-route ACA, predominantly i(17q) and trisomy 19. In fact, trisomy 19 was not reported as an isolated ACA; it was found in 50% of patients with complex karyotype (data not shown). Forty-three patients received CT as part of their management strategy. From 1988 to 2002, 27 patients were treated with standard induction CT alone and from 2003 to 2013, 16 patients received standard induction CT plus TKI (imatinib in 13 cases, secondgeneration TKI in 3 patients). Two patients were treated with TKI alone and 6 patients received only supportive care because of age > 65 years and poor performance status (Table 1). The most used CT regimens were standard dose cytarabine plus anthracycline in 71.4% of myeloid BP and vincristine plus prednisone-based regimens in 91.7% of lymphoid BP. One patient with mixed phenotype BP was treated with a myeloid leukemic regimen and the other 2 patients with lymphoid leukemic regimens. Imatinib was provided continuously from the start of treatment and adjusted if significant adverse effects were present. Median dose of imatinib was 600 mg per day (range, 400-800 mg). One patient received dasatinib 140 mg per day, and 2 patients were treated with nilotinib 800 mg per day. Only 3 patients received consolidation with allogeneic HSCT in CHR.
Table 2 Differences Between Myeloid and Lymphoid Blast Phase Variable
Myeloid Blast Phase
Lymphoid Blast Phase
Gender, n (%)
P .09
Male
22 (61)
4 (33)
Female
14 (39)
8 (67)
Median age, years
40
49
.55
Median time to progression, months
29
31
.88
Mean hemoglobin, g/dL
8.6
9.2
.425 .68
Mean leukocyte count, 10 /L
85
104
Mean platelet count, 109/L
191
36
.04
Mean bone marrow blast count, %
36
61
.002
9
Extramedullary disease, n (%)
9 (25)
3 (25)
.75
15 (41)
4 (30)
.34
CT
18 (50)
8 (66.7)
CT þ TKI
10 (27.8)
4 (33.3)
Additional cytogenetic alterations, n (%) Treatment, n (%)
TKI Response rate
.59
2 (5.5)
0 (0)
25.9%
72.9%
.01
Abbreviations: CT ¼ chemotherapy; TKI ¼ tyrosine kinase inhibitor.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-3
Prognostic Factors for Survival in CML-BP Table 3 Multivariate Analysis for Response and Survival Responsea Characteristic Age >60 years Hemoglobin <10 g/dL Complex karyotype Myeloid lineage CT without TKI
Survivalb
OR
P
HR
95% CI
P
0.7 0.31 0.42 0.028 0.024
.73 .25 .47 .05 .03
3.68 2.51 4.70 1.55 0.48
1.60-5.71 1.30-5.70 1.96-9.46 0.72-3.34 0.22-1.04
.003 .012 .001 .225 .063
Abbreviations: CI ¼ confidence interval; CT ¼ chemotherapy; HR ¼ hazard ratio; OR ¼ odds ratio; TKI ¼ tyrosine kinase inhibitor. a Binary logistic regression model. b Cox proportional hazard regression model.
4
-
Five early deaths (11%) were observed among the 43 patients who received CT with or without TKI. The remaining 38 patients were evaluable for response. Sixteen patients (42%) experienced CHR, and 10 of them (62.5%) received CT plus TKI. Complete CyR was observed in 2 patients, minor CyR was recorded in 2 cases, and 6 patients did not experience CyR. We did not observe any response in the 2 patients who received imatinib as single agent. The response rate was 25.9% in patients with myeloid BP versus 72.9% in those with lymphoid BP (P ¼ .01). We assessed the association between pretreatment characteristics and CHR. Only myeloid lineage BP and CT alone were factors associated with less likelihood of experiencing CHR (Table 3). As shown in Figure 1, median OS of the entire cohort was 4 months (95% confidence interval [CI], 1.7-6.2). There was no statistical difference in median OS between patients with myeloid BP compared to lymphoid BP (2 months vs. 4 months respectively; P ¼ .21). Patients who experienced CHR had a median OS of 7 months (95% CI, 1.7-44.8) versus 2 months (95% CI, 2.0-5.4) in those who did not experience CHR (P ¼ .004; data not shown). Patients older than 60 years had shorter OS compared to younger patients (1 vs. 5 months, P ¼ .007), and those who had major-route ACA or complex karyotype at time of diagnosis had a worse OS compared to patients with cytogenetic abnormalities (2 vs. 6 months, P ¼ .04; and 1 vs. 6 months, P ¼ .001, respectively) (Figure 2). Patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 had a trend to worse OS (1 vs. 5 months; P ¼ .051). On univariate analysis, we identified age > 60 years (hazard ratio [HR], 2.4; 95% CI, 1.6-5.0; P ¼ .018); ECOG 2 (HR, 1.96; 95% CI, 1.7-3.5; P ¼ .03), hemoglobin < 10 g/dL (HR, 1.96; 95% CI, 1.2e3.7; P ¼ .043), and complex karyotype (HR, 4.1; 95% CI, 1.9-9.6; P ¼ .001) as statistically significant factors for survival. On multivariate analysis, only age > 60 years, hemoglobin < 10 g/dL, and the presence of complex karyotype remained as independent prognostic factors for worse survival (Table 3). Median DFS in patients who experienced CHR was 5 months (95% CI, 2.8-5.8) (Figure 3). We did not find a statistically significant association between pretreatment characteristics and response duration on univariate or multivariate analysis. At the time of analysis, 50 patients had died (98%), mostly from disease progression (84%). One patient remained alive 10 years after allogeneic HSCT with a followup of 147 months.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
Discussion As reported by others,1,7,30,37 we found that most CML-BP cases were classified as myeloid BP, with megakaryocytic lineage the most frequently found. Previously, we reported in 19 patients with CMLBP 42% megakaryocytic antigen expression, which contrasts with the 19% found in the current series.38 This could be explained by the larger number of cases included in the present study. In our series, 25% of patients had extramedullary disease; the most common site involved was the central nervous system (46.1%). This frequency is higher than in previous reports, and we did not find any association between the presence of extramedullary disease and worse outcome.39-41 Clonal evolution was present in 53% of our patients. The frequency of ACA is lower than previously reported22,24 and is probably related to the fact that not all patients had an analyzable karyotype at CML-BP diagnosis. This pitfall was overcome after 2003, when laboratory techniques were improved. The main management strategies in our cohort were induction CT from 1988 to 2002 and CT plus TKI from 2003 onward. The most used induction regimens were a combination of an anthracycline
Figure 1 Overall Survival of Entire Cohort
Fernando Pérez-Jacobo et al Figure 2 OS by Age, ACA, and Karyotype. (A) OS According to Age. (B) OS According to Presence of Major-Route ACA. (C) OS According to Presence of Complex Karyotype
Abbreviations: ACA ¼ additional cytogenetic abnormalities; OS ¼ overall survival.
and cytarabine for myeloid BP and schedules containing vincristine and prednisone for lymphoid BP, similar to strategies used elsewhere.16-20,42 We observed a CHR rate of 42%. Using the definition of CHR for de novo acute leukemia,35 response rate is comparable to that in the previously published literature.20,30,31,42 However the comparison of data published in some series is confounded by the variability in response criteria used by others.30-32,43,44 Patients classified as having lymphoid BP had a better CHR rate, as consistently reported using regimens containing vincristine and glucocorticoids. However, in the current analysis, lymphoid lineage did not have an impact on OS or DFS, as suggested previously.30,45 Other pretreatment characteristics, including evidence of clonal evolution, had no effect on response rate, as has been reported before.30 This can be explained by the high proportion of patients without an evaluable karyotype at the time of diagnosis; these were excluded from the analysis. The CHR rate in our group treated with CT plus imatinib was higher than that reported for imatinib alone25,44 and was similar to that found for second-generation TKI.22-27 We observed complete CyR in 20% of patients treated with imatinib plus CT, similar to that of imatinib as a single agent for CML-BP.22-25 Data regarding combinations of CT plus TKI in CML-BP are limited, particularly for second-generation TKI. A small number of patients, different response definitions, and different proportions of patients who underwent HSCT differ among different series.46-48 Thus, the real benefit of this strategy is inconclusive. Because recommendations from the European LeukemiaNet consider the use of intensive CT to control and reduce tumour burden,36 on the basis of our results, combined therapy using CT plus TKI, mainly imatinib, could be a suitable strategy in developing countries with limited access to second-generation TKI. In our study, addition of TKI to CT did not improve OS or DFS. This lack of impact could be related to several factors. First, the number of patients treated with this strategy was small. Second, and possibly more important, only 18% of patients in CHR
underwent HSCT as a result of the lack of a matched donor and the short duration of CHR. In addition, in our institution we do not consider patients with active BP for HSCT. Overall, these factors negatively affected OS. We found our median OS to be short. Age > 60 years, hemoglobin < 10 g/dL, and the presence of complex karyotype were the only independent risk factors for worse OS, which is similar to the findings of the largest series yet published.30 We did not identify an association between patient characteristics and DFS. These results underline the dismal prognosis of CML-BP and highlight the importance of close surveillance to promptly identify progression from chronic phase to advanced phases in CML patients.
Figure 3 Disease-Free Survival of Patients With Complete Hematologic Response
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-5
Prognostic Factors for Survival in CML-BP Conclusion BP remains a challenge in the management of CML. To our knowledge, this is the largest series reported from Mexico regarding the characteristics and outcome of CML-BP patients. In our analysis, the most important factors associated with survival were age (> 60 years), hemoglobin (< 10 g/dL), and complex karyotype. Patients with lymphoid BP as well as those receiving CT plus TKI had a better CHR rate. Nevertheless, the prognosis of this group of patients is still poor, with transitory response to therapy and rapid disease progression.
Clinical Practice Points In recent years, the incidence of BP has decreased significantly
with the introduction of TKI as first-line therapy. Those who progress to BP have a very poor prognosis. In this analysis, characteristics associated with the patient (age),
marrow reserve (hemoglobin level), and the disease itself (chromosomal aberrations, blast cell lineage) determined the prognostic heterogeneity in this entity in relation to response to treatment and outcome. One important finding in our series addresses the potential benefit of combined therapy (CT plus TKI) in CML-BP, as the CHR rate was similar to those reported for second-generation TKI. This has important repercussions in countries with limited access to second-generation TKI, as in Mexico.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Vardiman JW, Melo JV, Baccarani M, et al. Chronic myelogenous leukaemia, BCR-ABL1 positive. In: Jaffe ES, Harris NL, Stein H, et al, eds. World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008:32-7. 2. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Hematol 2014; 89:547-56. 3. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]. Nature 1973; 243:290-3. 4. Sawyers CL, Callahan W, Witte ON. Dominant negative MYC blocks transformation by ABL oncogenes. Cell 1992; 70:901-10. 5. Shuai K, Halpern J, ten Hoeve J, et al. Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene 1996; 13:247-54. 6. Perrotti D, Cesi V, Trotta R, et al. BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet 2002; 30:48-58. 7. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000; 96:3343-56. 8. Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007; 7:441-53. 9. Cortes J. Natural history and staging of chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004; 18:569-84. 10. Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003; 349:1451-64. 11. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002; 107:76-94. 12. Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011; 118:6760-8. 13. Hehlmann R. How I treat CML blast crisis. Blood 2012; 120:737-47. 14. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol 2005; 23:4100-9. 15. Grossmann V, Kohlmann A, Zenger M, et al. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia 2011; 25:557-60.
6
-
Clinical Lymphoma, Myeloma & Leukemia Month 2015
16. Karbasian Esfahani M, Morris EL, Dutcher JP, et al. Blastic phase of chronic myelogenous leukemia. Curr Treat Options Oncol 2006; 7:189-99. 17. Dutcher JP, Lee S, Paietta E, et al. Phase II study of carboplatin in blast crisis of chronic myeloid leukemia: Eastern Cooperative Oncology Group Study E1992. Leukemia 1998; 12:1037-40. 18. Robak T, Góra-Tybor J. Cladribine combined with mitoxantrone in the treatment of blastic phase of chronic myeloid leukemia. Neoplasma 2001; 48:203-7. 19. Dutcher JP, Morris EL, Gaynor B, et al. A pilot study of carboplatin and mitoxantrone in blast crisis of chronic myeloid leukemia. Med Oncol 2010; 27: 728-35. 20. Kantarjian HM, Talpaz M, Kontoyiannis D, et al. Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, highdose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 1992; 10:398-405. 21. Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009; 23:1054-61. 22. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344:1038-42. 23. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosomeepositive chronic myelogenous leukemia in blast phase. Blood 2002; 99:3547-53. 24. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99:3530-9. 25. Palandri F, Castagnetti F, Testoni N, et al. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year followup. Haematologica 2008; 93:1792-6. 26. Saglio G, Hochhaus A, Goh YT, et al. Dasatinib in imatinib-resistant or imatinibintolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 2010; 116:3852-61. 27. Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinibresistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia 2012; 26:959-62. 28. Gratwohl A, Brand R, Apperley J, et al. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 2006; 91:513-21. 29. Deininger M, Schleuning M, Greinix H, et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica 2006; 91:452-9. 30. Kantarjian HM, Keating MJ, Talpaz M, et al. Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. Am J Med 1987; 83:445-54. 31. Coleman M, Silver RT, Pajak TF, et al. Combination chemotherapy for terminalphase chronic granulocytic leukemia: Cancer and Leukemia Group B studies. Blood 1980; 55:29-36. 32. Rosenthal S, Canellos GP, Whang-Peng J, et al. Blast crisis of chronic granulocytic leukemia. Morphologic variants and therapeutic implications. Am J Med 1977; 63: 542-7. 33. López-Karpovitch X, Cárdenas R, Piedras J. Immunophenotypic characteristics of the blast crisis in chronic myeloid leukemia. Rev Invest Clin 1997; 49:31-6. 34. Tang X, Wu D, Xue Y, et al. The morphological, immunophenotypical and cytogenetic characteristics study of blast crisis in chronic myeloid leukemia. Zhonghua Nei Ke Za Zhi 2002; 41:685-7. 35. Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Instituteesponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990; 8:813-9. 36. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122:872-84. 37. Giles FJ, Cortes JE, Kantarjian HM, et al. Accelerated and blastic phases of chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004; 18:753-74. 38. Crespo E, López-Karpovitch X, Abraham-Simón J, et al. Survival, clinical and laboratory characteristics of de novo and secondary megakaryoblastic leukemia. Rev Invest Clin 2003; 55:494-501. 39. Specchia G, Palumbo G, Pastore D, et al. Extramedullary blast crisis in chronic myeloid leukemia. Leuk Res 1996; 20:905-8. 40. Saikia TK, Dhabhar B, Iyer RS, et al. High incidence of meningeal leukemia in lymphoid blast crisis of chronic myelogenous leukemia. Am J Hematol 1993; 43: 10-3. 41. Cervantes F, Rozman M, Rosell J, et al. A study of prognostic factors in blast crisis of Philadelphia chromosomeepositive chronic myelogenous leukaemia. Br J Haematol 1990; 76:27-32. 42. Kantarjian HM, Walters RS, Keating MJ, et al. Treatment of the blastic phase of chronic myelogenous leukemia with mitoxantrone and high-dose cytosine arabinoside. Cancer 1988; 62:672-6. 43. Muehleck SD, McKenna RW, Arthur DC, et al. Transformation of chronic myelogenous leukemia: clinical, morphologic, and cytogenetic features. Am J Clin Pathol 1984; 82:1-14. 44. Silver RT, Cortes J, Waltzman R, et al. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for
Fernando Pérez-Jacobo et al accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica 2009; 94:743-4. 45. Cervantes F, Villamor N, Esteve J, et al. “Lymphoid” blast crisis of chronic myeloid leukaemia is associated with distinct clinicohaematological features. Br J Haematol 1998; 100:123-8. 46. Deau B, Nicolini FE, Guilhot J, et al. The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the
survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study). Leuk Res 2011; 35:777-82. 47. Quintas-Cardama A, Kantarjian H, Garcia-Manero G, et al. A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase. Leuk Lymphoma 2012; 48:283-9. 48. Strati P, Kantarjian H, Thomas D, et al. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. Cancer 2014; 120:373-80.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-7
Prognostic Factors, Response to Treatment, and Survival in Patients With Chronic Myeloid Leukemia in Blast Phase: A Single-Institution Survey Fernando Pérez-Jacobo, Elena Tuna-Aguilar, Roberta Demichelis-Gómez, Erick Crespo-Solís, Ubaldo Valencia-Rocha, Álvaro Aguayo, Xavier López-Karpovitch Abstract We retrospectively analyzed data from 51 patients with chronic myeloid leukemia in blast phase (BP) at a single institution. Disease characteristics and prognostic factors are described. Lymphoid BP and use of tyrosine kinase inhibitors were independent prognostic factors for response. Age, hemoglobin level, and chromosomal aberrations were identified as prognostic factors for overall survival. Introduction: Data from 51 patients (23 women) with chronic myeloid leukemia (CML) in blast phase (BP) were analyzed in order to identify prognostic factors for complete hematologic response (CHR) and survival. Patients and Methods: Forty-four patients experienced disease progression from chronic or accelerated phase, and 7 cases presented as CML-BP. Thirteen patients (25.5%) had extramedullary involvement at diagnosis, and 71% were myeloid BP. Clonal evolution was identified in 53% of the cases, and the abnormalities most frequently observed were isochromosome (17q), double Philadelphia chromosome, and trisomy 8. Forty-five patients received treatment: 60% chemotherapy (CT) alone and 40% CT plus tyrosine kinase inhibitors (TKI) or TKI alone; 42% of them experienced CHR. Results: Median overall survival (OS) in patients whose disease responded to treatment was 7 months (95% confidence interval, 1.7-6.2 months), with a median disease-free survival of 5 months (95% confidence interval, 2.85.8 months). One out of 3 patients who underwent hematopoietic stem-cell transplantation remains alive. Multivariate analysis revealed that lymphoid BP and TKI therapy had a statistically significant positive impact as prognostic factors for CHR. In the multivariate analysis, age > 60 years, hemoglobin < 10 g/dL, and complex karyotype were statistically significant negative prognostic factors for OS. There was no statistical significant difference in OS between patients who received only CT (1988-2002) with those treated with CT plus TKI (2003-2013). Conclusion: This is the first study in Mexico to report prognostic factors associated with CHR and OS in patients with CML-BP. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Characteristics, Chronic myeloid leukemia blast phase (CML-BP), Cytogenetic, Immunophenotype, Treatment
Introduction Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of 1 or 2 cases per 100,000 adults.1,2 The hallmark of the disease is a balanced translocation Chronic Leukemia Clinic, Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, México Submitted: Jul 9, 2015; Revised: Sep 15, 2015; Accepted: Sep 21, 2015 Address for correspondence: Xavier López-Karpovitch, MD, Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Tlalpan 14000, México, DF E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.09.007
involving chromosome 9 and chromosome 22, known as the Philadelphia chromosome (Ph).3 The resulting oncoprotein, termed BCRABL, promotes growth and replication driving leukemogenesis.2,4-8 At diagnosis, approximately 90% of CML patients present in chronic phase. As the disease progresses, it may follow a biphasic or triphasic course evolving through an accelerated phase and/or blast phase (BP), in which hematopoietic differentiation has become arrested and immature blasts accumulate in the bone marrow (BM) and spill into the peripheral blood.8-10 The mechanisms for progression to BP are varied and not entirely understood. These include differentiation arrest, genomic instability, telomere shortening, alterations in apoptotic signals, and loss
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-1
Prognostic Factors for Survival in CML-BP of tumor-suppressor functions, which leads to clonal evolution.8 This is evidenced as nonrandom additional cytogenetic aberrations (ACA)11-13 and molecular alterations including mutations in the BCR-ABL tyrosine kinase domain, p53, RUNX1, and IKZF1, among others.11,14,15 CML-BP is highly refractory to treatment. Multiple induction CT regimens have been evaluated with response rates of approximately 30%.16-20 Among those with response, median overall survival (OS) is approximately 3.5 to 19 months.16 Introduction of tyrosine kinase inhibitors (TKI) to the treatment of CML in chronic phase has greatly improved outcomes.21 In previously untreated CML-BP patients, complete hematologic and cytogenetic responses (CyR) are achieved with imatinib alone in about 50% and 15%, respectively, with a 12month OS of approximately 20% to 30%.22-25 Hematologic response rates for second-generation TKI range between 55% and 65%, and CyR are observed in 40% to 55% of cases. Despite this, responses are short, with median OS between 5.3 and 11.8 months.16,26,27 Allogeneic hematopoietic stem-cell transplantation (HSCT) is recommended in patients who experience complete hematologic response (CHR). However, the long-term survival rate is low—nearly 20%.28,29 Studies depicting CML-BP characteristics are scant,30-34 and to our knowledge there are no previous reports regarding the clinical characteristics and outcome of this entity in the Mexican population. Thus, the aim of this study was to retrospectively analyze our experience in patients with CML-BP and describe their clinical, cytogenetic, and immunophenotypic characteristics as well as their prognostic features and outcomes.
Patients and Methods
2
-
We retrospectively analyzed the characteristics of 51 patients with CML-BP diagnosed and treated at our institution between 1988 and 2013. All patients fulfilled World Health Organization 2008 criteria for CML-BP.1 Patients were evaluated with complete blood counts, BM aspiration and biopsy, blast immunophenotyping by flow cytometry, and conventional cytogenetics. Fluorescence in-situ hybridization (FISH) analysis started in 1999. CHR was defined as an absolute neutrophil count 1 109/L, platelet count 100 109/L, 5% marrow blasts with absence of blasts in peripheral blood and no evidence of extramedullary disease, lasting for at least 4 weeks.35 Relapse was defined as reappearance of blasts in peripheral blood or 5% of blasts in BM or extramedullary disease in those patients who previously had experienced CHR. Patients who died within 4 weeks from the beginning of therapy were considered as early deaths. CyR in patients who received TKI were determined by the percentage of Ph-positive cells in at least 20 analyzable BM metaphases. Depending on the percentage of Ph-positive cells, CyR was classified, according to the European LeukemiaNet recommendations,36 as complete (0), partial (1%-35%), major (0%-35%), minor (36%-65%), minimal (66%-95%), or none (96%-100%). The presence of ACA in Ph-positive clones at diagnosis was reported following the International System for Human Cytogenetic Nomenclature (ISCN) 2009.11-13 OS was calculated from the date of CML-BP diagnosis to the date of death from any cause or loss during follow-up. Disease-free survival (DFS) was calculated from the date of documented CHR to the date of relapse.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
Numerical variables were described in terms of mean standard deviation or median and range; categorical variables were described in frequencies and proportions. In order to compare categorical or
Table 1 Characteristics of Patients With CML in BP Characteristic Gender, n (%) CML phase at initial diagnosis, n (%)
Treatment previous to progression, n (%)
Complete hematologic response to previous treatment, n (%)
Cytogenetic response in TKI-treated cases, n (%)
Blast cell lineage, n (%)
Extramedullary disease, n (%)
Available karyotype at BP diagnosis Complex karyotype, n (%) ACA, n (%)
Hemoglobin count, g/dL, median (range) WBC count, 109/L, median (range) Platelet count 109/L, median (range) Treatment, n (%)
Variable
Value
Male Female Chronic
28 (54.9) 23 (45.1) 35 (68.6)
Accelerated Blast Total
9 (17.6) 7 (13.7) 44 (86.3)
Busulfan Imatinib Hydroxyurea Interferon-a Total
15 12 10 7 31
(29.4) (23.5) (22.7) (13.7) (60.8)
Other therapies Treated with TKI Total
22 (43.1) 9 (17.7) 12 (23.5)
Complete CyR Partial CyR Minor CyR No response Not available Myeloid Lymphoid Mixed phenotype Total Central nervous system Skin Bones Ganglion Intestinal
3 3 3 2 1 36 12 3 13 6
(25) (25) (25) (16.7) (8.3) (70.6) (23.5) (5.9) (25.5) (46.1)
3 2 1 1 36
(23.1) (15.4) (7.7) (7.7) (70.5)
8 19 12 7 8.8
(22.2) (53) (63) (37) (4.4-15.2)
Total Major route ACAs Other ACAs
36 (1.9-648) 68 (6-1060) CT CT þ TKI TKI alone Supportive care
27 16 2 6
(52.9) (31.4) (3.92) (11.7)
Abbreviations: ACA ¼ additional cytogenetic alterations; BP ¼ blast phase; CML ¼ chronic myeloid leukemia; CT ¼ chemotherapy; CyR ¼ cytogenetic response; TKI ¼ tyrosine kinase inhibitors; WBC ¼ white blood cell count.
Fernando Pérez-Jacobo et al continuous variables, the c2 test and Student’s t test were used, respectively. Survival curves were estimated by the Kaplan-Meier method and were compared by the log rank test. Risk factors related to CHR and OS were identified through univariate and multivariate analysis by means of the binary logistic regression model and the Cox proportional hazard regression model, respectively. A P value of .05 was considered statistically significant. Data were analyzed by SPSS 21 (IBM, Armonk, NY).
Results At diagnosis, the median age of the 51 patients with CML-BP was 41 years (range, 13-75 years), 54.9% were men, and 86.3% experienced disease progression from chronic phase or accelerated phase. The median time to progression to BP was 22 months (range, 1-124 months). The demographical, clinical, and laboratory characteristics of the 51 patients analyzed are detailed in Table 1. Immunophenotype analysis of blast cells in BM and peripheral blood specimens showed 36 cases (70.6%) of myeloid BP, 12 (23.5%) lymphoid BP, and 3 (5.9%) mixed phenotype BP. Patients with lymphoid BP presented with a higher BM blast cell count compared to those who had myeloid BP (mean 61% vs. 31%, P ¼ .002) and a lower platelet count (mean 36 109/L vs. 191 109/L, P ¼ .004) (Table 2). In patients classified as myeloid BP, overall antigen expression was as follows: CD13, 85%; CD15, 41%; CD33, 71%; CD117, 40% and myeloperoxidase, 72%. Seven patients (19.4%) expressed megakaryocyte-associated antigens. In 6 patients (16.7%), myeloblasts and monoblasts were demonstrated in the BM aspirate and expressed CD11b and CD64. One case (2.8%) was classified as erythroleukemia on the basis of expression of glycophorin and CD71 (transferrin receptor). Finally, 2 cases (5.5%) presented as isolated biopsy-confirmed myeloid sarcoma. In lymphoid BP cases, 16% depicted early precursor B-cell immunophenotype and 84% precursor B-cell immunophenotype.
Overall expression of B-celleassociated antigens was as follows: CD10, 75%; CD19, 83%; CD20, 41%; and CD22, 67%. Two cases were classified as B-cell lymphoid/myeloid lineage. In both cases, blast cells expressed CD13, CD117, myeloperoxidase, CD19, and CD79a. One case was classified as an uncommon case of mixed lymphoid B/T phenotype on the basis of expression of B-cell markers CD10, CD19, and CD22 and T-cell markers CD5 and CD7 (data not shown). At the time of CML-BP diagnosis, the karyotype was available in 36 patients. ACA were identified in 19 cases (53%); 63% had major-route ACA and 37% other ACA. The most common majorroute ACA was i(17q), present in 6 patients (50%), and trisomy 8 as well as double Ph, present in 25% of cases. Complex karyotype was found in 8 cases (22%), often associated with a major-route ACA, predominantly i(17q) and trisomy 19. In fact, trisomy 19 was not reported as an isolated ACA; it was found in 50% of patients with complex karyotype (data not shown). Forty-three patients received CT as part of their management strategy. From 1988 to 2002, 27 patients were treated with standard induction CT alone and from 2003 to 2013, 16 patients received standard induction CT plus TKI (imatinib in 13 cases, secondgeneration TKI in 3 patients). Two patients were treated with TKI alone and 6 patients received only supportive care because of age > 65 years and poor performance status (Table 1). The most used CT regimens were standard dose cytarabine plus anthracycline in 71.4% of myeloid BP and vincristine plus prednisone-based regimens in 91.7% of lymphoid BP. One patient with mixed phenotype BP was treated with a myeloid leukemic regimen and the other 2 patients with lymphoid leukemic regimens. Imatinib was provided continuously from the start of treatment and adjusted if significant adverse effects were present. Median dose of imatinib was 600 mg per day (range, 400-800 mg). One patient received dasatinib 140 mg per day, and 2 patients were treated with nilotinib 800 mg per day. Only 3 patients received consolidation with allogeneic HSCT in CHR.
Table 2 Differences Between Myeloid and Lymphoid Blast Phase Variable
Myeloid Blast Phase
Lymphoid Blast Phase
Gender, n (%)
P .09
Male
22 (61)
4 (33)
Female
14 (39)
8 (67)
Median age, years
40
49
.55
Median time to progression, months
29
31
.88
Mean hemoglobin, g/dL
8.6
9.2
.425 .68
Mean leukocyte count, 10 /L
85
104
Mean platelet count, 109/L
191
36
.04
Mean bone marrow blast count, %
36
61
.002
9
Extramedullary disease, n (%)
9 (25)
3 (25)
.75
15 (41)
4 (30)
.34
CT
18 (50)
8 (66.7)
CT þ TKI
10 (27.8)
4 (33.3)
Additional cytogenetic alterations, n (%) Treatment, n (%)
TKI Response rate
.59
2 (5.5)
0 (0)
25.9%
72.9%
.01
Abbreviations: CT ¼ chemotherapy; TKI ¼ tyrosine kinase inhibitor.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-3
Prognostic Factors for Survival in CML-BP Table 3 Multivariate Analysis for Response and Survival Responsea Characteristic Age >60 years Hemoglobin <10 g/dL Complex karyotype Myeloid lineage CT without TKI
Survivalb
OR
P
HR
95% CI
P
0.7 0.31 0.42 0.028 0.024
.73 .25 .47 .05 .03
3.68 2.51 4.70 1.55 0.48
1.60-5.71 1.30-5.70 1.96-9.46 0.72-3.34 0.22-1.04
.003 .012 .001 .225 .063
Abbreviations: CI ¼ confidence interval; CT ¼ chemotherapy; HR ¼ hazard ratio; OR ¼ odds ratio; TKI ¼ tyrosine kinase inhibitor. a Binary logistic regression model. b Cox proportional hazard regression model.
4
-
Five early deaths (11%) were observed among the 43 patients who received CT with or without TKI. The remaining 38 patients were evaluable for response. Sixteen patients (42%) experienced CHR, and 10 of them (62.5%) received CT plus TKI. Complete CyR was observed in 2 patients, minor CyR was recorded in 2 cases, and 6 patients did not experience CyR. We did not observe any response in the 2 patients who received imatinib as single agent. The response rate was 25.9% in patients with myeloid BP versus 72.9% in those with lymphoid BP (P ¼ .01). We assessed the association between pretreatment characteristics and CHR. Only myeloid lineage BP and CT alone were factors associated with less likelihood of experiencing CHR (Table 3). As shown in Figure 1, median OS of the entire cohort was 4 months (95% confidence interval [CI], 1.7-6.2). There was no statistical difference in median OS between patients with myeloid BP compared to lymphoid BP (2 months vs. 4 months respectively; P ¼ .21). Patients who experienced CHR had a median OS of 7 months (95% CI, 1.7-44.8) versus 2 months (95% CI, 2.0-5.4) in those who did not experience CHR (P ¼ .004; data not shown). Patients older than 60 years had shorter OS compared to younger patients (1 vs. 5 months, P ¼ .007), and those who had major-route ACA or complex karyotype at time of diagnosis had a worse OS compared to patients with cytogenetic abnormalities (2 vs. 6 months, P ¼ .04; and 1 vs. 6 months, P ¼ .001, respectively) (Figure 2). Patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 had a trend to worse OS (1 vs. 5 months; P ¼ .051). On univariate analysis, we identified age > 60 years (hazard ratio [HR], 2.4; 95% CI, 1.6-5.0; P ¼ .018); ECOG 2 (HR, 1.96; 95% CI, 1.7-3.5; P ¼ .03), hemoglobin < 10 g/dL (HR, 1.96; 95% CI, 1.2e3.7; P ¼ .043), and complex karyotype (HR, 4.1; 95% CI, 1.9-9.6; P ¼ .001) as statistically significant factors for survival. On multivariate analysis, only age > 60 years, hemoglobin < 10 g/dL, and the presence of complex karyotype remained as independent prognostic factors for worse survival (Table 3). Median DFS in patients who experienced CHR was 5 months (95% CI, 2.8-5.8) (Figure 3). We did not find a statistically significant association between pretreatment characteristics and response duration on univariate or multivariate analysis. At the time of analysis, 50 patients had died (98%), mostly from disease progression (84%). One patient remained alive 10 years after allogeneic HSCT with a followup of 147 months.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
Discussion As reported by others,1,7,30,37 we found that most CML-BP cases were classified as myeloid BP, with megakaryocytic lineage the most frequently found. Previously, we reported in 19 patients with CMLBP 42% megakaryocytic antigen expression, which contrasts with the 19% found in the current series.38 This could be explained by the larger number of cases included in the present study. In our series, 25% of patients had extramedullary disease; the most common site involved was the central nervous system (46.1%). This frequency is higher than in previous reports, and we did not find any association between the presence of extramedullary disease and worse outcome.39-41 Clonal evolution was present in 53% of our patients. The frequency of ACA is lower than previously reported22,24 and is probably related to the fact that not all patients had an analyzable karyotype at CML-BP diagnosis. This pitfall was overcome after 2003, when laboratory techniques were improved. The main management strategies in our cohort were induction CT from 1988 to 2002 and CT plus TKI from 2003 onward. The most used induction regimens were a combination of an anthracycline
Figure 1 Overall Survival of Entire Cohort
Fernando Pérez-Jacobo et al Figure 2 OS by Age, ACA, and Karyotype. (A) OS According to Age. (B) OS According to Presence of Major-Route ACA. (C) OS According to Presence of Complex Karyotype
Abbreviations: ACA ¼ additional cytogenetic abnormalities; OS ¼ overall survival.
and cytarabine for myeloid BP and schedules containing vincristine and prednisone for lymphoid BP, similar to strategies used elsewhere.16-20,42 We observed a CHR rate of 42%. Using the definition of CHR for de novo acute leukemia,35 response rate is comparable to that in the previously published literature.20,30,31,42 However the comparison of data published in some series is confounded by the variability in response criteria used by others.30-32,43,44 Patients classified as having lymphoid BP had a better CHR rate, as consistently reported using regimens containing vincristine and glucocorticoids. However, in the current analysis, lymphoid lineage did not have an impact on OS or DFS, as suggested previously.30,45 Other pretreatment characteristics, including evidence of clonal evolution, had no effect on response rate, as has been reported before.30 This can be explained by the high proportion of patients without an evaluable karyotype at the time of diagnosis; these were excluded from the analysis. The CHR rate in our group treated with CT plus imatinib was higher than that reported for imatinib alone25,44 and was similar to that found for second-generation TKI.22-27 We observed complete CyR in 20% of patients treated with imatinib plus CT, similar to that of imatinib as a single agent for CML-BP.22-25 Data regarding combinations of CT plus TKI in CML-BP are limited, particularly for second-generation TKI. A small number of patients, different response definitions, and different proportions of patients who underwent HSCT differ among different series.46-48 Thus, the real benefit of this strategy is inconclusive. Because recommendations from the European LeukemiaNet consider the use of intensive CT to control and reduce tumour burden,36 on the basis of our results, combined therapy using CT plus TKI, mainly imatinib, could be a suitable strategy in developing countries with limited access to second-generation TKI. In our study, addition of TKI to CT did not improve OS or DFS. This lack of impact could be related to several factors. First, the number of patients treated with this strategy was small. Second, and possibly more important, only 18% of patients in CHR
underwent HSCT as a result of the lack of a matched donor and the short duration of CHR. In addition, in our institution we do not consider patients with active BP for HSCT. Overall, these factors negatively affected OS. We found our median OS to be short. Age > 60 years, hemoglobin < 10 g/dL, and the presence of complex karyotype were the only independent risk factors for worse OS, which is similar to the findings of the largest series yet published.30 We did not identify an association between patient characteristics and DFS. These results underline the dismal prognosis of CML-BP and highlight the importance of close surveillance to promptly identify progression from chronic phase to advanced phases in CML patients.
Figure 3 Disease-Free Survival of Patients With Complete Hematologic Response
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-5
Prognostic Factors for Survival in CML-BP Conclusion BP remains a challenge in the management of CML. To our knowledge, this is the largest series reported from Mexico regarding the characteristics and outcome of CML-BP patients. In our analysis, the most important factors associated with survival were age (> 60 years), hemoglobin (< 10 g/dL), and complex karyotype. Patients with lymphoid BP as well as those receiving CT plus TKI had a better CHR rate. Nevertheless, the prognosis of this group of patients is still poor, with transitory response to therapy and rapid disease progression.
Clinical Practice Points In recent years, the incidence of BP has decreased significantly
with the introduction of TKI as first-line therapy. Those who progress to BP have a very poor prognosis. In this analysis, characteristics associated with the patient (age),
marrow reserve (hemoglobin level), and the disease itself (chromosomal aberrations, blast cell lineage) determined the prognostic heterogeneity in this entity in relation to response to treatment and outcome. One important finding in our series addresses the potential benefit of combined therapy (CT plus TKI) in CML-BP, as the CHR rate was similar to those reported for second-generation TKI. This has important repercussions in countries with limited access to second-generation TKI, as in Mexico.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Vardiman JW, Melo JV, Baccarani M, et al. Chronic myelogenous leukaemia, BCR-ABL1 positive. In: Jaffe ES, Harris NL, Stein H, et al, eds. World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008:32-7. 2. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Hematol 2014; 89:547-56. 3. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]. Nature 1973; 243:290-3. 4. Sawyers CL, Callahan W, Witte ON. Dominant negative MYC blocks transformation by ABL oncogenes. Cell 1992; 70:901-10. 5. Shuai K, Halpern J, ten Hoeve J, et al. Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene 1996; 13:247-54. 6. Perrotti D, Cesi V, Trotta R, et al. BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. Nat Genet 2002; 30:48-58. 7. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000; 96:3343-56. 8. Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007; 7:441-53. 9. Cortes J. Natural history and staging of chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004; 18:569-84. 10. Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003; 349:1451-64. 11. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002; 107:76-94. 12. Fabarius A, Leitner A, Hochhaus A, et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011; 118:6760-8. 13. Hehlmann R. How I treat CML blast crisis. Blood 2012; 120:737-47. 14. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol 2005; 23:4100-9. 15. Grossmann V, Kohlmann A, Zenger M, et al. A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia 2011; 25:557-60.
6
-
Clinical Lymphoma, Myeloma & Leukemia Month 2015
16. Karbasian Esfahani M, Morris EL, Dutcher JP, et al. Blastic phase of chronic myelogenous leukemia. Curr Treat Options Oncol 2006; 7:189-99. 17. Dutcher JP, Lee S, Paietta E, et al. Phase II study of carboplatin in blast crisis of chronic myeloid leukemia: Eastern Cooperative Oncology Group Study E1992. Leukemia 1998; 12:1037-40. 18. Robak T, Góra-Tybor J. Cladribine combined with mitoxantrone in the treatment of blastic phase of chronic myeloid leukemia. Neoplasma 2001; 48:203-7. 19. Dutcher JP, Morris EL, Gaynor B, et al. A pilot study of carboplatin and mitoxantrone in blast crisis of chronic myeloid leukemia. Med Oncol 2010; 27: 728-35. 20. Kantarjian HM, Talpaz M, Kontoyiannis D, et al. Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, highdose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 1992; 10:398-405. 21. Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009; 23:1054-61. 22. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344:1038-42. 23. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosomeepositive chronic myelogenous leukemia in blast phase. Blood 2002; 99:3547-53. 24. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99:3530-9. 25. Palandri F, Castagnetti F, Testoni N, et al. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year followup. Haematologica 2008; 93:1792-6. 26. Saglio G, Hochhaus A, Goh YT, et al. Dasatinib in imatinib-resistant or imatinibintolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 2010; 116:3852-61. 27. Giles FJ, Kantarjian HM, le Coutre PD, et al. Nilotinib is effective in imatinibresistant or -intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia 2012; 26:959-62. 28. Gratwohl A, Brand R, Apperley J, et al. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 2006; 91:513-21. 29. Deininger M, Schleuning M, Greinix H, et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica 2006; 91:452-9. 30. Kantarjian HM, Keating MJ, Talpaz M, et al. Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. Am J Med 1987; 83:445-54. 31. Coleman M, Silver RT, Pajak TF, et al. Combination chemotherapy for terminalphase chronic granulocytic leukemia: Cancer and Leukemia Group B studies. Blood 1980; 55:29-36. 32. Rosenthal S, Canellos GP, Whang-Peng J, et al. Blast crisis of chronic granulocytic leukemia. Morphologic variants and therapeutic implications. Am J Med 1977; 63: 542-7. 33. López-Karpovitch X, Cárdenas R, Piedras J. Immunophenotypic characteristics of the blast crisis in chronic myeloid leukemia. Rev Invest Clin 1997; 49:31-6. 34. Tang X, Wu D, Xue Y, et al. The morphological, immunophenotypical and cytogenetic characteristics study of blast crisis in chronic myeloid leukemia. Zhonghua Nei Ke Za Zhi 2002; 41:685-7. 35. Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Instituteesponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990; 8:813-9. 36. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122:872-84. 37. Giles FJ, Cortes JE, Kantarjian HM, et al. Accelerated and blastic phases of chronic myelogenous leukemia. Hematol Oncol Clin North Am 2004; 18:753-74. 38. Crespo E, López-Karpovitch X, Abraham-Simón J, et al. Survival, clinical and laboratory characteristics of de novo and secondary megakaryoblastic leukemia. Rev Invest Clin 2003; 55:494-501. 39. Specchia G, Palumbo G, Pastore D, et al. Extramedullary blast crisis in chronic myeloid leukemia. Leuk Res 1996; 20:905-8. 40. Saikia TK, Dhabhar B, Iyer RS, et al. High incidence of meningeal leukemia in lymphoid blast crisis of chronic myelogenous leukemia. Am J Hematol 1993; 43: 10-3. 41. Cervantes F, Rozman M, Rosell J, et al. A study of prognostic factors in blast crisis of Philadelphia chromosomeepositive chronic myelogenous leukaemia. Br J Haematol 1990; 76:27-32. 42. Kantarjian HM, Walters RS, Keating MJ, et al. Treatment of the blastic phase of chronic myelogenous leukemia with mitoxantrone and high-dose cytosine arabinoside. Cancer 1988; 62:672-6. 43. Muehleck SD, McKenna RW, Arthur DC, et al. Transformation of chronic myelogenous leukemia: clinical, morphologic, and cytogenetic features. Am J Clin Pathol 1984; 82:1-14. 44. Silver RT, Cortes J, Waltzman R, et al. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for
Fernando Pérez-Jacobo et al accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica 2009; 94:743-4. 45. Cervantes F, Villamor N, Esteve J, et al. “Lymphoid” blast crisis of chronic myeloid leukaemia is associated with distinct clinicohaematological features. Br J Haematol 1998; 100:123-8. 46. Deau B, Nicolini FE, Guilhot J, et al. The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the
survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study). Leuk Res 2011; 35:777-82. 47. Quintas-Cardama A, Kantarjian H, Garcia-Manero G, et al. A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase. Leuk Lymphoma 2012; 48:283-9. 48. Strati P, Kantarjian H, Thomas D, et al. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. Cancer 2014; 120:373-80.
Clinical Lymphoma, Myeloma & Leukemia Month 2015
-7