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184 Chapter 14 · Philadelphia Chromosome-Positive <strong>Acute</strong> Lymphoblastic Leukemia Table 14.3. Outcomes after hematopoietic stem cell transplant Ref. Author Years N EFS years [94] Barrett, et al. 1978–1990 67 31% 2y [101] Snyder, et al. 1984–1997 23 64% 3y appear to have a significant effect on outcome, as the higher risks of relapse in the related setting is offset by problems with GVHD in the unrelated setting [41]. 14.5 The Detection of Minimal Residual Disease As noted above, disease burden at the time of transplant has a strong impact on survival. This effect is also evident when looking at more subtle levels of disease that can be detected by sensitive methods of MRD detection (especially RT-PCR assays for BCR-ABL). Thus, the detection of MRD after induction and consolidation therapy is fairly common in Ph+ ALL, and is associated with an increase risk of relapse [103–105]. By using quantitative RT-PCR for BCR-ABL, Pane et al. [104] found that patients who achieved >3 log reduction after consolidation had a significantly better DFS and OS. Moreover, analysis of the MRD during the phase II Imatinib studies showed that the kinetics in the reduction in the number BCR-ABL predicted the group of “good responders” with a longer time to progression [106]. Furthermore, high levels of MRD at diagnosis, and an increase in the level of MRD ³2 logs predicted patients at a high risk of relapse [107]. MRD after HSCT also predicts relapse. Unlike the chemotherapy setting, a significant percentage of patients who undergo allogeneic HSCT become BCR- @ 26%/22% 3y ABL negative after transplant. The detection of MRD by RT-PCR correlates strongly with subsequent relapse, usually within 3 months; the risk seems to be higher for patients with the p190 BCR-ABL transcript compared to the p210 variant [10, 41, 98, 103, 105, 108, 109]. Moreover, the MRD status prior to transplant has been shown to be significantly predictive of EFS [41, 74, 110]. 14.6 Conclusion Despite advances in conventional chemotherapy and targeted therapy, Ph+ ALL continues to be a very poor prognostic variable in adult and pediatric ALL. A better understanding of the molecular biology of BCR-ABL may lead to advances in more active targeted therapies, but for now, the only curative modality remains stem cell transplantation. As advances in this modality increase, the likelihood of potential cures with transplantation combined with novel targeted therapy likely looms at the best strategy for curative therapy. References Comments Similar results for CR1 and >CR1 All patients studied in CR1 [95] Dunlop, et al. 1986–1995 19 EFS: 2/9 autologous, 2/11 MRD (12 CR1, 3 CR, 5 RLPS) [42] Arico, et al. 1986–1996 38 *65% 5y EFS with autologous transplant: 6/25 [100] Sierra, et al. 1988–1995 18 49% 2y All matched unrelated donors [96] Kroger, et al. 1990–1997 14 38% 3y 13 MRD, 6 URD, 5 autologous. DFS for allogeneic transplants in 1 st CR 46% at 3y. [97] Esperou, et al. 1992–2000 121 – 2 yr OS: 50% for CR1 and 17% for >CR1 [75] Thomas, et al. 1994–2002 140 **24% 5y 75 allogeneic, 65 autologous. 3 year DFS 15% for autografted patients and 34% for allografted MRD: matched related donor. URD: unrelated donor. (@): 26% 3y DFS for autologous bone marrow transplantation; 22% 3y DFS for allogeneic bone marrow transplantation. (-) Not reported. (*) Estimated EFS in patients treated with HLA-Matched related donor. (**) Reported on 198 patients diagnose with Ph+ ALL and treated on protocol LALA-94. 1. Rubin CM, Carrino JJ, Dickler MN, Leibowitz D, Smith SD, Westbrook CA (1988) Heterogeneity of genomic fusion of BCR and ABL in Philadelphia chromosome-positive acute lymphoblastic leukemia. Proc Natl Acad Sci 85(8):2795–2799
a References 185 2. Kurzrock R, Shtalrid M, Gutterman JU, Koller CA, Walters R, Trujillo JM, et al. (1987) Molecular analysis of chromosome 22 breakpoints in adult Philadelphia-positive acute lymphoblastic leukaemia. Br J Haematol 67(1):55–59 3. Hooberman AL, Carrino JJ, Leibowitz D, Rowley JD, Le Beau MM, Arlin ZA, et al. (1989) Unexpected heterogeneity of BCR-ABL fusion mRNA detected by polymerase chain reaction in Philadelphia chromosome-positive acute lymphoblastic leukemia. Proc Natl Acad Sci 86(11):4259–4263 4. Hermans A, Heisterkamp N, von Linden M, van Baal S, Meijer D, van der Plas D, et al. (1987) Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell 51(1):33–40 5. Gehly GB, Bryant EM, Lee AM, Kidd PG, Thomas ED (1991) Chimeric BCR-abl messenger RNA as a marker for minimal residual disease in patients transplanted for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 78(2):458–465 6. Maurer J, Kinzel H, Nentwig T, Thiel E (1990) Molecular diagnosis of the Philadelphia chromosome in chronic myelogenous and acute lymphoblastic leukemias by PCR. Dis Markers 8(4):211–218 7. Okamoto K, Karasawa M, Sakai H, Ogura H, Morita K, Naruse T (1997) A novel acute lymphoid leukaemia type BCR/ABL transcript in chronic myelogenous leukaemia. Br J Haematol 96(3):611–613 8. Inukai T, Sugita K, Suzuki T, Ijima K, Goi K, Tezuka T, et al. (1993) A novel 203 kD aberrant BCR-ABL product in a girl with Philadelphia chromosome positive acute lymphoblastic leukaemia. Br J Haematol 85(4):823–825 9. Secker-Walker LM, Craig JM, Hawkins JM, Hoffbrand AV (1991) Philadelphia positive acute lymphoblastic leukemia in adults: Age distribution, BCR breakpoint and prognostic significance. Leukemia 5(3):196–199 10. Radich J, Gehly G, Lee A, Avery R, Bryant E, Edmands S, et al. (1997) Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation. Blood 89(7):2602–2609 11. Saglio G, Pane F, Gottardi E, Frigeri F, Buonaiuto MR, Guerrasio A, et al. (1996) Consistent amounts of acute leukemia-associated P190BCR/ABL transcripts are expressed by chronic myelogenous leukemia patients at diagnosis. Blood 87(3):1075–1080 12. Lichty BD, Keating A, Callum J, Yee K, Croxford R, Corpus G, et al. (1998) Expression of p210 and p190 BCR-ABL due to alternative splicing in chronic myelogenous leukaemia. Br J Haematol 103(3):711–715 13. Secker-Walker LM, Cooke HM, Browett PJ, Shippey CA, Norton JD, Coustan-Smith E, et al. (1988) Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. Blood 72(2):784–791 14. Haferlach T, Winkemann M, Ramm-Petersen L, Meeder M, Schoch R, Weber-Matthiesen K, et al. (1997) New insights into the biology of Philadelphia-chromosome-positive acute lymphoblastic leukaemia using a combination of May-Grunwald-Giemsa staining and fluorescence in situ hybridization techniques at the single cell level. Br J Haematol 99(2):452–459 15. Anastasi J, Feng J, Dickstein JI, Le Beau MM, Rubin CM, Larson RA, et al. (1996) Lineage involvement by BCR/ABL in Ph+ lymphoblastic leukemias: Chronic myelogenous leukemia presenting in lymphoid blast vs Ph+ acute lymphoblastic leukemia. Leukemia 10(5):795–802 16. Estrov Z, Talpaz M, Kantarjian HM, Zipf TF, McClain KL, Kurzrock R (1993) Heterogeneity in lineage derivation of Philadelphia-positive acute lymphoblastic leukemia expressing p190BCR-ABL or p210BCR-ABL: Determination by analysis of individual colonies with the polymerase chain reaction. Cancer Res 53(14):3289– 3293 17. Secker-Walker LM, Craig JM (1993) Prognostic implications of breakpoint and lineage heterogeneity in Philadelphia-positive acute lymphoblastic leukemia: A review. Leukemia 7(2):147–151 18. Craig JM, Hawkins JM, Yamada T, Ganeshaguru K, Mehta AB, Secker-Walker LM (1990) First intron and M-bcr breakpoints are restricted to the lymphoid lineage in Philadelphia positive acute lymphoblastic leukemia. Leukemia 4(10):678–681 19. Pajor L, Vass JA, Kereskai L, Kajtar P, Szomor A, Egyed M, et al. (2000) The existence of lymphoid lineage restricted Philadelphia chromosome-positive acute lymphoblastic leukemia with heterogeneous bcr-abl rearrangement. Leukemia 14(6):1122–1126 20. Kasprzyk A, Harrison CJ, Secker-Walker LM (1999) Investigation of clonal involvement of myeloid cells in Philadelphia-positive and high hyperdiploid acute lymphoblastic leukemia. Leukemia 13(12):2000–2006 21. Castor A, Nilsson L, Astrand-Grundstrom I, Buitenhuis M, Ramirez C, Anderson K, et al. (2005) Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 11(6):630–637 22. Schenk TM, Keyhani A, Bottcher S, Kliche KO, Goodacre A, Guo JQ, et al. (1998) Multilineage involvement of Philadelphia chromosome positive acute lymphoblastic leukemia. Leukemia 12(5): 666–674 23. Cobaleda C, Gutierrez-Cianca N, Perez-Losada J, Flores T, Garcia- Sanz R, Gonzalez M, et al. (2000) A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood 95(3): 1007– 1013 24. Hotfilder M, Rottgers S, Rosemann A, Schrauder A, Schrappe M, Pieters R, et al. (2005) Leukemic stem cells in childhood high-risk ALL/t(9;22) and t(4;11) are present in primitive lymphoid-restricted CD34+CD19- cells. Cancer Res 65(4):1442–1449 25. Voncken JW, Morris C, Pattengale P, Dennert G, Kikly C, Groffen J, et al. (1992) Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice. Blood 79(4):1029– 1036 26. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J (1990) <strong>Acute</strong> leukaemia in bcr/abl transgenic mice. Nature 344(6263):251–253 27. Voncken JW, Kaartinen V, Pattengale PK, Germeraad WT, Groffen J, Heisterkamp N (1995) BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice. Blood 86(12):4603–4611 28. Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC, et al. (1998) Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/ abl-transduced bone marrow. Blood 92(10):3780–3792 29. Wetzler M, Talpaz M, Van Etten RA, Hirsh-Ginsberg C, Beran M, Kurzrock R (1993) Subcellular localization of Bcr, Abl, and Bcr- Abl proteins in normal and leukemic cells and correlation of expression with myeloid differentiation. J Clin Invest 92(4):1925– 1939
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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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Molecular Biology and Genetics Meir
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a 6.3 · Structural Aberrations 97
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a 6.3 · Structural Aberrations 99
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a 6.5 · Molecular Aberrations 101
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a References 103 clear that homozyg
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a References 105 53. Chim CS, Tam C
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a References 107 122. Lennard L, Li
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Diagnosis of Acute Lymphoblastic Le
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a 8.3 · Cytochemistry and Immunoph
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a 8.5 · Cytogenetic and Molecular
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a 8.5 · Cytogenetic and Molecular
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a References 127 including the reti
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a References 129 47. Kita K, Shirak
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Acute Lymphoblastic Leukemia: Clini
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a 7.3 · Diagnosis 111 or neoplasti
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a 7.3 · Diagnosis 113 Fig. 7.2. Hi
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a 7.3 · Diagnosis 115 The vast maj
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a References 117 dren: Biologic bas
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236 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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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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