Acute Leukemias - Republican Scientific Medical Library

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a 10.3 · CALGB Study 9111 139 Table 10.1. CALGB chemotherapy regimen for acute lymphoblastic leukemia in adults [1, 6] Course I: Induction (4 weeks) Cyclophosphamide* IV 1200 mg/m2 Day 1 Daunorubicin* IV 45 mg/m2 Days 1, 2, 3 Vincristine IV 2 mg Days 1, 8, 15, 22 Prednisone* PO/IV 60 mg/m2/d Days 1–21 L-Asparaginase (E. Coli) SC/IM 6000 IU/m2 Days 5, 8, 11, 15, 18, 22 *For patients >60 years old: Cyclophosphamide 800 mg/m2 Day 1 Daunorubicin 30 mg/m2 Days 1, 2, 3 Prednisone 60 mg/m2/d Days 1–7 In CALGB study 9111, patients received G-CSF 5 lg/kg subcutaneously once daily, starting on day 4 and continuing until the absolute neutrophil count was >1000/ll on two consecutive determinations >24 h apart (see text). Course IIA: Early intensification (4 weeks; repeat once for Course IIB) Intrathecal methotrexate 15 mg Day 1 Cyclophosphamide IV 1000 mg/m2 Day 1 6-Mercaptopurine PO 60 mg/m2/d Days 1–14 Cytarabine SC 75 mg/m2/d Days 1–4, 8–11 Vincristine IV 2 mg Days 15, 22 L-Asparaginase (E. Coli) SC/IM 6000 IU/m2 Days 15, 18, 22, 25 Course III: CNS prophylaxis and interim maintenance (12 weeks) Cranial irradiation 2400 cGy Days 1–12 Intrathecal methotrexate 15 mg Days 1, 8, 15, 22, 29 6-Mercaptopurine PO 60 mg/m2/d Days 1–70 Methotrexate PO 20 mg/m2 Days 36, 43, 50, 57, 64 Course IV: Late intensification (8 weeks) Doxorubicin IV 30 mg/m2 Days 1, 8, 15 Vincristine IV 2 mg Days 1, 8, 15 Dexamethasone PO 10 mg/m2/d Days 1–14 Cyclophosphamide IV 1000 mg/m2 Day 29 6-Thioguanine PO 60 mg/m2/d Days 29–42 Cytarabine SC 75 mg/m2/d Days 29–32, 36–39 Course V: Prolonged maintenance (until 24 months from diagnosis) Vincristine IV 2 mg Day 1 of every 4 weeks Prednisone PO 60 mg/m2/d Days 1–5 of every 4 weeks 6-Mercaptopurine PO 60 mg/m2/d Days 1–28 Methotrexate PO 20 mg/m2 Days 1, 8, 15, 22
140 Chapter 10 · Recent Clinical Trials in <strong>Acute</strong> Lymphoblastic Leukemia by the Cancer and Leukemia Group B However, the patients in the G-CSF group did not complete the planned first 3 months of chemotherapy any more rapidly than did the patients in the placebo group. Overall toxicity was not lessened by the use of G-CSF. After a median follow-up of 4.7 years, the DFS for the patients assigned to G-CSF (median, 2.3 years) was greater compared to those assigned to placebo (median, 1.7 years), although this did not reach statistical significance. The same is true for OS in the two groups (medians, 2.4 years with G-CSF and 1.8 years with placebo). Older age (>60 years) was associated with a lower CR rate, slower neutrophil and platelet recovery, and longer hospitalization during induction, all of which were improved by G-CSF therapy. There was no adverse effect of G-CSF on the outcome of patients with myeloid antigen positive or Ph+ ALL. It was concluded that the addition of G-CSF to the CALGB induction treatment reduced the duration of hematologic toxicity and improved some measures of clinical outcomes, particularly in older patients. G-CSF was therefore added as part of the induction regimen in subsequent trials. 10.4 CALGB Study 9311 Half of all older adults with B-lineage ALL have Ph+ disease, and most of these are not able to undergo allogeneic stem cell transplantation (SCT). In addition, there is considerable room for improving the outcome for the remaining patients with B-lineage ALL. Clinical experience using the immunotoxin, anti-B4 blocked ricin (anti-B4-bR), had demonstrated reduction in tumor size in patients with B-cell lymphoproliferative disorders [7]. There was also evidence that this immunotoxin might be useful in bone marrow purging for patients with follicular lymphomas undergoing autologous bone marrow transplant. Anti-B4-bR (ImmunoGen, Inc., Cambridge, MA) is comprised of an anti-CD19 monoclonal antibody conjugated to blocked ricin, which has cytotoxic activity in lymphoid malignancies and is capable of killing malignant cells resistant to chemotherapy. The Leukemia Committee of the CALGB therefore explored the use of anti-B4 blocked ricin in B-lineage ALL during a minimal disease state. In CALGB study 9311, two 7-day courses of the immunotoxin were given 1 week apart after completion of the first 2 months of intensive therapy given as in the 9111 protocol and prior to the central nervous system (CNS) prophylaxis phase [8]. Serial polymerase chain reaction (PCR) assays of BCR-ABL, immunoglobulin heavy chain (IGH), and Tcell receptor (TCR) genes were used to measure the impact of lineage-specific intensification treatment on minimal residual disease. Eighty-two adults were enrolled; 78 were eligible. The median age was 34 years (range 17 to 81). Sixtysix patients (85%) achieved a complete remission. Forty-six patients received the anti-B4-blocked-ricin, which was generally well tolerated; 80% were able to receive both courses. The most common toxicity was asymptomatic transient elevation of liver function tests in 72%. Lymphopenia occurred in 46%. Two patients developed antibodies to the anti-B4-blocked-ricin. Molecular monitoring before and after the experimental course of intensification did not show a consistent change in the number of leukemia cells remaining, and the immediate posttreatment PCR studies did not correlate with remission duration. Although, intensification therapy with anti-B4-blocked-ricin is feasible for patients with CD19-positive ALL, there was little evidence for additional clinical benefit from the anti-B4blocked ricin. Six patients enrolled on study 9311 had T-cell ALL and lacked the CD19 antigen. In place of the anti-B4bR course, these patients received one course of highdose cytarabine (2 gm/m 2 every 12 h for 6 days) for postremission consolidation. The toxicity of this course was acceptable. Four (67%) of these patients have remained in CCR for longer than 3 years. 10.5 CALGB Study 9511 Two components of these more recent CALGB ALL trials differed from previous group trials: the more extensive use of asparaginase and the use of cyclophosphamide [9]. The addition of these agents appears to have led to improved CR rates and better DFS. CALGB 9511 was a phase II study of pegylated (PEG)-asparaginase as a replacement for E. coli asparaginase in previously untreated adult patients with ALL. The protocol otherwise used the same chemotherapy treatment schedule as delivered in CALGB studies 8811, 9111, and 9311. ALL cells lack asparagine synthetase and are thus dependent on exogenous asparagine for survival. Rapid depletion of asparagine results in selective killing of ALL cells since normal cells are able to synthesize aspar-
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E.H. Estey · S.H. Faderl · H. M.
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E. H. Estey Department of Leukemia
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VI Table of Contents 14 Philadelphi
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VIII Contributors S. H. Faderl Depa
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X Contributors D. Wartenberg Depart
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Therapy of AML Elihu Estey Contents
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a 1.2 · Standard Therapy 3 Table 1
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a 1.2 · Standard Therapy 5 Table 1
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a 1.2 · Standard Therapy 7 tween G
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a 1.2 · Standard Therapy 9 Fig. 1.
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a 1.2 · Standard Therapy 11 of tre
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a 1.2 · Standard Therapy 13 Table
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a 1.2 · Standard Therapy 15 permit
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a References 17 19. Care RS, Valk P
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a References 19 6-thioguanine in th
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Acute Myeloid Leukemia: Epidemiolog
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a 3.1 · Epidemiology 49 3.1.4 Gend
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a 3.2 · Etiology 51 part of the in
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a 3.2 · Etiology 53 for the develo
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a References 55 38. Crane MM, Stom
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Relapsed and Refractory Acute Myelo
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a 4.2 · Prognostic Factors in Pati
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a 4.3 · Treatment of Relapsed and
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a 4.4 · Hematopoietic Stem Cell Tr
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a 4.6 · Gemtuzumab Ozogamicin 65 T
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a 4.7 · Relapsed and Refractory Ac
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a 4.7 · Relapsed and Refractory Ac
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a References 71 The ability of immu
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a References 73 39. Vogler WR, McCa
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a References 75 95. Sievers EL, Lar
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Part II - Acute Lymphoblastic Leuke
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78 Chapter 5 · Acute Lymphoblastic
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Page 71 and 72: 86 Chapter 5 · Acute Lymphoblastic
Page 79 and 80: Molecular Biology and Genetics Meir
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Page 143 and 144: ALL Therapy: Review of the MD Ander
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Page 149 and 150: Treatment of Adult ALL According to
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Page 159 and 160: Philadelphia Chromosome-Positive Ac
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192 Chapter 15 · Burkitt’s Acute
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204 Chapter 16 · Treatment of Lymp
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216 Chapter 17 · The Role of Allog
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230 Chapter 18 · The Role of Autol
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238 Chapter 19 · Novel Therapies i
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248 Chapter 20 · Minimal Residual
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264 Chapter 21 · Central Nervous S
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276 Chapter 22 · Relapsed Acute Ly
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278 Chapter 22 · Relapsed Acute Ly
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Emergencies in Acute Lymphoblastic
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a 23.5 · Hyperleukocytosis 283 LA
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a 23.9 · Neurological Complication
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a References 287 29. Hingorani AD,
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Subject Index A aberrant methylatio
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a Subject Index 291 CREB, see enhan
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a Subject Index 293 MUD, see matche
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