Chapter 6
Acute Lymphoblastic Leukemia James Nachman • Giuseppe Masera • . W. Archie Bleyer
Contents 6.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . 83 6.2 Classification System and Methods. . . . . . . . . 83 6.3 Incidence. . . . . . . . . . . . . . . . . . . . . . . . . . 84 6.3.1 Age-Specific Incidence. . . . . . . . . . . . 84 6.3.2 Gender-Specific Incidence. . . . . . . . . . 84 6.3.3 Racial/Ethnic Differences in Incidence. . . 85 6.3.4 Incidence Trends . . . . . . . . . . . . . . . . 85 6.4 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . 85 6.5 Clinical Presentations and Molecular Biology. . 86 6.6 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . 88 6.7 Toxicity and Late Effects. . . . . . . . . . . . . . . . 91 6.8 Outcome. . . . . . . . . . . . . . . . . . . . . . . . . . 92 6.9 Summary and Conclusions . . . . . . . . . . . . . . 92 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
6.1 Introduction Acute lymphoblastic leukemia (ALL) represents approximately 2% of the cancers that occured in 15- to 29-year-olds in the United States during the period 1975–2000 [1]. Their dramatically lower survival rate than in children with ALL, and the recent demonstration that pediatric treatment approaches have been substantively more effective than those used by adult oncologists [2–7], lend emphasis to inclusion of this disease in this textbook of cancer during adolescence and young adulthood.
6.2 Classification System and Methods In the International Classification of Childhood Cancer (ICCC) (see Chap. 1), ALL is a subgroup of category I(a), lymphoid leukemia. ICCC has two subcategories of lymphoid leukemia, ALL, and non-ALL lymphoid leukemia. ICCC I(b) is labeled “acute leukemia”, even though the ALLs are in category I(a). ALL is specified by the ICCC to correspond to the International Classification of Disease – Oncology (ICD-O), Version 3 in Morphology Categories 9828-9837. Incidence and survival in this chapter are presented for 15- to 29-year-olds, with comparisons to the age groups 0–15 years and 30–44+ years, as appropriate. For some analyses the entire age range from birth to 85+ years is included. The absence of data in any figure or table within this chapter means that too few cases were available for analysis; it does not mean that the rate or change in rate was zero.
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6.3 Incidence 6.3.1 Age-Specific Incidence Figure 6.1 illustrates the strong dependence of ALL incidence on age, with incidence peaks at the ends of the age spectrum and a nadir between 35 and 40 years of age, which is lower than in any other younger or older age group except infants younger than 1 year of age. Table 6.1 lists, for 5-year age intervals less than 40 years of age, the incidence and incidence trends during 1975–2000, and estimates the number of patients with ALL in the United States in the year 2000. The incidence of ALL as a percentage of all cancers was inversely proportional to age, reflecting the rise in incidence of other cancers beginning at 10 years of age. Within 5-year age groups there was a decrease in incidence in ALL relative to all cancer from 5.8% in 15- to 19-year-olds to 2.0% and 0.3% in 20- to 24-yearolds and 25- to 29-year-olds, respectively. For 15- to 29-year-olds as a group, ALL represented only 2.1% of all cancers. Figure 6.2 shows the age-dependent incidence of ALL relative to other types of leukemia. ALL decreased in incidence across all age groups, while acute myeloblastic leukemia (AML) and chronic myelogenous leukemia increased in incidence beyond age 5 years. ALL was the most common type in the 15- to 19-year group, occurring at an annual rate of 11.5 per million, twice that of AML. However, over the subsequent two 5-year age groups, ALL and AML incidence curves crossed:
Figure 6.1 Incidence of acute lymphoblastic leukemia (ALL) . as a function of age, United States Surveillance, Epidemiology, and End Results (United States SEER) registry, 1975–2000
they were approximately equal in the 20- to 24-year age group, at about 6.6 per million; in the 25- to 29year age group AML occurred at a rate of 7.5 per million, compared with a rate of 4.9 per million for ALL.
6.3.2 Gender-Specific Incidence ALL occurred with greater frequency in males of all ages, as shown in Fig. 6.3, with the male predominance greatest in 15- to 29-year-olds at ratios varying from 1.9 to 2.1.
Table 6.1 Incidence, incidence trends and number of patients with acute lymphoblastic leukemia (ALL) in persons younger than 30 years of age, United States (U.S.), 1975–2000 Age at diagnosis (years)
50 x 109/ l
67.7%
67.7%
65.8%
0.50
CALLA Negative
4.2%
8.4%
8.4%
0.0001
Normal liver
46.3%
60.1%
69.4%
0.0000
49%
54.2%
58.8%
0.05
Normal nodes
48.5%
56.3%
61.7%
0.0007
Hemoglobin > 110 g/ l
8.2%
22.4%
27.3%
0.0000
Normal spleen
Table 6.4 Incidence of presenting features in T-Lineage ALL by age Age (years)
p value
1–9
10–15
16+
WBC > 50 x 109/ l
62.4%
50.3%
60%
0.3
CALLA Negative
69.1%
75%
73.8%
0.38
Normal liver
37.3%
48.8%
48.5%
0.06
Normal spleen
29.4%
44.5%
40.0%
0.002
Normal nodes
24.4%
33.7%
31.1%
0.13
Hemoglobin > 110 g/ l
31.1%
51.0%
60.5%
0.0003
Drug sensitivity testing revealed that leukemic cells from older patients demonstrate an increased in vitro drug resistance to prednisone (PDN) and daunomycin (DNR) [25]. Also, ALL in older adolescents may have a different pattern of promoter methylation compared to younger patients [26]. There appears to be no significant difference in presenting features for patients aged 10–15 years and those aged 16–21 years, with the exception that, in the CCG 1961 trial, the percentage of Hispanic patients decreased and the percentage of African American patients increased in the 16- to 21-year age group compared to the 10- to 15-year age group.
6.6 Treatment Current pediatric protocols are generally based on a model developed by Dr. Riehm for the BFM (BerlinFrankfurt-Munster) study group. Therapy consists of induction/consolidation, interim maintenance, reinduction/reconsolidation (often referred to as delayed intensification), and maintenance phases. Pediatric protocols are characterized by the dose-intensive use of nonmyelosuppressive drugs such as vincristine (VCR), l-asparaginase (l-ASP), corticosteroids; and continuous antimetabolite-based maintenance. CCGmodified BFM therapy is shown in Table 6.5. A fourdrug induction including VCR, PDN, l-ASP, and DNR is followed by an intensive consolidation phase including cyclophosphamide (CPM), cytosine arabinoside
Acute Lymphoblastic Leukemia
(ARA-C), and 6-mercaptopurine (6-MP), and intensive intrathecal methotrexate (MTX) with or without cranial radiation. Interim maintenance consists of high-dose methotrexate with rescue and 6-MP or intravenous (i.v.) VCR, i.v. MTX without rescue, and intramuscular lASP. Following interim maintenance, patients receive a delayed reinduction-reconsolidation phase (European – protocol II; American – delayed intensification) in which dexamethasone (DXM) replaces PDN, doxo-
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rubicin (Dox) replaces DNR, and 6-thioguanine (6TG) replaces 6-MP. Patients then receive maintenance therapy consisting of daily oral 6-MP and weekly oral MTX with or without VCR, PDN pulses and intrathecal MTX. On the other hand, most adult protocols incorporate blocks of high-dose intermittent myelosuppressive chemotherapy including anthracyclines, CPM, etoposide (VP-16), and high doses of ARA-C and MTX [27, 28]. Few adult protocols incorporate a
Table 6.5 Children’s Cancer Group (CCG)-modified Berlin-Frankfurt-Munster (BFM) therapy (CM-BFM). PDN Prednisone, VCR vincristine, DNR daunomycin, l-ASP l-asparaginase, MTX methotrexate, IT ARA-C intrathecal cytosine arabinoside, IT MTX intrathecal MTX, CPM cyclophosphamide, 6-MP 6-mercaptopurine, RT radiation therapy, DEX dexamethasone, DOX doxorubicin, 6-TG 6-thioguanine, CNS central nervous system, p.o. Per os, bid twice daily, tid three times daily, subg. subcutaneous i.m. intramuscular, i.v. intravenous, qd daily, gw weekly Induction
PDN VCR DNR l-ASP IT ARA-C IT MTX
60 mg/m² p.o. days 1–28 (bid or tid) then taper 1.5 mg/m² i.v. days 1, 8, 15 and 22 25 mg/m² i.v. days 1, 8, 15 and 22 6000 U/m² i.m. 3 times per week × 3 weeks beginning day 3 day 1 (age adjusted dosing) day 8 (age adjusted dosing)
Consolidation
PDN CPM 6-MP ARA-C IT MTX RT
Taper 1000 mg/m² i.v. days 0, 14 60 mg/m² p.o. days 0–27 75 mg/m² i.v. days 1–4, 8-11, 15–18, 22–25 days 1, 8, 15, 22 1800 cGy cranial for no CNS disease at diagnosis 2400 cGy cranial + 600 cGy spinal for CNS disease at diagnosis
Interim maintenance (8 weeks)
6-MP MTX
60 mg/m² qd p.o. days 0–41 15 mg/m² qw p.o. days 0, 7, 14, 21, 28, 35
Delayed intensification (7 weeks)
Maintenance (12-week cycles)
CPM 6-TG ARA-C IT MTX
Reinduction (4 weeks) 10 mg/m² p.o. qd days 0–20, then taper for 7 days 1.5 mg/m² i.v. days 0, 7, 14 25 mg/m² i.v. days 0, 7, 14 600 U/m² i.m. days 3, 5, 7, 10, 12, 14 Reconsolidation (3 weeks) 1000 mg/m² i.v. day 28 60 mg/m² p.o. qd days 28–41 75 mg/m² subq/i.v. days 29–32, 36-39 days 29, 36
VCR PDN 6-MP MTX IT MTX
1.5 mg/m² i.v. days 0, 28, 56 60 mg/m² p.o. qd days 0–4, 28-32, 56–60 75 mg/m² p.o. days 0–83 20 mg/m² p.o. days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77 day 0
DEX VCR DOX l-ASP
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delayed-intensification phase and duration of therapy is generally shorter compared to pediatric protocols. There is also increased usage of allogeneic bone marrow transplant in first remission for adults with ALL. There is a perception on the part of adult oncologists that older individuals have significantly greater toxicity associated with VCR and l-ASP. A large number of pediatric trials have shown clearly that older adolescent and young adult ALL patients have a worse outcome compared to younger patients [29–36]. Older adolescent and young adult ALL patients have a higher incidence of induction deaths and deaths in remission compared to younger patients [37]. The fact that older adolescent and young adult patients have a low incidence of favorable cytogenetic abnormalities (t(12;21); hyperdiploidy) may account for some of the outcome difference. Adolescents with leukemia may receive care from either pediatric or medical oncologists. Five studies have suggested that young adult patients with ALL entered on pediatric clinical trials have a significantly better event-free survival (EFS) and overall survival compared to adolescents treated on adult clinical trials [2–7]. In the first published experience, the CCG and Cancer and Acute Leukemia Group B (CALGB) compared outcome for young adult patients aged 16– 21 years treated between 1988 and 1998 (CALGB) and between 1989 and 1995 (CCG) [2]. CALGB trials utilized a five-drug induction and a modified postremission BFM-type therapy. The majority of older adolescent and young adult patients treated on CCG protocols received either CCG-modified BFM or augmented BFM. Compared to CCG-modified BFM, patients receiving augmented BFM received additional courses of VCR and l-ASP during initial consolidation and delayed intensification phases. “Capizzi” MTX was administered during interim maintenance phases. Patients received a second interim maintenance and delayed-intensification phase prior to beginning maintenance. The augmented BFM chemotherapy regimen is shown in Table 6.6. A comparison of dose intensity for various drugs in CCG-modified and augmented BFM is shown in Table 6.7. For patients treated on CALGB trials, the induction rate was 93% and the 6-year EFS was 38%. For patients
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treated on CCG trials, the induction rate was 96% and the 6-year EFS was 64%. Thus, older adolescent and young adult patients with ALL had a significantly better outcome when treated on CCG versus CALGB trials. Comparing the adult and pediatric therapies, patients treated on CCG protocols received significantly more VCR, steroid, and particularly more lASP, and significantly less CPM and ARA-C compared to patients treated on the CALGB protocols. Patients in both groups were well matched for major presenting features such as WBC, unfavorable cytogenetic features, and immunophenotype. In a similar study design, French investigators compared outcomes for patients 15–20 years of age treated on either the FRALLE pediatric trial (N = 77) or the adult LALA trial (N = 100) between June 1993 and November 1999 [3]. FRALLE chemotherapy was similar to BFM therapy, but incorporated VP-16 into consolidation and delayed intensification, and included vindesine in reinduction. All patients received cranial radiotherapy. Adolescents treated on the LALA protocol received a four-drug induction consisting of PDN, VCR, idarubicin, and CPM without l-ASP. Patients were then randomized to an intensive consolidation (mitoxantrone, ARA-C) or a standard consolidation (CPM, ARA-C, 6MP), followed by sequential courses of intermediatedose MTX/ l-ASP, CPM/ARA-C, and VCR, DXM, and ADR. All patients received cranial radiation. On both trials, patients with unfavorable prognostic features who achieved a remission were to receive an allograft if a matched sibling was available, or an autograft. For the FRALLE 93 trial, unfavorable features included WBC > 50 x 109/l, t(9:22), t(4:11), hypodiploidy ( 30 x 109/l, t(9:22), t(1:19), t(4:11), CD10 and CD20 negativity, and myeloid marker positivity. There were no significant differences in presenting features for the two groups. Unfavorable cytogenetics (t(9:22), t(4:11), hypodiploidy) were found in 6% of the FRALLE patients and 5% of the LALA patients. Induction and 5-year EFS rates were 94% and 67%, respectively, for patients treated on FRALLE protocols compared to 83% and 41%, respectively, for patients treated on the LALA protocol.
Acute Lymphoblastic Leukemia
Italian investigators studied the outcome of adolescent patients treated on either pediatric (AIEOP) or adult (GIMEMA) protocols [4]. Patients included were 14–18 years of age and enrolled between April 1996 and October 2003 (AIEOP – 150 patients; GIMEMA – 95 patients). AIEOP protocols were BFM based, while GIMEMA protocols include induction with high-dose anthracycline (550 mg/m2) and high-dose ARA-C as consolidation. No high-dose MTX or a delayed intensification phase was given as in the BFM protocol. Maintenance consisted of courses of VCR, DNR, and CPM. Prognostic features such as immunophenotype and incidence of t(9:22) were similar between the two groups. Initial complete response rates were 94% for AIEOP vs. 89% for GIMEMA. The relapse rate was 17% in the AIEOP trial and 45% for the GIMEMA trial. Two-year overall survival was 80% for AIEOP and 71% for GIMEMA. Dutch investigators compared the outcome for patients 15–20 years of age treated on either the pediatric ALL-9 trial or adult (HOVON) trial (1985–1999) [5]. Compared to the adult chemotherapy program, ALL-9 included a delayed intensification phase, therapy with either high-dose MTX and/or oral low-dose MTX, and maintenance therapy. Fifty-eight percent of patients on the Hovon trial received a bone marrow transplant in first remission compared to only 3% of patients treated on ALL protocols. Remission and 5year EFS rates were 98% and 69% for patients treated on ALL-9 versus 91% and 34% for patients treated on the adult protocols. CCG has presented preliminary outcome results for 262 older adolescent and young adult patients entered on the CCG 1961 trial between November 1996 and June 2002 [8]. Patients were assigned to either a rapid responder (MI Day 7 marrow) or slow responder subgroup (M2/3 Day 7 marrow). Rapid responders were randomized in a 2×2 design to augmented or standard-intensity BFM-type therapy and to one or two delayed intensification phases. Slow early responders received augmented BFM and were randomized to receive or not receive pulses of idarubicin and CPM in the two delayed intensification phases. Seventy three percent of patients had a WBC of 10 years of age developed avascular necrosis (AVN) compared to a 1% incidence for patients 10 years, the incidence was higher for females than for males, 17.4% vs. 11.7% (p = 0.03). On CCG 1882, rapid early responders (Day 7 M1/ M2 marrow) received CCG-modified BFM with or without cranial radiation. Slow responders (Day 7 M3 marrow) were randomized to receive CCG-modified BFM or augmented BFM. All slow responder patients received cranial radiation therapy. Patients receiving CCG-modified BFM received one delayed intensification phase, while patients receiving augmented BFM received two phases. Patients received 21 consecutive days of DXM during the delayed intensification phases. The incidence of AVN was 8.6% for rapid early responder patients, 16.2% for slow responder patients receiving one delayed intensification phase, and 23.2% for slow responder patients receiving two delayed intensification phases [38]. It is unclear why slow responder patients receiving one delayed intensification phase had a twofold increased risk of AVN compared to rapid responder patients receiving the same therapy. Since continuous steroid exposure was thought to be associated with an increased risk for AVN, on the CCG 1961 protocol, rapid early responder patients randomized to two delayed intensification phases and all slow early responder patients (two delayed intensification phases) received DXM on days 0–6 and 14–20 of each delayed intensification phase. Rapid early
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Figure 6.6
Figure 6.7
Five-year survival, ALL, by era during the period 1975–1998, United States SEER
Survival, ALL, 1993–1998, by age, United States SEER
responder patients randomized to one delayed intensification phase received continuous DXM (days 0–20). For patients older than 10 years, rapid early responder patients receiving one delayed intensification (continuous DEX) had an AVN incidence of 13.4% compared to 7.5% for patients receiving two delayed intensification phases (discontinuous DXM; p = 0.002) [38, 39]. For patients receiving the augmented intensity regimens, the incidence of AVN was 15.2% for patients receiving continuous DXM vs. 5.3% for those receiving discontinuous DXM. In the older adolescent and young adult subgroup, the incidence of AVN was 12.4% for patients receiving discontinuous DXM vs. 28% for those receiving continuous DXM.
6.8 Outcome Figure 6.6 illustrates the steady progress in survival that has been accomplished in ALL, with four equal 6-year eras from 1975 to 1998 represented. The 5-year age-dependent survival rates for ALL improved in each age category, with survival being correlated inversely with age. For the population in general, and for both genders, 5-year survival rates for ALL declined with advancing
age. For the most recent interval evaluated, 1993–1998, the 5-year survival rates were highest among those younger than 10 years of age, both above 85% (Fig. 6.7). The 5-year rates decreased substantively for the next age group (10–14 years, 72%); and for the 15- to 19year, 20- to 24-year, and 25- to 29-year age groups were 58%, 49% and 53%, respectively. For the older patients, the 5-year rate was 20–40% (Fig. 6.7). Among females, the 5-year survival rates for the period 1993–1998 were 87%, 55%, 42%, and 14%, respectively, and for males, the corresponding values were 84%, 53%, 18%, and 20%, respectively (Figs. 6.8 and 6.9)
6.9 Summary and Conclusions ALL represented 2.1% of all cancers that occurred in 15to 29-year-olds in the United States over the time period 1975–1999. In the year 2000, approximately 530 persons 15–29 years of age were diagnosed as having ALL. In the years between adolescence and older adulthood, the incidence of ALL decreased gradually as the incidence of acute and chronic myeloid leukemias increased. ALL was the most common type of leukemia in the 15- to 19-year group. In the 20- to 24-year age group,
Acute Lymphoblastic Leukemia
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Figure 6.8
Figure 6.9
Survival, ALL, 1993–1998, females, by age, United States SEERdence of ALL by race/ethnicity,
Survival, ALL, 1993–1998, males, by age, United States SEER
age 0–45 years, United States SEER registry, 1992– 2000
ALL and acute myelogenous leukemia occurred at approximately equal rates; in the 25- to 29-year age group, acute myelogenous leukemia occurred at a rate 1.5 times that of ALL. ALL occurred with greater frequency in males of all ages, with the male predominance greatest in 15- to 29-year-olds, essentially double that in females. At all ages Hispanics had the highest rate of ALL, and African Americans the lowest rate. Among 15- to 29-yearolds the incidence in Hispanics was 1.7-fold higher than in non-Hispanic whites, 2.8-fold greater than in African Americans/blacks, and 2.1 times increased over Asians/Pacific Islanders. Compared to younger patients, older adolescent and young adult patients with ALL have a higher incidence of T-cell immunophenotype, higher hemoglobin levels, a higher (although still low) rate of the t(9:22), a lower incidence of favorable cytogenetics such as high hyperdiploidy or the t(12:21), and a lower incidence of lymphomatous features. During the period 1975–2000, the incidence of ALL increased significantly among those diagnosed before 30 years of age. Among 15- to 29-year-olds, most of the increase was in males, who had the greatest increase in this age group compared with all other ages.
Risk factors for ALL include male gender, young age (2–5 years), Caucasian race/ethnicity, pre- and postnatal radiation exposure; and constitutional syndromes including trisomy 21, neurofibromatosis type 1, Bloom syndrome, Shwachman syndrome, and ataxia-telangiectasia. Survival rates for ALL declined dramatically with advancing age. For the period 1993–1998, the 5-year survival rates were 58, 49 and 53% for the 15- to 19year, 20- to 24-year, and 25- to 29-year age groups, respectively. An improvement in survival has occurred since 1975 in each category of leukemia, although the decrease in mortality among adolescent and young adult patients with ALL lags behind that of younger patients. At present, EFS for older adolescent and young adult patients treated on pediatric trials is 60–70% and the overall survival is between 65 and 75%. Older adolescent and young adult patients have a higher incidence of induction death and death in remission compared to younger patients. The lower incidence of favorable cytogenetics in older adolescent and young adult patients with ALL may, in part, account for the worse outcome. AVN is a serious treatment complication observed almost exclusively in patients >10 years of age, and the
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incidence is highest in the older adolescent and young adult subgroup. The use of discontinuous DXM in DI phases produces a significant decrease in the incidence of AVN. In multiple comparisons of older adolescent and young adult patients with ALL treated on pediatric and adult protocols, there was a consistent and significant difference in both EFS and overall survival favoring patients treated on pediatric trials with the EFS advantage ranging from 20 to 30%. In an editorial accompanying the presentation of the French FRALLE and LALA comparison [40], Dr. Charles Schiffer raised the issue whether the outcome difference favoring adolescents treated on pediatric protocols was a consequence of better regimens, better doctors, or both. The most likely explanation for the EFS and overall survival difference favoring older adolescent and young adult patients with ALL treated on pediatric protocols is the significant differences in chemotherapy utilized by pediatric and adult oncologists, although other factors may also be operating. It appears that pediatric protocols which incorporate a DI, utilize more steroids, VCR and l-ASP; and use lower amounts of alkylating agents, high-dose ARA-C, and anthracyclinies are more effective in treating older adolescent and young adult ALL than adult protocols. Among adult oncologists, there is a perception that older patients have significantly increased toxicity associated with the administration of VCR and l-ASP compared to younger patients. However, pediatric protocols have demonstrated that it is feasible to use intensive VCR and l-ASP in older adolescent and young adult patients with ALL. The vast majority of older adolescent and young adult patients with ALL treated on pediatric trials are treated by university-based pediatric oncologists, while 25–40% of patients treated on adult trials are treated by community-based adult oncologists. However, a United Kingdom study suggested no difference in outcome for adults with ALL treated by universityor community-based adult oncologists [41], but this issue has not been examined in the United States adult ALL trials. Physician compliance with drug administration as mandated by protocol may be an important issue. In
J. Nachman • G. Masara • A. Bleyer
his editorial [40], Dr. Schiffer commented on protocol compliance by pediatric oncologists as “military precision on the basis of a near religious conviction about the necessity of maintaining prescribed dose and schedule come hell, high water, birthdays, Bastille day, or Christmas.” He concluded that, although there are few if any studies proving an advantage for such rigor, it is likely that neither adult university-based nor community-based oncologists meet the pediatric standard. Currently, the three largest adult oncology groups in the United States are developing a clinical trial for young adult patients with ALL that will utilize one arm of the current CCG AALL0232 High Risk ALL pro tocol. On the AALL0232 trial, standard therapy for older adolescent and young adult patients with rapid morphological response, and 3 × 109/l and platelet > 60 × 109/l. High risk for CNS disease, cycles 1–8; low-risk patient, cycles 1, 2; unknown risk, cycles 1–4
b
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