Which Patients with Adult Acute Lymphoblastic Leukemia Should Undergo a Hematopoietic Stem Cell Transplantation? Case-Based Discussion

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1 Which Patients with Adult Acute Lymphoblastic Leukemia Should Undergo a Hematopoietic Stem Cell Transplantation? Case-Based Discussion Hillard M. Lazarus and Selina Luger Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio The decision to proceed to transplant for adult patients with acute lymphoblastic leukemia (ALL) is not clearcut. Relapse and nonrelapse mortality continue to plague the outcome of hematopoietic stem cell transplantation (HSCT) even when undertaken in complete remission (CR). Those considered to be at high risk for relapse often are considered for HSCT in first complete remission (CR1) while those at lower risk may not be referred until they have relapsed, when their chances for cure are very poor. In some patients who have a suitable histocompatible sibling, disease- or patient-related factors may override the potential benefit of allogeneic HSCT. Because many patients do not have a suitable histocompatible sibling, Would You Recommend Stem Cell Transplantation for Either of These Patients? Case 1: A 32-year-old woman with no significant past medical history presented to her physician with a 2- week history of abdominal discomfort, a 20-pound weight loss over 2 months, and hepatosplenomegaly. Laboratory studies revealed a white blood cell (WBC) count of 14,200/µL with circulating blasts expressing CD34, CD45, CD19 and CD20. Cytogenetics revealed a normal karyotype. The final diagnosis was pre B-cell acute lymphoblastic leukemia (ALL), Philadelphia-chromosome negative (Ph ). She was given induction therapy and attained a complete remission (CR). She has an HLA-identical brother. Case 2: A 64-year-old man was evaluated for a 4- month history of progressive cytopenias. Bone marrow exam showed extensive, diffuse infiltration by mostly small- and intermediate sized mononuclear cells that, on flow cytometry, expressed CD45 dim, CD38 and CD19 and the karyotype revealed t(4:11). The final diagnosis was pre-b cell ALL, Ph, with a t(4:11) karyotype abnormality. He was treated with daunorubicin, vincristine and prednisone. Repeat bone marrow study revealed persistent leukemia. The patient was believed to be refractory to induction therapy. He also had fever and typhlitis. He later was given highdose methotrexate, cytarabine, cyclophosphamide, vincristine, doxorubicin and dexamethasone. The bone marrow examination revealed no residual leukemia. He attained a CR and has an HLA-identical sister. one has to consider the relative merits of autologous transplantation versus use of an alternative allogeneic stem cell source, such as a matched-unrelated donor (MUD), umbilical cord blood (UCB) donor, or haploidentical donor. Deciding among these options in comparison to chemotherapy even in high-risk patients is difficult. In the review, the risks and benefits of these choices are discussed to determine whether and by what means to proceed to HSCT in adult patients with ALL who are in CR1. Presented are two patients with ALL and a discussion of how the data we provide would lead to a decision about the selection of therapy. Discussion Contrary to the excellent results achieved in pediatric patients, the outcomes for ALL in adult patients are disappointing. There is considerable evidence that the biologic and clinical characteristics of this disease change dramatically from childhood to adult age groups, including immunophenotype and karyotype. These differences must be recognized when making treatment recommendations for adult ALL patients. While in recent multicenter trials more than 90% of adult patients with ALL younger than 60 years attain CR, conventional chemotherapy is a long arduous process and will result in long-term survival in only one-third of patients. A number of prognostic factors identified at diagnosis are associated with low probability of cure in adult patients with ALL receiving conventional therapy. Such factors include high WBC count at diagnosis (>30,000/µL for B-cell lineage and >100,000/µL for T-cell lineage), specific clonal cytogenetic abnormalities such as the presence of Ph, age older than 35 years, extramedullary disease and time to attain CR longer than 4 weeks, although the latter was not observed in the largest ALL study conducted in adults. 1 Adverse Factors The presence of the Ph chromosome affects the chance of remission after induction, as well as the risk of relapse, when using conventional chemotherapy. A recent publication by Moorman et al 2 described other karyotypes that portend a poor prognosis. Age remains an important prognostic factor. In many studies including the French proto- 444 American Society of Hematology

2 col LALA-87, 3 age older than 35 years decreases the chance of remission as well as increases the risk of relapse in patients given conventional chemotherapy. In the international MRC-ECOG UKALLXII/E2993 trial, patients older than 35 years with high WBC counts at presentation had a dismal outcome when using conventional chemotherapy. 1 It remains unclear whether that outcome can be improved with transplantation. Molecular Monitoring Several investigators have introduced more sensitive molecular techniques such as clonal immunoglobulin or T- cell receptor gene rearrangements to detect minimal residual disease (MRD) that can accurately predict relapse in patients with ALL. 4 Pediatricians have recognized that molecular persistence of residual ALL at the end of induction chemotherapy or afterward effectively predicted relapse independent of other risk factors. 5,6 Molecular marker monitoring has been used less extensively in adult ALL but appears to be an extremely powerful tool that has yet to be exploited. Brüggemann and colleagues 7 of the German Multi-Center Study Group for Adult ALL reported that patients with standard-risk ALL who had a rapid decline in MRD within the first month of therapy had a 0% 3-year relapse rate while those with molecular persistence of ALL by week 16 of therapy had a 94% 3-year relapse rate (Figure 1). In a subset of patients treated on the MRC-ECOG adult ALL trial discussed above, detection of MRD (especially in the pre B-cell subtype) had prognostic significance. 8,9 In their hands, the detection of MRD by the completion of the second month of induction therapy appeared to be the optimal timepoint to ascertain ultimate prognosis. 8,9 The measurement of MRD has been incorporated into the successor MRC-ECOG led Intergroup trial in order to help restratify low-risk patients (based on clinical prognostic features) into those patients who now would be considered high-risk due to detection of MRD at the end of induction therapy. The use of this technique will require standardization for methodology when it is used in the clinical course of the patient. How allogeneic hematopoietic stem cell transplantation (HSCT) is affected by or impacts upon these risk factors has been less well studied. Although the risk of relapse decreases with allogeneic HSCT, the concomitant treatment-related mortality (TRM) eliminates the potential survival benefit. Doney et al 10 reported on 182 ALL patients with ALL in first CR (CR1) or beyond and found improved disease-free survival (DFS) and overall survival (OS) in younger patients and those in CR1. Allogeneic HSCT conferred similar OS and relapse rates for Ph + patients compared with those with normal cytogenetics supporting a graft-versus-leukemia (GVL) effect that is particularly beneficial in that group. Although other karyotypic abnormalities have been shown to portend a poor prognosis with conventional chemotherapy, 2 available data are insufficient to determine if there is a benefit to allogeneic HSCT in these patients. Gorin for the European Group for Blood and Marrow Transplantation (EBMT) 11 reviewed data on 1402 patients with ALL given allogeneic HSCT in CR1 and noted that time to transplant was a major prognostic factor. Of 414 patients who received transplants within 3 months after achieving CR, patient age, attainment of CR1 with 1 or more induction courses and recipient/donor sex combination predicted outcome. Patients with no unfavorable factors (age younger than 35 years, less than 1 induction course, female donor graft to male recipient) had a 3-year leukemia-free survival (LFS) of 56% compared with 48% for those with 1 adverse factor and 29% for 2 or 3 adverse factors. OS rates were 65%, 53% and 29%, respectively. Although risk factors have been defined, the impact of transplantation on relapse and survival in affected patients is not clear. Related Donor Allogeneic HSCT: Ph There are no trials in the field of HSCT in which patients with a suitable sibling-matched donor have been randomized to an allogeneic HSCT or chemotherapy. Genetic randomization or assignment, along with intent-to-treat analyses, have been the established methods of comparing allogeneic HSCT with chemotherapy treatment. 12 Gupta and colleagues 13 at the Princess Margaret Hospital reported a small single-institution series in which adult patients with ALL in CR1 age 55 years or younger were offered a myeloablative allogeneic HSCT. They found no difference in Figure 1. Probability of disease-free (DFS) and overall survival (OS) for standard-risk adult acute lymphoblastic leukemia patients. Patients are further stratified into lowrisk (LR), intermediate-risk (IR) and high-risk (HR) as determined by extent of minimal residual disease. Reprinted with permission from Brüggemann M, et al. Blood 2006;107: Hematology

3 outcome between the donor versus no-donor groups. Highrisk adults in CR1 (which included Ph + patients) who had a sibling matched-related donor (MRD; N = 41) were assigned a myeloablative allogeneic HSCT, while the others proceeded to an autologous HSCT (N = 115) in the GOELAMS-02 trial. 14 Six-year DFS and OS were statistically superior in those who underwent allogeneic HSCT, 75% versus 39% (P =.0027). The French LALA group has addressed this question prospectively in their LALA-94 trial. 15 Because of the suggestion of a benefit in LALA-87 to allogeneic HSCT in patients under age 55 years who did not have standard-risk disease, 3 they designed a trial of risk-adapted postremission strategy in adult ALL. Patients ages 15 to 55 years with any high-risk ALL features and an HLA-identical sibling were assigned to allogeneic HSCT. Five-year DFS in the group with Ph high-risk ALL in first CR was improved in the allogeneic HSCT (45% vs 23%, sibling donor vs those with no sibling donor). In multivariate analysis, both age and WBC count were found to be prognostic factors for DFS; however, the impact on the two groups (donor vs no donor) was not discussed. In the largest trial reported to date (MRC-ECOG UKALLXII/E2993), 1826 adult patients with ALL were given induction therapy that resulted in a 91% CR rate. 1 All patients younger than 50 years old, irrespective of risk, with a sibling MRD were recommended to undergo a myeloablative HSCT using a total body irradiation (TBI) containing conditioning regimen. 16 For 919 patients in CR, 389 with a donor were compared with 524 patients with no donor (Table 1). Event-free survival (EFS) and OS were statistically superior in the donor group: 50% versus 41% (P =.009) and 53% versus 45% (P =.02). As noted historically with most HSCT reports, in general, the optimal allogeneic effect for EFS and OS were observed in the standard-risk rather than the high-risk group (where high risk was defined by age and WBC count). Although in both risk groups the relapse rates were significantly lower in the donor group compared with the no donor group, supporting a Table 1. MRC-ECOG UKALLXII/EC2993: outcome after allogeneic hematopoietic stem cell transplantation (HSCT) in Ph patients who had donors versus those who did not have donors. 5-y 5-y 2-y overall relapse nonrelapse No. survival, % rates, % mortality, % High-risk* 401 Donor No donor Standard-risk 512 Donor No donor * High-risk is defined as age 35 years, WBC > 30,000/µL for patients with B-cell disease or WBC > 100,000/µL for patients with T-cell disease, or time to attain CR > 4 weeks. strong GVL effect, the TRM rates at 2 years were significantly increased in the high-risk group, 39% versus 20%. Such findings, in large part, reflect poor tolerance to a myeloablative conditioning regimen in those patients older than 35 years. Thus, the majority of the data in Ph patients favor an improved outcome in younger patients who underwent a MRD allogeneic HSCT, an effect lost when older patients are conditioned using a myeloablative regimen. The number of patients with sibling donors, however, far exceeds the usual ratio of success in finding HLA-matched siblings (such as observed in acute myeloid leukemia HSCT trials). Although the number of patients with a donor appears high, it is consistent with some of the previously published ALL HSCT studies. For example, in the LALA- 94 study, for the high-risk group 100 patients had a donor compared with 159 without a donor. 15 Table 2 compares several large trials for ALL CR1 patient outcome. These and other data support the use of a MRD myeloablative allogeneic HSCT for the 32-year-old woman in CR1 described in Case 1. Due to advanced age, however, the 64-year-old man described in Case 2 is not a viable candidate for a MRD myeloablative allogeneic HSCT. Allogeneic HSCT: Ph + Although Ph + patients have a lower remission rate and higher relapse rate using conventional chemotherapy compared to those with Ph disease, allogeneic HSCT is particularly effective in Ph + patients. Dombret and co-workers 17 reported the LALA-94 trial data for 154 Ph + patients who proceeded to transplant (N = 103) after attainment of CR1. Sixty patients who underwent allogeneic HSCT (n = 46 MRD and n = 14 MUD) had the same 2-year TRM as 43 patients who underwent autologous HSCT, but OS at 3 years was significantly superior, 37% versus 12% (P =.02). Attainment of BCR-ABL negative status conferred a significantly better OS as well, 54% versus 12% (P =.006). The French Bone Marrow Transplantation Society 18 reported outcome of 121 patients with Ph + ALL, including 102 adults, of whom 76 were in CR1 at time of transplant. Two-year OS in the CR1 patients was 50% and the 2-year relapse incidence rate was 37%. Stirewalt and colleagues 19 at the Fred Hutchinson Cancer Research Center retrospectively analyzed 90 patients with Ph + ALL aged 2 to 56 years (median, 33 years) who underwent myeloablative allogeneic HSCT. Morphologic or cytogenetic evidence of ALL at time of transplantation as well as autologous or MRD use predicted for highest risk of relapse, while development of chronic graft-versus-host disease (GVHD) after transplantation lowered the relapse rates. These investigators proposed that patients without molecular evidence of disease ( low risk ) undergo a less intense (nonmyeloablative) HSCT. They advocated a more aggressive conditioning be used in high-risk patients who have minimal residual or overt disease at time of transplantation including consideration of post-transplantation imatinib consolidation. Gupta and coworkers 13 reported a study in which unrelated donor 446 American Society of Hematology

4 Table 2. Comparison of several large trials for acute lymphoblastic leukemia (ALL) CR1 patient outcome. No. pts. Group Study, considered Outcome Chemo- Autologous Allogeneic citation for HSCT measure therapy, % HSCT, % HSCT, % P MRC-ECOG OS at 5 y JALSG-ALL OS at 6 y NS LALA OS at 10 y LALA-87 high-risk OS at 10 y LALA DFS at 3 y LALA-94 high-risk OS at 5 y but median Not stated OS not reached GOELAMS 02 high-risk OS at 6 y 40 at 6 y 75 at 6 y.0027 PETHEMA 93 high-risk OS at 5 y Abbreviations: OS, overall survival; HSCT, hematopoietic stem cell transplantation; NS, not significant (URD) allogeneic HSCT was offered to a small number of patients with Ph + ALL in CR1. Three-year DFS and OS were 46% and 57%, respectively; OS did not differ when compared with those Ph patients at their center who underwent allogeneic HSCT. Finally, in the largest prospective allogeneic HSCT study (conducted during the preimatinib era), 5-year OS was superior in those who underwent MRD allogeneic HSCT compared with chemotherapy or autologous HSCT. 20 Early relapse, prior to transplantation, however, was common supporting referral for allogeneic HSCT as soon as possible after attaining CR. 20 These and other data suggest that allogeneic HSCT provides significant GVL effect in CR1 patients with Ph + ALL. The addition of imatinib to the armamentarium for treating Ph + ALL has significantly improved the CR rate from approximately 60% to 90% and has greatly enhanced the access of such patients to allogeneic HSCT by reducing early pretransplantation relapses, a large problem in the past. Yanada et al 21 recently reported a significantly improved OS in 49 adult patients with Ph + ALL who were given post-transplantation imatinib therapy compared with historic controls, i.e., 1-year EFS and OS, 60% and 76%, respectively. Although median follow-up was short at 1 year, both patients who underwent allogeneic HSCT recipients and patients who did not had significantly better outcome. Further, imatinib appeared to prevent earlier relapse, enabling a greater percentage of patients to proceed to allogeneic HSCT. de Labarthe and coworkers 22 similarly showed that imatinib in combination with conventional chemotherapy provided results comparable with allogeneic HSCT. On the other hand, Pfeifer, for the GMALL, recently reported the prevalence of kinase domain mutations in newly diagnosed and imatinib-naive Ph + ALL. 23 BCR-ABL mutations conferring high-level imatinib resistance were present in a substantial proportion of patients with de novo Ph + ALL and eventually gave rise to relapse. These data support the recommendation to search for a wellmatched donor in this population. Until there are published reports of larger studies with longer follow-up, imatinib therapy cannot be considered the standard treatment, and allogeneic HSCT, in general, remains the preferred approach in this subgroup of patients. Imatinib s positive effect on pretransplantation PCR status, i.e., rendering patients tumor-negative before transplantation, could improve outcome. One can speculate, however, that in the post-transplantation setting, imatinib therapy is only likely to provide time until a GVL effect can develop to eradicate disease. Prophylactic imatinib after HSCT can be given safely. 24 Blood Versus Marrow as the Stem Cell Source Blood has nearly supplanted bone marrow as the hematopoietic cellular graft source for patients who undergo allogeneic HSCT. Ringden and the EBMT 25 reported a retrospective analysis of their observational database in which they compared outcome for 826 patients (513 in CR1) given marrow versus 345 patients (189 in CR1) given blood after conditioning. Engraftment, as anticipated, was faster with blood, but also resulted in an increased risk of chronic GVHD. LFS and OS did not differ among the groups. In a subsequent retrospective EBMT analysis, blood stem cell grafts obtained from URD were associated with inferior outcome compared with bone marrow grafts in ALL. 26 The incidence of 2-year TRM in 36 patients receiving blood grafts was 61% compared with 47% in 66 bone marrow recipients, resulting in significantly inferior 2-year LFS (32% vs 21%) and OS (34% vs 24%) rates, P =.04. Finally, Dahlke et al 27 reported a single-center, donor-source comparison in ALL allogeneic HSCT (46 MRD vs 38 URD). Younger patients had a significantly lower TRM, but the relapse rates did not differ, indicating similar antileukemic efficacy. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) has an ongoing, prospective, randomized clinical trial examining URD blood versus marrow source grafts after myeloablative HSCT. Current data in adults do not indicate definitively that one graft source is superior; however, due to significantly greater ease of Hematology

5 collecting stem cells, worldwide, 80% of HSCT procedures are performed using blood rather than bone marrow. Alternative Donor Stem Cell Transplantation: Unrelated Donor Marrow or Blood Kiehl and associates 28 reported a 12-year retrospective multicenter experience comparing myeloablative HSCT in adult patients with ALL according to donor source. Fiveyear DFS rates were not statistically different according to donor source, MRD (N = 62) versus URD (N = 32), 42% versus 45%. Similarly, TRM did not differ, 39% versus 31%, respectively. The vast majority of these patients were considered high risk or very high risk. Further, these results were significantly better than if the patients underwent HSCT at CR2 or beyond or at time of active leukemia. Of interest, as observed in sibling MRD HSCT studies, Ph + patients had no poorer outcome than did Ph patients. Cornelissen and associates 29 reported a multi-national, myeloablative MUD HSCT trial in CR1 patients. Their data again support a strong GVL effect in Ph + patients, as the relapses were significantly lower in these patients compared with the t[4;11] and t[1;19] groups. Weisdorf et al 30 in a retrospective analysis compared outcome and toxicities in 712 patients who underwent HSCT in CR1 or beyond according to donor graft source. DFS was significantly better after the first 6 months in MUD HSCT versus autologous HSCT for younger patients, those in CR2 with a long CR1 duration (more than 1 year) and an initial WBC count less than /µl. At this time, there are insufficient data to conclude whether a myeloablative URD should be offered even to high-risk adult patients with ALL in CR1. Given the GVL effect that seems to be particularly beneficial in Ph + patients, this patient population may be reasonable to consider for URD transplantations in CR1. Yakoub- Agha et al, for the French Society of Bone Marrow Transplantation and Cell Therapy, recently reported the first prospective study in which outcomes for standard-risk malignancy patients who underwent sibling MRD HSCT were comparable with HLA-allellically matched (10 of 10) unrelated donor HSCT. 31 Such data enhance the case for performing MUD HSCT in this patient population. The successor trial to MRC-ECOG UKALLXII/E2993 will investigate whether the benefits of using a sibling-matched allogeneic HSCT in high-risk patients can be extended to unrelated donor allogeneic HSCT. Umbilical Cord Blood Transplantation One single-institution trial compared a myeloablative HSCT regimen followed by either an umbilical cord blood (UCB) graft (N = 100) or a related donor blood or marrow graft (N = 71). 32 UCB was safe and effective compared to a related marrow or mobilized blood graft, but only 16 adult ALL patients were included and an ALL diagnosis carried with it a nearly 2.5-fold increased risk for relapse. The analyses of UCB transplantation data are hampered by small patient numbers, heterogeneity of remission status, variability of matching, incomplete information about UCB cell dose (including the use of double UCB grafts), and high engraftment failure rates. 33 At present, there are insufficient data to recommend use of this donor stem cell source outside the context of a clinical trial. Haploidentical Donor Transplantations This specialized approach has been available at only a very few centers. The high rejection and unacceptable GVHD rates have been lowered by use of more intense preparative regimens and infusion of higher numbers of purified hematopoietic stem cells. 33 When applied to patients not in CR1 or CR2, haploidentical transplantations appear inferior to other alternative donor HSCT results. The major limitations, in addition to relapse in advance disease state, appear to be a proclivity for severe and often-fatal opportunistic infections. Some centers performing this procedure in highrisk CR1 (including Ph + ) patients, however, attain results equivalent to MUD allogeneic HSCT. 34 Such data need to be corroborated in multi-institutional trials, but this strategy is a distinct option in those patients without a MRD. Reduced-Intensity Conditioning Although the GVL effect has been shown to be responsible for some of the benefit in fully ablative HSCT, TRM, especially in the older recipient, may offset the reduction in relapse. As donor lymphocyte infusion (DLI) has been shown to decrease MRD and potentially improve survival in those patients, there may be a role for nonmyeloablative or reduced-intensity conditioning in ALL. Hamaki et al 35 investigated reduced-intensity conditioning in 33 ALL patients with a median age of 55 years (range, years) using fludarabine-based conditioning regimens followed by MRD or URD grafts; 9 patients died of TRM. The 1-year progression-free survival (PFS) rate for the 19 patients who underwent transplantation in CR1 or CR2 is 31%. Six of 13 patients have a median DFS of 14 months (range, 4-37 months). The City of Hope recently reported their single-center experience in 21 patients with ALL median age 46 years (range, 6-68 years) given fludarabine-melphalan conditioning followed by a MRD (N = 7) or a MUD (N = 14) graft. 36 Ten patients were in CR1 and 11 patients had Ph + ALL. In this high-risk group, who were either elderly (older than 50 years), had failed a previous HSCT, or had a comorbid condition precluding use of a myeloablative regimen, the 100- day mortality and 1-year relapse rates were 11% and 8%, respectively, while 1-year DFS and OS rates were 77% and 71%, respectively. The MRC-ECOG led Intergroup-planned successor to the MRC-ECOG UKALLXII/E2993 international trial will use a fludarabine- and melphalan-containing regimen in patients considered high-risk by virtue of age older than 40 years. The addition of Campath-1H to the regimen could be beneficial, as this agent has significant antileukemic as well as anti-gvhd effects. 37 While intriguing, reducedintensity preparative regimens must be validated in pro- 448 American Society of Hematology

6 spective, multicenter trials. Hence, the 64-year-old man described in Case 2 should be considered a candidate for a MRD reduced-intensity conditioning allogeneic HSCT, but only in the context of a clinical trial. Autologous HSCT This modality first was used nearly 50 years ago as treatment for relapsed/refractory ALL. More recently, this approach has been used in patients significantly earlier in their disease course, to provide the potential benefit of myeloablative therapy to those for whom a MRD is not available, as MRD are available only for a minority of patients. 38 While long-term DFS has been attained in some patients, few prospective, randomized trials have analyzed sufficiently large enough numbers of patients to determine if this treatment is appropriate therapy. A variety of preparative regimens have been used for autologous HSCT in adult patients with ALL, but there is no clear benefit to any one approach. 39 On the other hand, an analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) by Marks and associates 40 reported in CR1 and CR2 patients with ALL receiving sibling-matched allogeneic HSCT that etoposide or cyclophosphamide in combination in a TBI-containing regimen, or use of TBI dose >1300 cgy were associated with reduced risk of relapse and treatment failure. These allogeneic HSCT data suggest a threshold TBI dose for antileukemia efficacy and could have implications for autologous HSCT regimens; these conclusions, however, have to be regarded as speculative based on retrospective analysis of registry data. Thomas and associates 15 for the French LALA-94 trial reported a prospective multicenter trial comparing autologous HSCT, MRD allogeneic HSCT, and chemotherapy in 1000 patients. Ph patients at high risk for relapse in CR1 who did not have MRD (N = 129) were randomized to an autologous HSCT and 2-year maintenance therapy (6-MP and methotrexate) or chemotherapy. Three-year DFS were 39% in the autologous HSCT versus 24% in the chemotherapy-treated group, not statistically significant. Other small series include reports of long-term survivors in younger patients who underwent autologous HSCT, but such studies do not include control subject comparisons. 41 A recent article by Dhédin et al 42 updated autologous HSCT results for the LALA-85, -87 and -94 trials. A subset analysis of 180 high-risk CR1 patients showed no differences in either DFS or OS at 10 years for the autologous HSCT versus the chemotherapy treatment groups, 20% versus 12% (P =.10) and 20% versus 13% (P =.78). The joint MRC-ECOG UKALLXII/E2993 trial 16 compared 446 CR1 patients randomized to undergo either an autologous HSCT (N = 223) or 2.5 years of maintenance therapy (N = 223). EFS was statistically superior for the chemotherapy-treated patients, 42% versus 33% (P =.02). While OS also was improved in the chemotherapy group (47% versus 37%), these results were not statistically significant (P =.06). Those assigned to an autologous HSCT did not receive post-transplantation maintenance therapy and continued to relapse at a higher rate. Other groups have reported that use of maintenance chemotherapy after autologous HSCT can prolong remission (see below). These and other data do not support the routine use of autologous HSCT in adult patients with ALL, and patients should be referred for participation in clinical trials addressing this concept. In Vitro Stem Cell Purging and Post-Transplantation Maintenance Therapy In vitro purging of the stem cell graft also has been used in a number of autologous HSCT studies in ALL. 43 Although such an approach may reduce the number of leukemic progenitor cells in the graft, there has been no correlation between purging efficacy or dose of residual tumor infused and patient outcome. Two groups have suggested that use of maintenance chemotherapy after autologous HSCT can reduce relapse rates. 44,45 In the UK, Mehta and colleagues 44 noted that increased intensity of treatment was more efficacious but that many patients could not tolerate such an approach, a result similar to the Johns Hopkins group data. 45 Until less marrow-toxic agents are readily available to provide a more-targeted therapy, this postautologous HSCT maintenance strategy cannot be recommended for widespread use. Other Issues: Approach to Younger Adults Adolescent and young adult patients appear to be a distinct population compared with older adults. The pattern of referral may influence whether patients are treated by a pediatrician or adult hematologist-oncologist specialist. Emerging data indicate that such patients have a consistent survival advantage when treated on a pediatric regimen This issue is being addressed prospectively in a CALGB-led intergroup study. Conclusions Adult ALL remains a challenging disease. While the only treatment that results in long-term DFS in patients with ALL in CR2 is allogeneic HSCT, and outcomes from transplantation are better if performed in CR1 rather than CR2, the decision to proceed to transplantation in CR1 remains a complicated one. Current data indicate that autologous HSCT is inferior to other approaches and cannot be recommended at this time. In patients at high risk for relapse such as those with adverse biologic, clinical, or laboratory factors, allogeneic HSCT with a sibling MRD is the preferred option (Table 3). The outcome after salvage therapy with any HSCT or nontransplantation therapy in relapsed patients is extraordinarily poor, as demonstrated by a 5-year OS rate of only 7% in the MRC-ECOG trial discussed above. 49 Even in younger patients whose initial CR1 exceeded 2 years, 5-year OS in this subset was only 11%. A similar experience has been reported recently for patients who relapse after receiving therapy per the LALA-94 study. 50 Hematology

7 Table 3. Recommendations regarding decision to proceed to a sibling-matched related donor (MRD) or matchedunrelated donor (MUD) allogeneic hematopoietic stem cell transplant (HSCT) as therapy for acute lymphoblastic leukemia (ALL) patients < age 55 years. MRD transplant MUD transplant Disease indication recommended? recommended? Comments CR1 patients < 40 y: Yes No Standard-risk CR1 patients < 40 y: Yes Yes For high-risk cytogenetics,* increased relapse risk with High-risk standard chemotherapy. Unknown if allogeneic HSCT decreases risk. CR1 patients 40 y Possibly, No Allogeneic transplantation decreases relapse risk, but TRM using reduced- offsets benefit; reduced-intensity conditioning regimens being intensity conditioning explored. CR2 Yes Yes Primary refractory disease Yes Yes Ph + disease Yes Yes Highly potent allogeneic GVL effect in Ph + disease Minimal residual disease Yes Possibly Patients with minimal residual disease have increased positivity after induction relapse risk with standard therapy alone. in Ph disease patients Only Ph + disease shown to benefit from allogeneic HSCT. Insufficient data on impact of HSCT in others. *High-risk cytogenetics defined as: t(4:11), t(8:14), complex karyotype ( 5 abnormalities), hypodiploidy/near triploidy Abbreviations: CR1, first complete remission; CR2, second complete remission; TRM, treatment-related mortality; GVL, graft-versusleukemia; Ph, Philadelphia chromosome The 32-year-old woman in CR1 (Case 1) who has no comorbid conditions should be referred for a MRD myeloablative allogeneic HSCT. Although she has no high-risk features, paradoxically, the best results for allogeneic HSCT have been observed in standard-risk patients. On the other hand, the 64-year-old man in Case 2 who did not readily attain CR is not a viable candidate for a myeloablative allogeneic HSCT due to advanced age. Despite the highrisk cytogenetic karyotype abnormality t(4:11), it is unknown if there is a substantial benefit to allogeneic HSCT in this situation. This patient, however, has an extremely poor prognosis given his age and primary induction failure status. He should strongly be encouraged to undergo an allogeneic HSCT using his histocompatible sister as a donor, as the benefits may outweigh the risks. The use of reduced-intensity conditioning HSCT is the subject of ongoing investigation. This approach cannot be recommended routinely at this time due to the paucity of data, but in the near future sufficient data likely will be available to assess the contribution of this strategy. If such a transplantation is to be considered in this patient, it should be performed in the context of a clinical trial. Finally, some trials have demonstrated that URD transplantations appear to provide results comparable to MRD HSCT. 27 Although the use of alternative donor HSCT and reduced-intensity transplantations remain controversial, a number of investigators suggest this option for high-risk patients. Further studies need to be done to better define high risk, i.e., improve understanding of cytogenetic abnormalities and prognosis, and determine which high-risk disease patients are most likely to benefit from standard myeloablative allogeneic HSCT. Age, which repeatedly has been shown to be a factor in defining high-risk disease, also puts patients at higher risk for therapy-related morbidity and mortality and offsets the decreased relapse rate using allogeneic HSCT. Alternative strategies will be necessary to maximize the risk-benefit ratio in patients who have a high likelihood of relapse without transplantation. Similarly, there is a group of adult patients with ALL who have prognostic factors that suggest high remission and long-term DFS rates. In those who are younger with a low WBC count, allogeneic HSCT appears to further improve their longterm DFS. Further analysis, however, will need to take into account other prognostic factors such as karyotype, time to CR, and MRD. Unlike with conventional therapy, for patients with Ph + disease, outcomes after allogeneic HSCT are no different than for Ph disease. There may be a group of patients for whom the risk of relapse is so low that even a reduced TRM incidence may not justify transplant such as T-cell ALL with the TXL1 (Hox11) mutation. As future prospective studies are done, it should allow us to define subsets of patients who are most and least likely to benefit from the various allogeneic HSCT options. Correspondence Hillard Lazarus, MD, Ireland Cancer Center, Univ. Hospitals of Cleveland, Euclid Ave., Wearn Bldg., Room 341, Cleveland, OH ; phone (216) ; fax (216) ; hillard.lazarus@case.edu 450 American Society of Hematology

8 References 1. Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia (ALL): results of over 1,500 patients from the International ALL Trial (MRC UKALL/ECOG E2993). Blood. 2005;106: Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/ Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109: Thiebaut A, Vernant JP, Degos L, et al. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000;14: Moppett J, Burke GA, Steward CG, Oakhill A, Goulden NJ. The clinical relevance of detection of minimal residual disease in childhood acute lymphoblastic leukaemia. J Clin Pathol. 2003;56: Coustan-Smith E, Sancho J, Behm FG, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood. 2002;100: Campana D. Determination of minimal residual disease in leukaemia patients. Br J Haematol. 2003;121: Brüggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107: Foroni L, Mitchell W, Rai LJ, et al. Molecular monitoring of residual disease (MRD) during induction and intensification phases in low risk adult B cell ALL treated according to the MRC UKALL12 protocol [abstract]. Blood. 2005;106:abstract no Foroni L, Mitchell W, Rai LJ, Richards S, Fielding A, Goldstone AH. The value of molecular monitoring for residual disease (MRD) in early morphological remitters among adults diagnosed with B cell ALL and treated according to the MRC UKALL12 Protocol. Blood. 2005;106:abstract no Doney K, Hagglund H, Leisenring W, Chauncey T, Appelbaum FR, Storb R. Predictive factors for outcome of allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2003;9: Gorin NC, Labopin M, Polge E, et al Risk assessment in adult acute lymphoblastic leukaemia before early haemopoietic stem cell transplantation with a geno-identical donor; an easy clinical prognostic score to identify patients who benefit most from allogeneic haemopoietic stem cell transplantation. Leukemia. 2003;17: Gray R, Wheatley K. How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant. 1991;7: Gupta V, Yi QL, Brandwein J, et al. The role of allogeneic bone marrow transplantation in adult patients below the age of 55 years with acute lymphoblastic leukemia in first complete remission: a donor vs no donor comparison. Bone Marrow Transplant. 2004;33: Hunault M, Harousseau JL, Delain M, et al. Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial. Blood. 2004;104: Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004;22: Rowe JM, Buck G, Fielding A, et al. In adults with standardrisk acute lymphoblastic leukemia (ALL) the greatest benefit is achieved from an allogeneic transplant in first complete remission (CR) and an autologous transplant is less effective than conventional consolidation/maintenance chemotherapy: Final results of the International ALL Trial (MRC UKALL XII/ECOG E2993) [abstract]. Blood. 2006;108:5a. 17. Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia results of the prospective multicenter LALA-94 trial. Blood. 2002;100: Esperou H, Boiron JM, Cayuela JM, et al. A potential graftversus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: results from the French Bone Marrow Transplantation Society. Bone Marrow Transplant. 2003;31: Stirewalt DL, Guthrie KA, Beppu L, et al. Predictors of relapse and overall survival in Philadelphia chromosomepositive acute lymphoblastic leukemia after transplantation. Biol Blood Marrow Transplant. 2003;9: Goldstone AH, Chopra R, Buck G, et al. The outcome of 267 Philadelphia positive adults in the International UKALLXII/ ECOG E2993 study. Final analysis and the role of allogeneic transplant in those under 50 years [abstract]. Blood 2003;102:80a. 21. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABLpostive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006;24: de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007;109: Pfeifer H, Wassmann B, Pavlova A, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood. 2007;110: Carpenter PA, Snyder DS, Flowers ME, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood. 2007;109: Ringden O, Labopin M, Bacigalupo A, et al. Transplantation of peripheral blood stem cells as compared with bone marrow from HLA-identical siblings in adult patients with acute myeloid leukemia and acute lymphoblastic leukemia. J Clin Oncol. 2002;20: Garderet L, Labopin M, Gorin NC, et al. Patients with acute lymphoblastic leukaemia allografted with a matched unrelated donor may have a lower survival with a peripheral blood stem cell graft compared to bone marrow. Bone Marrow Transplant. 2003;31: Dahlke J, Kroger N, Zabelina T, et al. Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation. Bone Marrow Transplant. 2006;37: Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission. J Clin Oncol. 2004;22: Cornelissen JJ, Carston M, Kollman C, et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood. 2001;97: Hematology

9 30. Weisdorf D, Bishop M, Dharan B, et al. Autologous versus allogeneic unrelated donor transplantation for acute lymphoblastic leukemia; comparative toxicity and outcomes. Biol Blood Marrow Transplant. 2002;8: Yakoub-Agha I, Mesnil F, Kuentz M, et al. Allogeneic marrow stem-cell transplantation from human leukocyte antigenidentical siblings versus human leukocyte antigen-allelicmatched unrelated donors (10/10) in patients with standardrisk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol. 2006;24: Takahashi S, Ooi J, Tomonari A, et al. Comparative singleinstitute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen. Blood. 2007;109: Marks DI, Aversa F, Lazarus HM. Alternative donor transplants for adult acute lymphoblastic leukaemia: a comparison of the three major options. Bone Marrow Transplant. 2006;38: Aversa F, Terenzi A, Tabilio A, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005;23: Hamaki T, Kami M, Kanda Y, et al. Reduced-intensity stemcell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients. Bone Marrow Transplant. 2005;35: Stein A, O Donnell M, Snyder D, et al. Reduced-intensity stem cell transplantation for high-risk acute lymphoblastic leukemia [abstract]. Biol Blood Marrow Transplant. 2007;13:abstract no Piccaluga PP, Martinelli G, Malagola M, et al. Anti-leukemic and anti-gvhd effects of campath-1h in acute lymphoblastic leukemia relapsed after stem-cell transplantation. Leuk Lymphoma. 2004;45: Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant. 2006;12: Gorin NC. Autologous stem cell transplantation in acute lymphocytic leukemia. Stem Cells. 2002;20: Marks DI, Forman SJ, Blume KG, et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant. 2006;12: Abdallah A, Egerer G, Goldschmidt H, Wannenmacher M, Korbling M, Ho AD. Continuous complete remission in adult patients with acute lymphocytic leukaemia at a median observation of 12 years after autologous bone marrow transplantation. Br J Haematol. 2001;112: Dhedin N, Dombret H, Thomas X, et al. Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials. Leukemia. 2006;20: Mato AR, Luger SM. Autologous stem cell transplant in ALL: who should we be transplanting in first remission? Bone Marrow Transplant. 2006;37: Mehta J, Powles R, Sirohi B, Treleaven J, Kulkarni S, Singhal S. High-dose melphalan and autotransplantation followed by post transplant maintenance chemotherapy for acute lymphoblastic leukemia in first remission. Bone Marrow Transplant. 2004;33: Sotomayor EM, Piantadosi S, Miller CB, et al. Long-term follow-up of intensive ara-c-based chemotherapy followed by bone marrow transplantation for adult acute lymphoblastic leukemia: impact of induction Ara-C dose and postremission therapy. Leuk Res. 2002;26: Ramanujachar R, Richards S, Hann I, Webb D. Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer. 2006;47: Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2007;48: Huguet F, Raffoux E, Thomas X, et al. Towards a pediatric approach in adults with acute lymphoblastic leukemia (ALL): the GRAALL-2003 Study. Blood. 2006;108:abstract no Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukaemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109: Tavernier E, Boiron JM, Huguet F, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia [Epub ahead of print] 51. Takeuchi J, Kyo T, Naito K, et al. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002;16: Ribera JM, Oriol A, Bethencourt C, et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial. Haematologica. 2005;90: American Society of Hematology