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62 Chapter 4 · Relapsed and Refractory <strong>Acute</strong> Myeloid Leukemia 4.4 Hematopoietic Stem Cell Transplantation 4.4.1 Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation 4.4.1.1 In Relapsed AML Allogeneic HSCT remains the only known curative treatment for patients with relapsed or refractory AML. However, only a minority of patients benefit from this strategy. Gale and colleagues demonstrated significantly better leukemia-free survival (LFS) with matched sibling donor (MSD) HSCT compared to chemotherapy in adults younger than or equal to 30 years and CR1 longer than 1 year (41% vs. 17%; P = 0.017) or adults older than 30 years and CR1 shorter than 1 year (18% vs. 7%) [52]. Three-year probabilities of TRM with chemotherapy and transplantation were 7% vs. 56%, respectively. It is reasonable to consider HSCT in early first relapse in younger (< 60 years) adults if a suitable MSD is readily available. Clift and colleagues demonstrated a 5-year DFS of 28% and a cure rate of 25–30% among 126 patients transplanted for AML in first untreated relapse [53]. These results are comparable when MSD-HSCT is carried out in CR2 [54, 55]. Reiffers and colleagues demonstrated a 3-year DFS of 35% among 459 patients. Moreover, approximately 50% of patients in first relapse successfully achieved CR2 and 15–20% died during reinduction chemotherapy [55]. A widely adopted strategy is to induce CR2 with salvage chemotherapy followed by allogeneic HSCT. There is no standard chemotherapy regimen for this clinical setting. The selection of one regimen over the other is based on CR1 duration and age. The FLAG +/– idarubicin regimen (fludarabine, ara-C, G-CSF) had been used for cytoreduction, followed by either matched sibling or MUD-HSCT with some success [56]. Promising results have been reported with either autologous or allogeneic HSCT using a preparative regimen which includes increased radiation dose delivered by 131 I-labeled anti- CD45 antibody [57, 58]. Generally, younger patients proceed to HSCT. A MSD may be preferred compared to a matched-unrelated donor (MUD) to avoid potentially prohibitive TRM, but the best choice between either of these strategies and auto-HSCT has not been prospectively studied. The role of autologous HSCT in younger patients with CR1 > 1 year is unclear, since there are no randomized trials comparing this approach with MUD- HSCT. Finally, patients between the ages of 30 to 60 and CR1 duration of < 1 year are also candidates for MSD- HSCT. All other adult patient subgroups may be best approached with investigational agents in the context of a well-design clinical trial. It is important to emphasize that interpretation of data comparing HSCT and chemotherapy as consolidation therapy should be viewed with caution. Differing results are likely, in part, due to patient selection bias and difficulties in defining duration of response in chemotherapy arm because most patients proceed to other therapies including HSCT. Lastly, the superiority of any particular treatment modality should account for the prognostic factors and associated treatment-related morbidity and mortality. 4.4.1.2 Relapse After Transplantation Relapse following allo-HSCT in CR2 is the major cause of treatment failure. The optimal management of patients relapsing after allo-HSCT is controversial. Without further therapy, the median survival of patients relapsing after an allo-HSCT is approximately 3–4 months. Options such as immunotherapy, donor lymphocyte infusion (DLI), or a second allo-HSCT after a fully myeloablative conditioning have been explored, but result in limited success. Choi and colleagues treated 16 patients who relapsed after allo-HSCT with cytoreductive chemotherapy followed immediately by G-CSF-primed DLI [59]. Ten of the 16 patients achieved CR, of whom 4 remained in CR at the time of publication. The OS at 2 years was 31%. The duration of CR after HSCT (> or < 6 months) was the only significant prognostic factor for OS. Interestingly, all five patients who relapsed after the chemotherapy followed by DLI strategy did so in extramedullary sites. This observation has been previously made [60]. Retrospective data indicate that response rates to DLI for relapsed AML range from 15 to 30%. However, CRs are durable in a minority of patients [61]. Associated toxicities of DLI include acute GVHD (> grade II in 30%) and a TRM rates are estimated to be up to 20%. In younger patients refractory to DLI, or among those with a longer CR duration after allo-HSCT, it is still important to consider a second allo- HSCT [62]. However, both relapse and mortality rates associated with second transplants are higher, 42% and 30%, respectively in the series from the Center For International Blood and Marrow Transplant Research (CIBMTR) [63] and reduced-intensity conditioning (RIC) transplantation is frequently required.
a 4.4 · Hematopoietic Stem Cell Transplantation 63 Further investigation and development of new approaches for this clinical setting to maximize the effects of GVL and minimize GVHD and toxicity are underway (discussed below). Umbilical cord blood-derived stem cells are yet an alternative source for transplantation for those patients who lack a suitable MSD or MUD [64, 65]. To increase the graft cell dose present in a single umbilical cord unit, double cord units have been evaluated with some success [66]. Although promising none of these transplant approaches from alternative donor stem cell sources can be considered standard of care and remain investigational. 4.4.1.3 In Refractory AML Allogeneic HSCT offers the best chance for achieving sustained CR in primary refractory AML (PR-AML) patients. The outcome appears to be better among patients without peripheral blood blasts and in patients with less than 30% blasts in the bone marrow prior to conditioning [67]. Data from the City of Hope showed a cumulative probability of DFS of 43% at 10 years in 21 young (< 41 years) AML (n = 16) and ALL (n =5) patients after MSD-HSCT [68]. Another study by Biggs and colleagues reported 88 AML patients (< 52 years) who were refractory to at least two courses of cytotoxic chemotherapy and subsequently proceeded to MSD-HSCT. The 3-year probability of LFS in these patients was 21% (14–31%) with a 3-year TRM of 44% [69]. Cook and coworkers showed that allo-HSCT can cure a small proportion of patients refractory to induction chemotherapy [70]. Similar to MUD-HSCT, the use of partially mismatched related donors (PMRD) extends access to allo- HSCT in PR-AML. This novel strategy is a reasonable alternative in patients with no MSD available, and may result in a similar outcome [71]. In a retrospective trial by Singhal and colleagues, the outcome of 24 MSD (median age 24 years) and 19 partially HLA-mismatched related donors (PMRD) (median age 34 years; P = 0.04) allogeneic HSCT recipients with primary refractory AML and other hematological malignancies were compared. All PMRD patients and 90% of the MSD patients achieved CR2 [72]. The advantage of PMRD transplantation over MUD-HSCT is the ready and rapid potential availability of the donor7a factor that is of critical importance in patients with refractory progressive acute leukemia. Haploidentical stem cell transplantation is another alternative strategy which has met with success [73–75]. 4.4.2 Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation During remission, selected patients who are precluded from receiving full ablative HSCT may benefit from RIC or nonmyeloablative (“mini”) HSCT [76–78]. RIC allows patients to benefit from GVL effect without incurring the toxicities of myeloablative conditioning regimens used in fully ablative HSCT. However, the GVL effect usually requires several months to be maximally therapeutic [79, 80]. Therefore, leukemia relapse prior to the establishment of donor chimerism remains a major limitation of RIC. The precise role of this modality as consolidation therapy awaits trials assessing refinements in preparative and immunosuppressive regimens, in the selection of subpopulations of infused effector cells [81] and in the identification of appropriate patients. In addition, RIC followed by haploidentical HSCT is a novel strategy which has also been explored [82, 83]. 4.4.3 Autologous Hematopoietic Stem Cell Transplantation The exact role of autologous HSCT in younger patients with relapsed AML without an HLA matched donor for allo-HSCT remains to be defined. With lack of randomized studies, the data are unclear and demonstrate variable results. Results from the European Group for Blood and Marrow Transplantation (EBMT) registry show DFS probabilities in the range of 30 to 35% for those undergoing autologous HSCT in CR2 [84, 85]. However, autologous HSCT when compared with chemotherapy has not shown statistically significantly improved survival [86]. Moreover, for the majority of AML patients who receive autologous HSCT in CR1 and relapse, a second autologous HSCT is rarely feasible. The EBMT data demonstrate that only 56 of 1579 AML patients (3.5%) were eligible for a second autologous HSCT after failure of the first autologous HSCT in CR1 [87]. A recent analysis by Lazarus and colleagues for the IBMTR (1989–1996) showed superior outcomes with autologous HSCT (n = 668) when compared with MUD-HSCT (n=476) in both CR1 (n =692) and CR2 (n = 452) [88] (Fig. 4.3). However, multiple confounding factors may have favored autologous HSCT including limitations in defining the degree of genetic disparity between unrelated donors–recipient pairs, accrual of
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
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Page 11 and 12: Therapy of AML Elihu Estey Contents
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Page 79 and 80: Molecular Biology and Genetics Meir
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Page 93 and 94: Diagnosis of Acute Lymphoblastic Le
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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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General Approach to the Therapy of
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a 9.3 · New Agents 133 dose methot
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a References 135 4. Gökbuget N, Ho
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138 Chapter 10 · Recent Clinical T
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146 Chapter 11 · Conventional Ther
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ALL Therapy: Review of the MD Ander
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a 12.2 · The Hyper-CVAD Regimen in
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a 12.3 · Subset-Specific Approache
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Treatment of Adult ALL According to
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a 13.2 · Therapy for Younger (15-6
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a 13.3 · Therapy of Ph/BCR-ABL-Pos
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a 13.5 · Prognostic Factors 173 13
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a References 175 Only patients with
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Philadelphia Chromosome-Positive Ac
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a 14.2 · Molecular Biology of the
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a 14.3 · Treatment of Ph+ ALL 181
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a 14.4 · Hematopoietic Stem Cell T
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a References 185 2. Kurzrock R, Sht
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a References 187 56. Mori T, Manabe
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a References 189 acute lymphoblasti
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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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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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