Prognostic Factors in Adolescent and Adult Patients With Acute Lymphoblastic Leukemia With Two Protocols of Chemotherapy: A Cross-Sectional Study

Original Study

Prognostic Factors in Adolescent and Adult Patients With Acute Lymphoblastic Leukemia With Two Protocols of Chemotherapy: A Cross-Sectional Study Edilson Diogenes Pinheiro Junior,1 Luis Fernando Pracchia,2 Beatriz Beitler de Mauriño,3 Gracia Aparecida Martinez,3 Pedro Enrique Dorlhiac-Llacer,4 Andrezza Bertolaci Medina,3 Elvira Deolinda Rodrigues Pereira Velloso5 Abstract Data about Adult Acute lymphoblastic leukemia treatment in South America population is scarce. 88 patients were treated with BFM86 modified or UCLA protocols. The median follow up was 49 months, the overall survival (OS) was 30.5%. Age less than 35y was associated to better OS and in young patients with no other adverse factor, BFM 86m treatment arm was superior. Background: We evaluated the clinical, laboratory, and prognostic factors in adolescent and adult patients with acute lymphoblastic leukemia (ALL). Materials and Methods: In this observational, retrospective, cross-sectional study, we examined the medical records of all consecutive patients with ALL admitted to a public hospital in Brazil from 1990 to 2005. Results: Of the 102 patients included, 88 were treated with 2 protocols of chemotherapy (Berlin-FrankfurtMünster [BFM] 86 modified [BFM-86M] and UCLA [University of California, Los Angeles] protocol). The complete remission (CR), disease-free survival, and overall survival (OS) rate was 70.6%, 27%, and 30.5%, respectively (median follow-up, 49 months). Age < 18 years and no leukemic infiltration in the central nervous system (CNS) at diagnosis were positively associated with CR (P ¼ .03); no bleeding and hepatomegaly at diagnosis and age < 35 years were associated with better OS on multivariate analyses of the whole population (P ¼ .01). OS at 4 years was superior with BFM-86M than with UCLA (49.5% vs. 16%; P ¼ .004), especially in young adults without risk factors. Conclusion: We identified age as the most important prognostic factor in patients with ALL. CNS infiltration, hepatomegaly, and bleeding were associated with lower OS but must be validated in future research with South American populations and worldwide. The BFM-86M protocol can be considered a therapeutic option for young adults (age < 35 years) without adverse prognostic factors. For other patients with ALL, we emphasize the need for different therapeutic approaches. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. 1, e7-14 Published by Elsevier Inc. Keywords: Acute leukemia, Acute lymphoblastic leukemia, Antineoplastic combined chemotherapy protocols, Drug therapy, Prognosis, Survival

1 Universidade de Fortaleza, Hemocentro do Ceará (HEMOCE) and Hospital Monte Klinikum, Fortaleza, CE, Brasil 2 Hospital São Camilo Pompéia, Oncology Program, Secretaria Municipal da Saúde de São Paulo, São Paulo, SP, Brasil 3 Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo and Fundação Pró-Sangue Hemocentro de São Paulo, São Paulo, SP, Brasil 4 Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil 5 Hematology Service, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo; and Cytogenetics Laboratories, Hospital Israelita Albert Einstein, São Paulo, SP, Brasil

2152-2650/$ - see frontmatter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.clml.2014.07.006

Submitted: Apr 15, 2014; Revised: Jul 3, 2014; Accepted: Jul 8, 2014; Epub: Jul 14, 2014 Address for correspondence: Elvira Deolinda Rodrigues Pereira Velloso, MD, MSc, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Avenida Eneas de Carvalho Aguiar, 155 e 1o Andar, São Paulo, SP 05403-000 Brasil E-mail contact: [email protected]

Clinical Lymphoma, Myeloma & Leukemia January 2015

- e7

Prognostic Factors for ALL Introduction Acute lymphoblastic leukemia (ALL) represents < 1% of all neoplasms and < 20% of the leukemia cases in adults, with a high incidence rate after the fifth decade of life. ALL in the childhood usually has a favorable prognosis and excellent induction treatment responses, with disease-free survival (DFS) at 5 years of 80%.1-3 In contrast, in adults, recognizable adverse factors can affect the outcomes, with a DFS of only 30% to 45% at 5 years.4-22 New drugs are progressively emerging, and, with them, the hope for better survival rates persists. Novel nucleosides analogs, such as nelarabine and clofarabine, have demonstrated cytotoxicity in B and T lymphocytes and have been used in pediatric and adult participants of clinical trials.23-28 Monoclonal antibodies, especially anti-CD20 (rituximab), have been used in mature B-cell leukemia, and some groups of researchers have obtained good results in those with the common ALL antigen (CALLA) and pre-B ALL in young and in older patients.29-33 Tyrosine kinase inhibitors have become a recent and excellent strategy to Philadelphia-positive (Phþ) ALL.8,29,34 Other immunotherapy agents, such as inotuzumab ozogamicin (anti-CD22) and the bispecific T-cell engaging compound blinatumomab, have exhibited marked antileukemic activity and are being tested in clinical trials against relapsed ALL.35,36 Very little is known of the clinical and laboratory characteristics of Brazilian patients with ALL or of the prognostic factors and the results of chemotherapy in the adult population. In contrast to the great availability of information for the pediatric ALL population, scanty information about adults in Brazil is a reality. The present study, to the best of our knowledge, reports on the largest series of Brazilian patients with ALL who were treated with 2 main protocols.

Materials and Methods In the present observational, retrospective, cross-sectional study, we examined all consecutive patients with ALL admitted to our institution (a public, university, tertiary hospital in Brazil) from 1990 to 2005. Because ours was a study of medical records only, the requirement for informed consent was waived. The local institutional review board approved the study protocol. The diagnostic criteria for ALL followed the French-AmericanBritish (FAB) cooperative group37 until 2000. Subsequently, the World Health Organization classification38 was used. The determination of complete remission (CR), DFS, and overall survival (OS) also followed international workshop response criteria.39 We verified some of the clinical and laboratorial variables frequently related to ALL at diagnosis and recorded them for analysis. The patients were divided into 3 age groups: 12 to 20, 20 to 35, and > 35 years. Signs and symptoms such as fatigue, bone pain, headache, leukostasis, fever, bleeding, hepatomegaly, splenomegaly, lymphadenopathy, and testicular infiltration, were obtained from the medical records. The laboratory variables analyzed from the medical records included the serum hemoglobin, platelet, leukocyte, circulating blast, and lactate dehydrogenase (LDH) levels, the presence of leukemic infiltration in the central nervous system (CNS), and the results of flow cytometry and karyotyping. We searched for an association between leukocytosis and immunophenotyping as a known prognostic factor (> 30,000/mm3 and B-ALL; and > 100,000/mm3 and T-ALL).4

e8

-

Clinical Lymphoma, Myeloma & Leukemia January 2015

Surface and cytoplasmic antigen expression was considered positive if present in  20% and  10% of the blasts, respectively. Immunologic classification of ALL was done according to the European Group for the Immunological Characterization of Leukemias (EGIL) classification.40 Three karyotype categories were defined with regard to prognosis: favorable (12p and 14q11 rearrangements, hyperdiploidy), intermediate (normal), and unfavorable [BCR/ABL1, 11q23 rearrangement, t(1;19), hypodiploidy, complex karyotype] prognosis.41-43 During the follow-up period, 4 protocols were sequentially used in the treatment of the patients with ALL, independent of patient age: CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), the protocol proposed by Lister et al.10 (vincristine, prednisolone, doxorubicin, and L-asparaginase), the regimen known as the UCLA [University of California, Los Angeles] protocol,44 and the modified protocol from the Berlin-FrankfurtMünster (BFM) study group (BFM-86M).45 Lister’s protocol and CHOP were used until 1994. The UCLA protocol was used without modification from 1994 to 1999. BFM-86M was used from 1999 until 2005, with some alterations, because hepatotoxicity, severe leukopenia, and cognitive alterations were observed. The modifications consisted of a reduction in the methotrexate dose from 5 to 3 g/m2 and in the infusion time from 24 to 4 hours in the consolidation block. 6-Mercaptopurine was reduced to 30 mg/m2 in the re-induction II block. Prophylactic radiotherapy, at the end of re-induction II, was suppressed, and intrathecal methotrexate was added weekly in the induction phase. The UCLA and BFM-86M protocols are detailed in Table 1. All data analysis was performed using the Statistical Package for Social Sciences, version 10.0, for Windows software (SPSS, Chicago, IL). The CR, DFS, and OS rates were measured for the whole population (n ¼ 102) and for the patients who had undergone UCLA or BFM-86M treatment (n ¼ 88) and are reported on an intention-to-treat basis. Associations between the continuous and categorical variables and CR were analyzed using the nonparametric Mann-Whitney U test and Pearson’s chi-square test, respectively. Multivariate analyses for CR were done using the logistic regression method. OS and DFS were estimated using the Kaplan-Meier curve and compared using the log-rank test. Multivariate analysis for OS of the entire population was completed using the Cox proportional hazards regression model. It was not possible to perform multivariate analyses for CR and OS in the subgroups according to the treatment received. All tests were 2-tailed, with an a level of 0.05. OS was measured from the date of diagnosis until death or the last contact with the patient. The 13 patients (11 in second complete remission and 2 with disease refractory to chemotherapy) who had received allografts were censored at the date of transplantation. The same approach was used for the DFS measure.

Results Pretreatment Characteristics During the study period, 189 patients with ALL were admitted to our hospital, and a retrospective analysis was possible for 102 patients. The reasons for the exclusion of the 87 patients, including those with ALL-L3, death before beginning treatment, incomplete medical records, temporary transfer to other hospitals

Edilson Diogenes Pinheiro Junior et al Table 1 Continued

Table 1 BFM-86M and UCLA Protocols Drug

Single or Daily Dosage

Day of Application per Element

Single or Daily Dosage

Day of Application per Element

50 mg/m2 IV

1, 2

Consolidation

BFM-86M protocol

Cycles 1, 3, 5, 7

Induction I Vincristine

Drug

1.5 mg/m2 IV 2

8, 15, 22, 29

Daunorubicin

Daunorubicin

40 mg/m IV

8, 15, 22, 29

Vincristine

2 mg IV

1, 8

L-asparaginase

10,000 U IM

19, 22, 25, 28, 31, 34, 37, 40

Prednisone

60 mg/m2 PO

1-14

L-asparaginase

6000 U/m2 IM

2, 4, 7, 9, 11, 14

Prednisone

60 mg/m2 PO

1-28

Cycles 2, 4, 6, 8

Methotrexate

12 mg IT

1, 8, 15, 22, 29

Teniposide

165 mg/m2 IV

1, 4, 8, 11

Dexamethasone

2 mg IT

1, 8, 15, 22, 29

Cytarabine

300 mg/m2 IV

1, 4, 8, 11

1 g/m2 IV

43 and 71

Cytarabine

75 mg/m2 IV

45-48, 52-55, 59-62, 66-69

6-Mercaptopurine

30 mg/m2 PO

43-70

Methotrexate

12 mg IT

45 and 59

Dexamethasone

2 mg IT

45 and 59

25 mg/m2 PO

1-56

3 g/m2 IV

8, 22, 36, 50

Induction II Cyclophosphamide

Cycle 9

Consolidation 6-Mercaptopurine Methotrexate

2

Citrovorum factor

50 mg/m IV

9, 23, 37, 51

Citrovorum factor

15 mg/m2 IV

9, 10, 23, 24, 37, 38, 51, 52

Methotrexate

12 mg IT

8, 22, 36, 50

Dexamethasone

2 mg IT

8, 22, 36, 50

Re-induction II Vincristine

1.5 mg/m2 IV

8, 15, 22, 29

Daunorubicin

30 mg/m2 IV

8, 15, 22, 29

L-asparaginase

10,000 U IM

8, 11, 15, 18

Dexamethasone

10 mg/m2 PO

1-21

1 g/m2 IV

36

Cyclophosphamide 6-Tioguanine Cytarabine

2

60 mg/m PO

36-45

75 mg/m2 IV/IM

38-41, 45-48

Methotrexate

12 mg IT

38 and 45

Dexamethasone

2 mg IT

38 and 45

6-Mercaptopurine

60 mg/m2 PO/d

18 mo

Methotrexate

20 mg/m2 IM/wk

18 mo

2 mg IV

1, 8, 15, 22

Maintenance

UCLA protocol Induction I Vincristine Daunorubicin

2

50 mg/m IV

1, 2, 3

L-asparaginase

6.000 U/m2 IM

17-28

Prednisone

60 mg/m2 PO

1-28

12 mg IT

8, 15, 22, 29, 36, 43

Dexamethasone

2 mg IT

8, 15, 22, 29, 36, 43

CNS radiotherapy

18 cGy (total dose)

36-50

Methotrexate

owing to crowding in the emergency room, no vacancies available in our hematology service, and the lack of induction chemotherapy drugs.

Methotrexate Leucovorin

690 mg/m2 IV

At 48 h

15 mg/m2 IV 6/6 h

Immediately after MTX

75 mg/m2 PO/d

20 mo

Maintenance 6-Mercaptopurine Methotrexate

2

20 mg/m IM/wk

20 mo

Abbreviations: BFM-86M ¼ Berlin-Frankfurt-Münster 86 modified protocol; CNS ¼ central nervous system; IM ¼ intramuscularly; IT ¼ intrathecally; IV ¼ intravenously; MTX ¼ methotrexate; PO ¼ orally. Patients with CNS infiltration were irradiated with 24 Gy at the end of re-induction II; patients with testicular infiltration were irradiated with 24 Gy at the beginning of BFM-86M treatment.

The mean age of the 102 patients included in the present study was 30.6 years. The median age was 25 years (range, 12-82 years), with 39.2% and 31.4% of the patients aged 12 to 20 years and 21 to 35 years, respectively; 29.4% were > 35 years old. Of the 102 patients analyzed, 57 were male (55.9%). Fatigue, splenomegaly, hepatomegaly, and lymphadenomegaly were the most common symptoms and signals at diagnosis (58.2%, 59.7%, 54.6%, and 52.6% of the patients, respectively). Other clinical findings at diagnosis were fever (38.8%), bone pain (28.6%), bleeding (27.6%), headache (15.3%), leukostasis (8.2%), and testicular infiltration (2.3%). The median hemoglobin, leukocyte, and platelet count was 8.5 g/dl, 26.2  103/mm3, and 47  103/mm3, respectively, with 39 patients having greater leukocytosis. The median percentage of peripheral blasts was 70% (range, 0%-99%). FAB classification was performed for 44 cases, which were equally identified between L1 and L2.37 The B immunophenotype was found in two thirds of the cases; the most prevalent type was BII and BIII (27.5% in each group).40 The expression of myeloid and CD20 antigens was positive in 13.7% and 20% of the patients, respectively. Cytogenetic analysis was possible in 40 patients, and 6 had t(9;22), 2 had BCR/ABL1 detected by polymerase chain reaction, so 8 (20%) were Phþ. A normal karyotype was common (42.5%, 17 of 40), and we identified t(4;11), t(10;11), and t(1;19) in 1 case each. In 4 cases, a hyperdiploid karyotype was detected. The LDH level was superior to 1000 U/L in 14 cases. The documented biopsy results showed skin (1 patient, immunophenotyping T IVb-EGIL), renal (2 patients), and pulmonary (1 patient) infiltration. At presentation, 2 patients were pregnant. CNS involvement was detected in 11 patients (11.8%) and mediastinal tumor in 6 (6.1%). Testicular biopsy confirmed disease in only 1 patient.

Clinical Lymphoma, Myeloma & Leukemia January 2015

- e9

Prognostic Factors for ALL Table 2 Continued

Table 2 Frequency of Clinical and Laboratory Variables Stratified by 2 Main Protocols: BFM and UCLA Variable

Patients (n)

BFM (%)

UCLA (%)

Age (years)

.88

60

No

80

53.8

46.3

4

50

50

Intermediate

20

50

50

Adverse

10

80

20

51.7

48.3

58.1

41.9

Cytogenetic

>35

28

53.6

46.4

Favorable

50

48

52

Female

38

63.2

36.8

52

53.8

46.2

No

33

51.5

48.5

Bone pain Yes

24

54.2

45.8

No

61

52.5

47.5

Headache

.4

Yes

12

41.7

58.3

No

73

54.8

42.5

Yes

8

66.7

33.3

No

79

51.9

48.1

Leukostasis

.48

Fever

.21

Yes

11

72.7

27.3

No

72

52.8

47.2

Yes

12

58.3

41.7

No

76

53.9

46.1

DHL >1000 U/L .88

.08

P Value

.27

CNS infiltration .83

Yes

UCLA (%)

40

31

Fatigue

.78

Abbreviations: BFM ¼ Berlin-Frankfurt-Münster protocol; CNS ¼ central nervous system; DHL ¼ lactate dehydrogenase; FAB ¼ French-American-British cooperative group criteria; UCLA ¼ University of California, Los Angeles, protocol.

The clinical and laboratory characteristics for the patients in the 2 main protocol arms (UCLA and BFM-86M) are listed in Table 2. ALL-L1 was more prevalent in those receiving the UCLA protocol. Although not significant, CNS disease, an unfavorable karyotype, and greater expression of myeloid antigens at diagnosis were more prevalent in the BFM-86M arm.

Yes

32

40.6

59.4

No

53

60.4

39.6

Yes

21

51.7

42.9

Induction Results

No

64

51.6

48.4

Yes

45

46.7

53.3

No

39

59

41

Yes

50

50

50

No

34

55.9

44.1

Yes

43

51.2

48.8

No

41

53.7

46.3

Of the 102 included patients, the CHOP protocol was used in 8, the Lister et al.10 protocol in 6, the UCLA protocol44 in 40, and the BFM-86M45 in 48 patients. Of the 102 patients, 10 died during induction phase before their remission status could be ascertained, and 92 (90.2%) were able to be evaluated for the induction chemotherapy response of the protocols.39 Of the 92 patients, 27 (29.3%) had induction failure and died, mainly of fungal infection. The CR rate was 70.7% (65 of 92), with 76.7% (33 of 43) in the BFM-86M arm and 63.9% (23 of 36) in the UCLA arm (P ¼ .21). Univariate analysis showed that age < 35 years, no complaints of fatigue, no CNS involvement, a BI or BIII immunophenotype, and < 10 application doses of L-asparaginase correlated with a better response. However, only age < 18 years and no CNS involvement were recognized as good independent factors for remission on multivariate analysis (Table 3). Analysis of the treatment variables related to response according to the treatment arm was not possible because of the insufficient number of cases included in each protocol arm.

Bleeding

.66

Hepatomegaly

.26

Splenomegaly

.6

Lymphadenomegaly

.82

Leukocytosis

.96

B cells >30,000 or T cells >100,000

36

52.8

47.2

None

45

53.3

46.7

FAB

.05

L1

14

21.4

78.6

L2

20

55

45

B

58

53.4

46.6

T

25

52

48

Immunophenotyping

.9

Myeloid antigen

-

5

29

Male

BFM (%)

.55

Yes

21-35

.16

Patients (n)

Mediastinal mass

12-20

Gender

e10

P Value

Variable

OS and DFS .17

Yes

14

71.4

28.6

No

74

51.4

48.6

Clinical Lymphoma, Myeloma & Leukemia January 2015

With a median follow-up of 49 months, we observed a median OS of 19 months, with 30.5% of the patients alive at 4 years (Figure 1). The DFS rate at 4 years was 27%. The BFM-86M treatment protocol resulted in better OS than the UCLA protocol

Edilson Diogenes Pinheiro Junior et al Table 3 Multivariate Analysis Results for Induction Response and Overall Survival

Significant Variables For induction response

Refractory CR (%) or Disease or OS at Patients Median OS 4 y (%) (n) (mo)

P Value

86

CNS and age

.03

No CNS, age < 18 years

20

90

10

CNSþ, age > 18 years

66

65.2

34.8

For OS

Figure 2 Overall Survival (OS) at 4 Years of Patients With Acute Lymphoblastic Leukemia According to Treatment Protocol

97

No. of factorsa

.01

1

47

45.2

46.6

>1

50

7.6

11.3

Abbreviations: CNS ¼ central nervous system; CR ¼ complete remission; OS ¼ overall survival. a Factors identified on multivariate analysis for OS were hepatomegaly, bleeding, and age > 35 years at diagnosis.

(49.5% vs. 16%; P ¼ .001; Figure 2). Other variables that favored OS on univariate analysis were age (< 35 years; P ¼ .02), no bleeding (P ¼ .002), no hepatomegaly at diagnosis (P ¼ .03), and CR with induction chemotherapy (P ¼ .001). Again, only age < 35 years, no bleeding, and no hepatomegaly were considered favorable independent prognostic variables on multivariate analysis (Table 3). We constructed a prognostic score using these 3 variables, which revealed an adverse outcome when  2 markers were present (Figure 3). The variables were equally distributed between the UCLA and BFM-86M protocols (Tables 2 and 4). Young patients (especially those aged 12-20 years; Figure 4), no bleeding and no hepatomegaly at diagnosis and the absence of leukocytosis were good prognostic factors for OS when analyzed in the BFM-86M arm on univariate analysis. Bleeding also had statistical relevance in the UCLA protocol arm, and, although few patients had the T immunophenotype or CNS disease at presentation, these patients had very poor OS (Table 4). Young patients, especially

Figure 1 Overall Survival (OS) at 4 Years of Patients With Acute Lymphoblastic Leukemia

Abbreviations: BFM-86M ¼ Berlin-Frankfurt-Münster group 86 modified protocol; UCLA ¼ University of California, Los Angeles, protocol.

those aged 21 to 35 years old, had greater DFS when treated with the BFM-86M protocol than with the UCLA protocol (Table 4).

Discussion The present retrospective analysis, performed in our hospital from 1990 to 2005, reports the clinical and laboratory characteristics, effects of prognostic factors, and outcomes according to the German (BFM-86M) and American (UCLA) treatment protocols44,45 used in Brazilian patients with ALL. The remission induction, OS, and DFS rate was 70.7%, 30.5%, and 27%, respectively, and concordant with many study groups of adult ALL. Age, identified by most study groups, was the main prognostic factor related to CR (age < 18 years) and OS (age < 35 years) in our population on multivariate analysis. The median age (25 years) in our study was younger than that reported Figure 3 Overall Survival (OS) of Patients With Acute Lymphoblastic Leukemia With High (2 or 3) or Low (0 or 1) Risk according to the Development Score (1 Point Each for Hepatomegaly, Bleeding, and Age > 35 Years)

Clinical Lymphoma, Myeloma & Leukemia January 2015

- e11

Prognostic Factors for ALL Table 4 Disease-Free Survival With Stratified Variables per Protocol BFM-86M Variable

Patients (n)

Median DFS (months)

UCLA DFS at 4 years (%)

Patients (n)

Median DFS

DFS at 4 years (%)

P Value

Age (years) 12-20

13

18

46.1

10

27

27.2

.79

21-35

15

60

50

11

15.3

12

.03

>35

7

17.8

0 (24 mo)

4

19.2

35.7

.67

Male

17

20.2

26.7

17

25.6

28.8

.76

Female

18

60

59

8

10.5

0 (12 mo)

.01

Yes

11

18

15

17

.73

No

21

47

10

3

.05

Yes

9

18

3

No

26

47

22

16

.04

Gender

Hepatomegaly

Myeloid antigen —

.12

Immunophenotype B

25

18

19

17

.76

T

9

48

5

16

.01

Abbreviations: BFM ¼ Berlin-Frankfurt-Münster protocol; DFS ¼ disease-free survival; UCLA ¼ University of California, Los Angeles, protocol.

e12

-

by other research studies, reflecting the presence of adolescent patients. The Southwest Oncology Group (SWOG) found that karyotype, but not age, was the most important factor, suggesting that the worse prognosis with advancing age could be related to the appearance of progressive cytogenetic abnormalities.42 CNS infiltration was another finding related to treatment response but not to OS in our investigation. Ten patients had CNS infiltration at diagnosis, and only 4 (40%) entered remission after induction therapy. The United Kingdom Acute Lymphoblastic Leukemia and Eastern Cooperative Oncology Group (UKALL/ ECOG) found inferior OS in patients with relapse in the CNS with or without bone marrow infiltration compared with those without CNS involvement at relapse.46 Treating this sanctuary tissue, whether at diagnosis or relapse, remains a problem. Radiotherapy and/or high-dose methotrexate/cytarabine remain the cornerstones of treatment, but neither can prevent relapse. In our study, hepatomegaly and bleeding at diagnosis were associated with inferior survival on multivariate analysis. Although these factors have not been recognized as relevant to the prognosis,7 they have been related to inferior induction responses and survival and a greater death rate during the induction phase.11,14,47 Considering that hyperleukocytosis is a known adverse prognostic factor, it might be that enlargement of the liver and bleeding (eg, low platelet counts) are both associated with blast infiltration, reflecting the greater tumor burden. We observed an induction remission response as a prognostic factor on univariate analyses but not as an independent variable for OS in our study. However, all the patients with disease refractory to induction treatment had died before the last follow-up examination (April 2005). Quantification of minimal residual disease, an important OS prognostic variable, was not performed in our study because, although this parameter was detected as a valuable tool for

Clinical Lymphoma, Myeloma & Leukemia January 2015

predicting the outcome in childhood ALL in the 1990s, its study in adults with ALL began only after 2002.48 In our study, the distribution of the clinical and laboratory features was balanced between the BFM-86M and UCLA protocols. Although few patients were allocated to each, BFM-86M proved to be superior to the UCLA protocol (Figure 2). We found the same proportion of OS in the age group of 12 to 20 years (childhood ALL), when our BFM-86M protocol was compared with the original treatment described by Reiter et al.45 Good results in the 4-year OS were also reached when young adults (aged 21-35 years) were treated with BFM-86M compared with the unacceptable treatment profile of the UCLA protocol (57% Figure 4 Overall Survival (OS) of Patients With Acute Lymphoblastic Leukemia Who Received the Berlin-Frankfurt-Münster Group 86 Modified Protocol Stratified by Patient Age

Edilson Diogenes Pinheiro Junior et al vs. 8%). Adults > 35 years had disappointing results with both treatment protocols. These data remind us that adults < 35 years should be treated with intensive pediatric protocols, which has suggested by some investigators.45,49,50 Patients with hepatomegaly and, in particular, bleeding had inferior survival with the BFM-86M protocol. This information was confirmed by Kantarjian et al.,14 who observed inferior survival for patients with hepatomegaly and low platelet counts at diagnosis, who had been treated with the hyper-CVAD (hyperfractionated chemotherapy: course A: cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone; course B: methotrexate, cytarabine) regimen.14 All 9 patients with T-lineage ALL who had received the UCLA protocol died within 24 months of their diagnosis. Linker et al.17 did not find the T-immunophenotype to be an unfavorable variable. To date, they have identified more remission responses with T-ALL than with B-CALLA-ALL.17 They presented findings contradictory to ours; however, we had few patients (n ¼ 9) with T-ALL. The absence of cyclophosphamide in the induction UCLA regimen for remission in our population could have been responsible for this poor result. In the BFM-86M arm (regimen containing cyclophosphamide), we observed better OS for those with T-ALL compared with those with B-ALL, without, however, statistical significance (Table 4). Boissel et al.,51 treating French adolescents, observed inferior outcomes with T-ALL for whole study population. When lineage subgroup analysis was performed, they observed an advantage for the T-lineage for event-free survival for adolescents treated with pediatric protocols (FRALLE [French Acute Lymphoblastic Leukaemia]-93). That protocol also did not include cyclophosphamide.51 Buyukasik et al.52 recently reported a retrospective analysis of adult patients with newly diagnosed ALL treated at 4 four institutions in Turkey, with either hyper-CVAD or CALGB 8811 (Cancer and Leukemia Group B; a BFM-based protocol). The CALGB regimen showed a better result, although a high incidence of relapse was observed with both regimens.52 Their study did not explore the risk factors associated with these 2 treatments.52

Conclusion We identified age as the most important prognostic factor in patients with ALL. CNS infiltration, hepatomegaly, and bleeding were associated with lower OS but must be validated in future research with South American populations and worldwide. From our data, the BFM-86M protocol can be considered a therapeutic option for young adults (age < 35 years) without adverse prognostic factors. For other patients with ALL, we emphasize the need for different therapeutic approaches.

Disclosure The authors have stated that they have no conflicts of interest.

References 1. Schorin MA, Blattner S, Gelber RD, et al. Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children’s Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85-01. J Clin Oncol 1994; 12:740-7.

2. Reiter A, Schrappe M, Ludwig WD, et al. Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutives studies of BFM group. Blood 1992; 80:2471-8. 3. Moricke A, Zimmermann M, Reiter A, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010; 24:265-84. 4. Le QH, Thomas D, Ecochard R, et al. Initial and late prognostic factors to predict survival in adult acute lymphoblastic leukaemia. Eur J Haematol 2006; 77:471-9. 5. Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; 106:3760-7. 6. Five-Year Relative and Period Survival (Percent) by Race, Sex, Diagnosis Year and Age: Table 13.15. Lymphocytic Leukemia. Available at: http://seer.cancer. gov/csr/1975_2010/browse_csr.php?sectionSEL¼13&pageSEL¼sect_13_table.15. html. Accessed: Feb 17, 2014. 7. Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol 2004; 22: 4075-86. 8. Ravandi F, O’Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Phþ) acute lymphoblastic leukemia. Blood 2010; 116: 2070-7. 9. Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. Cancer 1999; 86:1216-30. 10. Lister TA, Whitehouse JM, Berad ME, et al. Combination chemotherapy for acute lymphoblastic leukaemia in adults. BMJ 1978; 1:199-203. 11. Gaynor J, Chapman D, Little C, et al. A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 1988; 6:1014-30. 12. Hussein KK, Dahlberg S, Head D, et al. Treatment of acute lymphoblastic leukemia in adults with intensive induction, consolidation and maintenance chemotherapy. Blood 1989; 73:57-63. 13. Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood 1995; 85:2025-37. 14. Kantarjian HM, O’Brien S, Smith TL, et al. Results of treatment with hyperCVAD, a dose-intensive regimen, in adult acute lymphoblastic leukemia. J Clin Oncol 2000; 18:547-61. 15. Gökbuget N, Arnald R, Böhme A, et al. Improved outcome in high risk and very high risk ALL by risk adapted SCT and in standard risk ALL by intensive chemotherapy in 713 adult ALL patients treated according to the prospective GMALL study 07/2003. Blood (ASH Annual Meeting Abstracts) 2007; 110: abstract 12. Available at: http://abstracts.hematologylibrary.org/cgi/content/ abstract/110/11/12?maxtoshow¼&hits¼10&RESULTFORMAT¼&fulltext¼ ImprovedþOutcomeþinþHighþRiskþandþVeryþHighþRiskþALLþbyþRiskþ AdaptedþSCTþandþinþStandardþ&searchid¼1&FIRSTINDEX¼0&volume¼ 110&issue¼11&resourcetype¼HWCIT. Accessed: Feb 17, 2014. 16. Annino L, Vegna ML, Camera A, et al. Treatment of acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMENA ALL 0288 randomized study. Blood 2002; 99:863-71. 17. Linker C, Damon L, Ries C, Navarro W. Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol 2002; 20: 2464-71. 18. Ribera JM, Oriol A, Bethencourt C, et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia: results of the PETHEMA ALL-93 trial. Haematologica 2005; 90:1346-56. 19. Goldstone AH, Richards SM, Lasarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008; 111:1827-33. 20. Mohty M, Labopin M, Boiron JM, et al. Reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-STC) for patients with acute lymphoblastic leukemia (ALL): a survey from the European Group for Blood and Marrow Transplantation (EBMT). Blood (ASH Annual Meeting Abstracts) 2005; 106:abstract 659. Available at: http://abstracts.hematologylibrary.org/cgi/ content/abstract/106/11/659?maxtoshow¼&hits¼10&RESULTFORMAT¼& fulltext¼Reducedþintensityþconditioningþ%28RIC%29þallogeneicþstemþ cellþtransplantation&searchid¼1&FIRSTINDEX¼0&volume¼106&issue¼ 11&resourcetype¼HWCIT. Accessed: Feb 17, 2014. 21. Hunalt M, Harousseau JL, Delain M, et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood 2004; 104:3028-37. 22. Marks DI, Paietta EM, Moorman AV, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood 2009; 114:5136-45. 23. Beesley AH, Palmer ML, Ford J, et al. In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia. Br J Haematol 2007; 137:109-16.

Clinical Lymphoma, Myeloma & Leukemia January 2015

- e13

Prognostic Factors for ALL 24. Jeha S, Gandhi V, Chan KW, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advance leukemia. Blood 2004; 103:784-9. 25. Karp JE, Ricklis RM, Balakrishnan K, et al. A phase 1 clinical-laboratory study of clofarabine followed by cyclophosphamide for adults with refractory acute leukemias. Blood 2007; 110:1762-9. 26. Gökbuget N, Basara N, Baurmann H, et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood 2011; 118:3504-11. 27. Barba P, Sampol A, Calbacho M, et al. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma: the Spanish experience. Am J Hematol 2012; 87: 631-4. 28. DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood 2007; 109:5136-42. 29. Hoelzer D, Goekbuget N, Beck J, et al. Subtype adjusted therapy improves outcome of elderly patients with acute lymphoblastic leukemia (ALL). Blood (ASH Annual Meeting Abstracts) 2004; 104:abstract 2732. Available at: http:// abstracts.hematologylibrary.org/cgi/content/abstract/104/11/2732?maxtoshow¼ &hits¼10&RESULTFORMAT¼&fulltext¼Subtypeþadjustedþtherapyþimprovesþ outcomeþofþelderlyþpatientsþwithþacuteþlymphoblasticþleukemia&searchid¼ 1&FIRSTINDEX¼0&volume¼104&issue¼11&resourcetype¼HWCIT. Accessed: Feb 17, 2014. 30. Raponi S, De Propris MS, Intoppa S, et al. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma 2011; 52: 1098-107. 31. Thomas DA, O’Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol 2010; 28:3880-9. 32. Jabbour E, Hagop K, Thomas D, et al. Phase II study of the hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with CD-20 positive acute lymphoblastic leukemia (ALL). Blood (ASH Annual Meeting Abstracts) 2013; 122:abstract 2664. Available at: http://bloodjournal. hematologylibrary.org/content/122/21/2664. Accessed: Jul 3, 2014. 33. Chevallier P, Robillard N, Houille G, et al. Simultaneous study of five candidate target antigens (CD20, CD22, CD33, CD52, HER2) for antibody-based immunotherapy in B-ALL: a monocentric study of 44 cases. Leukemia 2009; 23:806-7. 34. Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces complete remissions and prolong survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologie dell’Adulto (GIMEMA) LAL0201-B protocol. Blood 2007; 109:3676-8. 35. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an antiCD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol 2012; 13:403-11. 36. Topp MS, Gökbuget N, Zugmaier G, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood 2012; 120:5185-7.

e14

-

Clinical Lymphoma, Myeloma & Leukemia January 2015

37. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33:451-8. 38. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November, 1997. Hematol J 2000; 1:53-66. 39. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21:4642-9. 40. Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9:1783-6. 41. Wetzler M. Cytogenetics in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am 2000; 14:1237-49. 42. Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood 2008; 111:2563-72. 43. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007; 109:3189-97. 44. Linker CA, Levitt LJ, O’Donnell M, et al. Improved results of treatment of adult acute lymphoblastic leukemia. Blood 1987; 69:1242-8. 45. Reiter A, Schrappe M, Ludwig WD, et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood 1994; 84:3122-33. 46. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL): an MRC UKALL12/ECOG 2993 study. Blood 2007; 109:944-50. 47. Sancho JM, Ribera JM, Xicoy B, et al. Results of the PETHEMA ALL-96 trial in elderly patients with Philadelphia chromosome-negative acute lymphoblastic leukemia. Eur J Haematol 2007; 78:102-10. 48. Brüggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 2006; 107:1116-23. 49. Nachman J. Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 2005; 130:166-73. 50. Barry E, DeAngelo DJ, Neuberg D, et al. Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols. J Clin Oncol 2007; 25: 813-9. 51. Boissel N, Auclerc MF, Lhéritier V, et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 2003; 21: 774-80. 52. Buyukasik Y, Acar K, Kelkitli E, et al. Hyper-CVAD regimen in routine management of adult acute lymphoblastic leukemia: a retrospective multicenter study. Acta Haematol 2013; 130:199-205.