Acute Leukemias - Republican Scientific Medical Library

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a Acknowledgments 143 ment in DFS as reported by others. However, very few relapses after 2 years have been noted. CNS prophylaxis without cranial RT has been well tolerated and has not resulted in an increase in CNS relapses. Longer followup is needed to determine the potential benefit of intensified Dnr on late relapses. Nevertheless, further Dnr dose escalation seems unlikely to result in significant improvements in outcome. Novel agents that eradicate minimal residual disease should be introduced into clinical trials of adult ALL. 10.8 CALGB Study 19801: T-cell ALL in Relapse There have been almost no new drugs introduced into the treatment of ALL in recent years. Nelarabine (Compound 506U78; GlaxoSmithKline) is a pro-drug of 9-Darabinofuranosylguanine (ara-G), a deoxyguanosine analog. Previous studies have demonstrated that immature T-lymphocytes are extremely sensitive to the cytotoxic effects of deoxyguanosine [20]. The toxicity of deoxyguanosine to T-cells is related to the accumulation of deoxyguanosine triphosphate (dGTP) with subsequent inhibition of ribonucleotide reductase, inhibition of DNA synthesis, and resultant cell death. Recent information indicates that the rate of ara-GTP catabolism is similar in T-cells and B-cells, but that initial ara-G concentrations are higher in T-cells than B-cells for a given dose. Thus, T-cells have a greater intracellular exposure to ara-GTP than do B-cells. Prior phase I studies determined a maximum tolerated dose of 40 mg/kg/day for 5 days in adult patients. The dose limiting toxicity was neurologic, consisting of seizures, obtundation and ascending paralysis. As predicted by preclinical in vitro studies, the highest response rates were observed in patients with relapsed Tcell ALL and lymphoblastic lymphoma (LBL). In order to decrease the risk of neurologic toxicities, we tested a dosing regimen of 1.5 g/m 2 given IV once per day on an alternate day schedule (days 1, 3, 5) in an intergroup study carried out by the CALGB and the Southwest Oncology Group (SWOG). Between 1998 and 2001, a total of 40 patients were enrolled, 22 with T-ALL and 18 with LBL [21]. Patients with greater than 25% lymphoblasts within the bone marrow were considered to have ALL. The lymphoblasts had to express at least two T-cell antigens. All patients were refractory to at least one induction regimen or were in first or greater relapse after achieving a CR. Pa- tients could not have evidence of CNS disease and had to have a calculated creatinine clearance of greater than 50 ml/min. A maximum of two induction courses was administered. Each cycle was repeated every 21 days. Those patients achieving a CR were allowed to receive an additional two courses as consolidation therapy. The median age was 34 years (range 16 to 66). There were 33 males and seven females. Of the 21 evaluable patients with ALL, there were six CRs and two partial remissions (PR) for a total response rate of 38% (95% CI, 18–62%). For the 17 evaluable patients with LBL, there were four CRs and no PRs for a total response rate of 24% (95% CI, 7–50%). The overall response rate (CR+PR) for the 38 evaluable patients was 32% (95% CI, 18–49%). One patient had a seizure and subsequent confusion, which resolved. One patient developed hallucinations but was also receiving narcotics. He was retreated without the recurrence of additional neurologic symptoms. The principal toxicity was marrow suppression. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 43% and 33% of patients, respectively. The median OS for the 40 patients was 4.6 months (95% CI, 3–10 months). The median DFS for the 10 patients achieving CR was 9.8 months (95% CI, 3–15 months). The 1-year OS is 32% (95% CI, 16–47%) and the 1-year DFS is 40% (95% CI, 10–70%). These results suggest that nelarabine is well tolerated, and has significant antitumor activity in patients with relapsed or refractory T-cell lymphoblastic leukemia/lymphoma. Studies using nelarabine in patients with newly diagnosed T-cell malignancies are warranted. Acknowledgments We thank the many physicians, nurses, and data managers at each of the CALGB institutions and their affiliated hospitals for their assistance with the conduct of these clinical trials. Drs. Ted P. Szatrowski, Stanley R. Frankel, Edward J. Lee, David A. Rizzieri, Daniel J. DeAngelo, and Wendy Stock have chaired the clinical studies described above. Dr. Clara D. Bloomfield chaired the central cytogenetic review study. This research was supported in part by grants from the National Cancer Institute to the Cancer and Leukemia Group B (CA31946 and CA41287), to the CALGB Statistical Center (CA33601), and to CALGB member institutions.
144 Chapter 10 · Recent Clinical Trials in <strong>Acute</strong> Lymphoblastic Leukemia by the Cancer and Leukemia Group B References 1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, et al. (1995) A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and Leukemia Group B study 8811. Blood 85:2025–2037 2. Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, et al. (1984) Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: A prospective randomized trial by Cancer and Leukemia Group B. Blood 64:267–274 3. Ellison RR, Mick R, Cuttner J, Schiffer CA, Silver RT, Henderson ES, Woliver T, Royston I, Davey FR, Glicksman AS, et al. (1991) The effects of postinduction intensification treatment with cytarabine and daunorubicin in acute lymphocytic leukemia: A prospective randomized clinical trial by Cancer and Leukemia Group B. J Clin Oncol 9:2002–2015 4. Hoelzer D, Thiel E, Löffler H, Büchner T, Ganser A, Heil G. Koch P, Freund M, Diedrich H, Rühl H, et al. (1988) Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71:123–131 5. Sobol RE, Mick R, Royston I, Davey FR, Ellison RR, Newman R, Cuttner J, Griffin JD, Collins H, Nelson DA, et al. (1987) Clinical importance of myeloid antigen expression in adult acute lymphoblastic leukemia. N Engl J Med 316:1111–1117 6. Larson RA, Dodge RK, Linker CA, Stone RM, Powell BL, Lee EJ, Schulman P, Davey FR, Frankel SR, Bloomfield CD, et al. (1998) A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92:1556– 1564 7. Grossbard ML, Freedman AS, Ritz J, Coral F, Goldmacher VS, Eliseo L, Spector N, Dear K, Lambert JM, Blättler WA, T, et al. (1992) Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: A phase I trial of daily bolus infusion. Blood 79:576–585 8. Szatrowski TP, Dodge RK, Reynolds C, Westbrook CA, Frankel SR, Sklar J, Stewart C, Hurd D, Kolitz JE, Velez-Garcia E, et al. (2003) Lineage specific treatment of adult patients with acute lymphoblastic leukemia in first remission with anti-B4-blocked ricin or high-dose cytarabine: Cancer and Leukemia Group B study 9311. Cancer 97:1471–1480 9. Larson RA, Fretzin MH, Dodge RK, Schiffer CA (1998) Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia. Leukemia 12:660–665 10. Asselin BL, Whitin JC, Coppola DJ, Rupp IP, Sallan SE, Cohen HJ (1993) Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Onc 11:1780–1786 11. Kurtzberg J, Asselin B, Pollack B, Bernstein M, Buchanan G (1993) The Pediatric Oncology Group: PEG-L-Asparaginase (PEGasp) vs native E coli asparaginase (asp) for reinduction of relapsed acute lymphoblastic leukemia (ALL): POG #8866 Phase II trial. Proc Am Soc Clin Oncol 12:325 12. Frankel SR, Kurtzberg J, DeOleivera D, Dodge R, Peterson B, Powell BL, Larson RA, Schiffer CA (1996) Toxicity and pharmacokinetics of peg-asparaginase (peg-asp) in newly diagnosed adult acute lymphoblastic leukemia (ALL): CALGB 9511. Blood 88(Suppl 1):669a 13. Frankel SR, Kurtzberg J, DeOliveria D, Dodge R, Peterson B, Powell BL, Kolitz J, Larson RA, Schiffer CA (1997) Toxicity and pharmacokinetics of PEG-asparaginase (PEG-asn) in newly diagnosed adult acute lymphoblastic leukemia (ALL): CALGB 9511. Blood 90(Suppl 1):334a 14. Lee EJ, Petroni GR, Schiffer CA, Freter CE, Johnson JL, Barcos M, Frizzera G, Bloomfield CD, Peterson BA (2001) Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: Results of Cancer and Leukemia Group B study 9251. J Clin Oncol 19(20):4014–4022 15. Rizzieri DA Johnson JL, Niedzwiecki D, Lee EJ, Vardiman JW, Powell BL, Barcos M, Bloomfield CD, Schiffer CA, Peterson BA, et al. (2004) Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: Final results of Cancer and Leukemia Group B study 9251. Cancer 100:1438–1448 16. Hoelzer D, Ludwig WD, Thiel E, Gabmann W, Loffler H, Fonatsch C, et al. (1996) Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 88:495–508 17. Stock W, Dodge RK, Vardiman JW, Bloomfield CD, Caligiuri MA, Frankel S, Stone RM, Larson RA (2001) Treatment of adult acute lymphoblastic leukemia: Phase II trial of dose intensification of daunorubicin and cytarabine followed by high-dose methotrexate and intrathecal methotrexate in place of cranial irradiation (CALGB 19802). Blood 98(Suppl 1):590a (#2472) 18. Stock W, Yu D, Johnson J, Bloomfield CD, Stone RM, Kolitz JE, Wetzler M, Powell B, Vardiman JW, Larson RA (2003) Intensified daunorubicin during induction and postremission therapy of adult acute lymphoblastic leukemia (ALL): Results of CALGB 19802. Blood 102:379a (#1375) 19. Wetzler M, Dodge RK, Mrozek K, Carroll AJ, Tantravahi RR, Block AMW, Pettenati MJ, Le Beau MM, Frankel SR, Stewart CC, et al. (1999) Prospective karyotype analysis in adult acute lymphoblastic leukemia: The Cancer and Leukemia Group B Experience. Blood 93:3983–3993 20. Gandhi V, Plunkett W, Rodriquez CO Jr, Nowak BJ, Du M, Ayres M, Kisor DF, Mitchell BS, Kurtzberg J, Keating MJ (1998) Compound GW506U78 in refractory hematological malignancies: Relationship between cellular pharmacokinetics and clinical response. J Clin Oncol 16:3607–3615 21. De Angelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, Gockermann JP, Mitchell BS, Appelbaum FR, Larson RA (2007) A phase II study of 2-amino-9-D-arabinosyl-6-methoxy-9H-purine (506U78) in patients with relapsed or refractory T-lineage acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): CALGB Study 19801. Blood 109:5136–5142
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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 93 and 94: Diagnosis of Acute Lymphoblastic Le
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196 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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