Acute Leukemias - Republican Scientific Medical Library

More documents

Recommendations

Info

a 17.5 · Factors Influencing Transplant Outcome 223 received HLA-mismatched grafts and myeloablative regimens. The largest series was reported by Eurocord, and contains 108 adults, with 32 cases of ALL, with a mean follow up of 20 months. The mean age was 26 years (range 15 to 53 years), mean weight 60 kg (range 35 to 110 kg), and mean number of nucleated cells infused 1.7 ´ 10 7 /kg. The overall 1-year survival was 27%. Survival for early disease stage patients, including CML in chronic phase or acute leukemia in remission, was 39 vs. 17% for those transplanted with more advanced disease. The 60-day probability of neutrophil engraftment was 81% at a mean time of 32 days (range 13 to 60 days). The incidence of acute GVHD ³II was 38%. Most deaths were due to infection or GVHD. These findings were corroborated by other series. The TRM at 100 days approached 43–54% for the myeloablative regimens, and 28–48% using nonmyeloablative regimens [59], with main reasons for TRM being regimen-related toxicity, infection, and relapse. Nucleate cell dose was a significant variable, conferring better outcome when the cell dose was >2´10 7 /kg and/or CD34 cells > 1.2 ´ 10 5 /kg [60, 62]. HLA disparity had less influence on EFS [60]. In summary, despite cell dose limitations, UCBTon clinical protocols may be a viable option for selected adult patients with limited treatment options. Current research in UCB expansion may help to overcome the cell dose limitations and contribute toward reducing the TRM. 17.5.3 Source of Donor Cells: Partially Matched Related or Matched Unrelated Donors The majority of studies indicate that the best chance for cure for refractory or high-risk ALL is allogeneic SCT with a matched related donor. Unfortunately, less than 30% of these patients have a matched sibling donor. Thus, much work continues to be done in making partially matched related donor (PMRD) and matched unrelated donor (MUD) transplantation safe and more feasible as curative therapy. Typically these transplants have been associated with a higher risk of graft rejection, GVHD, and infection. However, more precise HLA matching of donor and recipient via the use of high resolution allele-based typing for class I and II HLA molecules has allowed selection of better matched donors; this has resulted in a progressive improvement in the incidence of severe GVHD, and survival in patients undergoing MUD transplantation [65]. Two large, retrospective series compared the outcome of MUD SCT with autologous SCT. Weisdorf et al. reported the results of 517 ALL patients (median age 14 years, range 1 to 50) who received MUD-SCT and compared them to 195 patients (median age 18 years, range 1 to 50) who underwent autologous SCT between 1989 and 1998. The proportion of patients in CR1 vs. CR2 was similar for both groups. However, patients receiving MUD transplants had a greater frequency of high-risk karyotypes and elevated WBC count at presentation. TRM was higher in the MUD- SCT vs. the autologous SCT group (42 vs. 20%, p=0.004). Conversely, relapse was more frequent after autologous SCT (49 vs. 14% in CR1, 64 vs. 25% in CR2), resulting in net similar outcomes with either transplant approach. Three-year survival rates were 45–50% for patients transplanted in CR1 and 30–40% for patients in CR2 [66]. The Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation (EBMT) reported very similar outcomes for ALL patients receiving MUD SCT (n = 118) compared to those receiving an autologous transplant (n = 236). A significantly higher TRM, from GVHD and graft failure, in the MUD-SCT group was offset by a significantly higher risk of relapse in the autologous SCT group, resulting in similar 2-year LFS for both groups (39% MUD, 32% auto) [67]. Due to the small numbers of patients and differing approaches to partially matched related donor (PMRD) transplantation, little data exists for this investigational approach. Most studies suggest a higher rate of rejection and acute GVHD, but similar overall survival for patients with donors matched for five of the six HLA A, B and DR antigens as with fully matched sibling donors [68]. Greater degrees of mismatch are associated for higher risks of rejection, GVHD and treatment related mortality. Singhal et al. reported the results of 164 patients (84 with ALL) who received a PMRD transplant between 1993 and 1999 at the South Carolina Cancer Center, and compared them to 164 patients (81 with ALL) who received an autologous transplant at the Royal Marsden Hospital, UK between 1984 and 1999 [69]. At 5 years, the cumulative TRM was 52%, incidence of relapse 32%, and DFS 16% for patients receiving PMRD transplants compared to 16%, 54%, and 30%, respectively, for those receiving autologous SCT. The retrospective nature of this study and differences in patient care that can result from two different treatment sites limit the conclusions regarding this comparative study;
224 Chapter 17 · The Role of Allogeneic Stem Cell Transplantation in the Therapy of Adult Acute Lymphoblastic Leukemia (ALL) it does, however, suggest that an autologous SCT may be preferable to PMRD transplantation in the absence of an HLA-matched donor. In summary, the decision to proceed with MUD or autologous transplantation, or to proceed with other “Phase I” approaches for these high-risk patients currently remains very complex, and should be based on the specific situation of each individual patient. 17.5.4 The Role of T-Cell Depletion Studies have shown consistently that a major therapeutic effect of allogeneic SCT is derived from the GVM. There is a reduced risk of relapse in patients with GVHD, and a major difficulty lies in separating the beneficial GVM effect from the adverse consequences of GVHD. This objective is a major focus of ongoing research. GVHD is primarily mediated by donor-derived Tlymphocytes. One approach to prevent acute GVHD, is to deplete T-cells from the donor marrow or PBSC. After initial immune reconstitution, donor T-lymphocytes (DLI) can be administered with a lower risk of GVHD to enhance the GVM anti-leukemic effect. As described previously, Campath-1H, directed against the CD52 antigen, provides a novel approach for both ex vivo and in vivo T-cell purging. The role of T-cell depleted SCT remains controversial. While T-cell depleted SCT are associated with a lower incidence of acute and chronic GVHD, GVM effects may be reduced and leukemia-free survival has not been improved in controlled trials for either matched sibling or unrelated donor transplants. Several groups have reported a decreased risk of relapse with Tcell-depleted SCT by manipulating the preparative regimen to compensate for potential lack of a GVM effect. Aversa et al. evaluated 54 consecutive acute leukemia patients with median age 30 (30 AML, 24 ALL) undergoing ex-vivo, T-cell-depleted BMT using bone marrow from HLA-identical or D-DR-mismatched (two patients) sibling donors [70]. Antithymocyte globulin and thiotepa were added to standard TBI/cyclophosphamide conditioning. The risk of relapse was 12% for AML patients and 28% for ALL patients. At median follow-up of 6.9 years, the EFS for AML was 74%, and 59% for ALL. Schattenberg et al. compared the outcome of HLA-identical, T-cell depleted BMT in patients less than 50 years old versus greater than 50 years old [71]. The standard conditioning regimen of TBI/cyclophosphamide was intensified with the addition of idarubicin at 42 mg/m 2 . The study evaluated 131 patients, which included 34 patients with ALL. The 2-year LFS for the ALL patients in this small study was 64%, which compares very favorably with HLA-identical transplants that are not T-cell depleted. Unmodified transplants from HLA haploidentical donors is associated with a prohibitively high risk of acute GVHD. Transplantation of high doses of CD34+ cells which are extensively depleted of T-lymphocytes has been effective to achieve engraftment without GVHD in these very high risk patients. 17.5.5 Immunomodulation with DLI The presence of a GVM effect is based primarily on observations of lower relapse rates in patients who develop GVHD. Table 17.5 summarizes results obtained from both single institution and registry data, and demonstrates a consistent decrease in relapse rates for patients who develop GVHD vs. those who do not [20, 72, 73]. A GVM effect that is associated with the presence of GVHD has been described in ALL, AML, and CML; interestingly this effect appears most potent in ALL and is reflected by the data in Table 17.5 [74]. In distinct contrast to these consistent observations of the benefit of GVHD in reducing the relapse rate following allogeneic SCT is the marked absence of a significant GVM effect in ALL following DLI. In contrast to CML and AML where DLI often results in complete remissions in patients with relapsed disease following allogeneic transplant, DLI does not appear to be effective for ALL with relapse following an allogeneic transplant. The EBMT Working Party for Acute and Chronic Leukemia studied the effect of DLI on acute and chronic leukemia in relapse after SCT. One hundred thirty-five patients were treated, including 22 with ALL (nine in CR1, five in CR2, eight beyond CR2). The median age of the ALL patients was 21.5. In contrast to 73% of CML patients achieving CR with DLI, no patients with ALL responded [75]. Collins et al. reviewed data on 140 patients receiving DLI at a number of transplant centers. Fifteen patients with ALL were included; three in CR and 12 with progressive disease. There was an 18% response rate to DLI seen in the ALL group in contrast to 60% seen in the CML group [76].
Page 1 and 2:
E.H. Estey · S.H. Faderl · H. M.
Page 3 and 4:
E. H. Estey Department of Leukemia
Page 5 and 6:
VI Table of Contents 14 Philadelphi
Page 7 and 8:
VIII Contributors S. H. Faderl Depa
Page 9 and 10:
X Contributors D. Wartenberg Depart
Page 11 and 12:
Therapy of AML Elihu Estey Contents
Page 13 and 14:
a 1.2 · Standard Therapy 3 Table 1
Page 15 and 16:
a 1.2 · Standard Therapy 5 Table 1
Page 17 and 18:
a 1.2 · Standard Therapy 7 tween G
Page 19 and 20:
a 1.2 · Standard Therapy 9 Fig. 1.
Page 21 and 22:
a 1.2 · Standard Therapy 11 of tre
Page 23 and 24:
a 1.2 · Standard Therapy 13 Table
Page 25 and 26:
a 1.2 · Standard Therapy 15 permit
Page 27 and 28:
a References 17 19. Care RS, Valk P
Page 29 and 30:
a References 19 6-thioguanine in th
Page 31 and 32:
Acute Myeloid Leukemia: Epidemiolog
Page 33 and 34:
a 3.1 · Epidemiology 49 3.1.4 Gend
Page 35 and 36:
a 3.2 · Etiology 51 part of the in
Page 37 and 38:
a 3.2 · Etiology 53 for the develo
Page 39 and 40:
a References 55 38. Crane MM, Stom
Page 41 and 42:
Relapsed and Refractory Acute Myelo
Page 43 and 44:
a 4.2 · Prognostic Factors in Pati
Page 45 and 46:
a 4.3 · Treatment of Relapsed and
Page 47 and 48:
a 4.4 · Hematopoietic Stem Cell Tr
Page 49 and 50:
a 4.6 · Gemtuzumab Ozogamicin 65 T
Page 51 and 52:
a 4.7 · Relapsed and Refractory Ac
Page 53 and 54:
a 4.7 · Relapsed and Refractory Ac
Page 55 and 56:
a References 71 The ability of immu
Page 57 and 58:
a References 73 39. Vogler WR, McCa
Page 59 and 60:
a References 75 95. Sievers EL, Lar
Page 61 and 62:
Part II - Acute Lymphoblastic Leuke
Page 63 and 64:
78 Chapter 5 · Acute Lymphoblastic
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
Page 75 and 76:
Page 77 and 78:
Page 79 and 80:
Molecular Biology and Genetics Meir
Page 81 and 82:
a 6.3 · Structural Aberrations 97
Page 83 and 84:
a 6.3 · Structural Aberrations 99
Page 85 and 86:
a 6.5 · Molecular Aberrations 101
Page 87 and 88:
a References 103 clear that homozyg
Page 89 and 90:
a References 105 53. Chim CS, Tam C
Page 91 and 92:
a References 107 122. Lennard L, Li
Page 93 and 94:
Diagnosis of Acute Lymphoblastic Le
Page 95 and 96:
a 8.3 · Cytochemistry and Immunoph
Page 97 and 98:
a 8.5 · Cytogenetic and Molecular
Page 99 and 100:
a 8.5 · Cytogenetic and Molecular
Page 101 and 102:
a References 127 including the reti
Page 103 and 104:
a References 129 47. Kita K, Shirak
Page 105 and 106:
Acute Lymphoblastic Leukemia: Clini
Page 107 and 108:
a 7.3 · Diagnosis 111 or neoplasti
Page 109 and 110:
a 7.3 · Diagnosis 113 Fig. 7.2. Hi
Page 111 and 112:
a 7.3 · Diagnosis 115 The vast maj
Page 113 and 114:
a References 117 dren: Biologic bas
Page 115 and 116:
General Approach to the Therapy of
Page 117 and 118:
a 9.3 · New Agents 133 dose methot
Page 119 and 120:
a References 135 4. Gökbuget N, Ho
Page 121 and 122:
138 Chapter 10 · Recent Clinical T
Page 123 and 124:
Page 125 and 126:
Page 127 and 128:
Page 129 and 130:
146 Chapter 11 · Conventional Ther
Page 131 and 132:
Page 133 and 134:
Page 135 and 136:
Page 137 and 138:
Page 139 and 140:
Page 141 and 142:
Page 143 and 144:
ALL Therapy: Review of the MD Ander
Page 145 and 146:
a 12.2 · The Hyper-CVAD Regimen in
Page 147 and 148:
a 12.3 · Subset-Specific Approache
Page 149 and 150:
Treatment of Adult ALL According to
Page 151 and 152:
a 13.2 · Therapy for Younger (15-6
Page 153 and 154: a 13.3 · Therapy of Ph/BCR-ABL-Pos
Page 155 and 156: a 13.5 · Prognostic Factors 173 13
Page 157 and 158: a References 175 Only patients with
Page 159 and 160: Philadelphia Chromosome-Positive Ac
Page 161 and 162: a 14.2 · Molecular Biology of the
Page 163 and 164: a 14.3 · Treatment of Ph+ ALL 181
Page 165 and 166: a 14.4 · Hematopoietic Stem Cell T
Page 167 and 168: a References 185 2. Kurzrock R, Sht
Page 169 and 170: a References 187 56. Mori T, Manabe
Page 171 and 172: a References 189 acute lymphoblasti
Page 173 and 174: 192 Chapter 15 · Burkitt’s Acute
Page 185 and 186: 204 Chapter 16 · Treatment of Lymp
Page 197 and 198: 216 Chapter 17 · The Role of Allog
Page 203: 222 Chapter 17 · The Role of Allog
Page 211 and 212: 230 Chapter 18 · The Role of Autol
Page 219 and 220: 238 Chapter 19 · Novel Therapies i
Page 229 and 230: 248 Chapter 20 · Minimal Residual
Page 245 and 246: 264 Chapter 21 · Central Nervous S
Page 255 and 256:
274 Chapter 21 · Central Nervous S
Page 257 and 258:
276 Chapter 22 · Relapsed Acute Ly
Page 259 and 260:
278 Chapter 22 · Relapsed Acute Ly
Page 261 and 262:
Emergencies in Acute Lymphoblastic
Page 263 and 264:
a 23.5 · Hyperleukocytosis 283 LA
Page 265 and 266:
a 23.9 · Neurological Complication
Page 267 and 268:
a References 287 29. Hingorani AD,
Page 269 and 270:
Subject Index A aberrant methylatio
Page 271 and 272:
a Subject Index 291 CREB, see enhan
Page 273 and 274:
a Subject Index 293 MUD, see matche
show all

Acute Leukemias - Republican Scientific Medical Library

Create successful ePaper yourself

Delete template?

Save as template?