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CONCISE REVIEW |
Department of Hematology, Hopital Saint-Antoine; Centre de Recherches sur la Thérapie Cellulaire, Université Paris VI et Association Claude Bernard, Paris, France
Key Words. Acute lymphocytic leukemia • Autologous stem cell transplantation • Review
N.C. Gorin, M.D., Ph.D., Department of Hematology, Hopital Saint-Antoine, Paris, France. Telephone: 33-1-49-28-2620; Fax: 33-1-43-44-5501; e-mail: norbert-claude.gorin{at}sat.ap-hop-paris.fr
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ABSTRACT |
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 Top Abstract IntroductionMinimal Residual Disease in...European Registry DataReports from Cooperative Groups...ASCT in ALL with...Conclusion and Future ProspectsReferences |
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INTRODUCTION |
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TopAbstractIntroductionMinimal Residual Disease in...European Registry DataReports from Cooperative Groups...ASCT in ALL with...Conclusion and Future ProspectsReferences |
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In contrast, trials in ALL have been disappointing, showing adult ALL to be more resistant to conventional chemotherapy than AML with a higher rate of failure, including late and even very late relapses. In a similar way, more relapses also have been observed following allogeneic stem cell transplantation for ALL than for AML. In addition to the greater resistance of ALL progenitors to the pretransplant regimen, there also has been a related lack of graft versus leukemia effect, in contrast to AML and chronic myelocytic leukemia [3]. Likewise, and not surprisingly, results of ASCT have been worse in ALL than in AML and the role, if any, of ASCT in ALL, as well as the importance of purging the autograft, have been questioned. Nonetheless, several reports have claimed good results with high-dose consolidation and ASCT in adult ALL; interesting observations in purging the autograft have been obtained in ALL with the Philadelphia chromosome and/or the bcr-abl translocation for which new treatment strategies are designed that will incorporate the STI571 anti-tyrosine kinase (STI). Double autografts and/or maintenance therapies following ASCT are being explored by some teams. The purpose of this review is to summarize the existing data and define possible strategies with ASCT in adult ALL.
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MINIMAL RESIDUAL DISEASE IN ALL: DOES IT MATTER? |
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TopAbstractIntroductionMinimal Residual Disease in...European Registry DataReports from Cooperative Groups...ASCT in ALL with...Conclusion and Future ProspectsReferences |
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Leading most recent examples with CT, the European Organization for Research and Treatment of Cancer (EORTC) [4] conducted a prospective study at 11 centers on 246 patients to determine the predictive value of the presence or absence of detectable residual disease at several points in time during the first 6 months after complete remission of childhood ALL had been induced. Junctional sequences of T-cell-receptor or immunoglobulin gene rearrangements were used as clonal markers of leukemic cells. Residual disease was quantitated with a competitive polymerase-chain-reaction (PCR) assay. The presence or absence and level of residual leukemia were significantly correlated with the risk of early relapse at each of the times studied. PCR measurements identified patients at high risk for relapse after the completion of induction therapy (those with 
10–2 residual blasts) and at later time points (those with 10–3 residual blasts). Multivariate analysis showed that, compared with immunophenotype, age, risk group, and white cell count at diagnosis, the presence or absence and level of residual disease were the most powerful independent prognostic factors.
In a more recent experience in children [5], using rapid flow cytometric techniques capable of detecting one leukemic cell in 104 normal cells, the Saint Jude team prospectively studied MRD in 195 patients with newly diagnosed ALL in clinical remission. Bone marrow aspirates were collected at the end of remission induction therapy and at three intervals thereafter. Detectable MRD, defined as 0.01% leukemic mononuclear cells, at each time point was associated with a higher relapse rate; patients with high levels of MRD at the end of the induction phase (1%) or at week 14 of continuation therapy (0.1%) had particularly poor outcomes. The incidence of relapse among patients with MRD at the end of the induction phase was 68% ± 16% if they remained with MRD through week 14 of continuation therapy, compared with 7% ± 7% if MRD became undetectable (p = 0.035). The persistence of MRD until week 32 was highly predictive of relapse. Analysis of ALL cells in comparison with normal CD10+/CD19+ lymphoid progenitors by cDNA microarrays in a limited number of patients identified seven proteins as expressed in B-lineage ALL cells at higher levels than in normal CD19+CD10+ B-cell progenitors. Of these, CD58 was chosen for further analysis because of its abundant and prevalent overexpression. Interestingly, an anti-CD58 antibody identified residual leukemic cells (median, 0.03%) in 9 of 104 bone marrow samples from children with ALL in clinical remission. MRD estimates by CD58 staining correlated well with those of PCR amplification of immunoglobulin genes. These results may well inaugurate further studies of gene expression with cDNA arrays to detect and monitor MRD in hematological malignancies [6].
In the context of ASCT, detection and quantification of MRD have been done in the past decade by the Minneapolis team on 14 patients with high-risk T-cell acute lymphoblastic leukemia (T-ALL) autografted with marrow purged by immunotoxins and 4 hydroperoxycyclophosphamide (4HC) [7], 14 patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) autografted with marrow purged by monoclonal antibodies (mAbs) and 4HC [8] and later, extended to a total of 83 adult ALL patients [9]. Leukemic progenitor cells were quantified after cell sorting with specific mAbs and culture. In all three studies, higher levels of MRD pretransplant (above median values) were associated with higher relapse incidences post-transplant, but purging efficacy and the doses of residual tumor infused with the autografts did not influence the outcome. The authors concluded that the primary reason for the recurrence of leukemia was inefficient pretransplant radiochemotherapy (leukemia resistance) rather than inefficient purging of autografts. In a recent Japanese study [10], pre- and post-purged marrow samples from 15 patients with high-risk common ALL were analyzed for MRD quantification by PCR amplification of the CDR3 region of the immunoglobulin gene. The leukemia-free survival (LFS) was significantly better in those with less residual disease evaluated before purging, and there was a linear correlation between the amount of MRD prepurging and the duration of the remission after autologous bone marrow transplant (ABMT). However, in this study as well as in the previous ones, outcome was not correlated with the efficacy of purging.
These studies support the use of high-dose intensification for the treatment of ALL, since reduction of MRD is associated with better survival. They also may imply that tumor purging of the autograft is a logical approach but, as indicated above and also detailed further below, data presently available suggest that, in contrast to AML, the purging methods in use for ALL may be inefficient.
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EUROPEAN REGISTRY DATA |
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TopAbstractIntroductionMinimal Residual Disease in...European Registry DataReports from Cooperative Groups...ASCT in ALL with...Conclusion and Future ProspectsReferences |
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The European Cooperative Group for Blood and Marrow Transplantation (EBMT) recently reviewed the outcome of children and adults with ALL autografted with bone marrow (BM) or peripheral blood (PB) in Europe from January 1987 to December 2000 (unpublished data). Thirteen hundred and sixty-six adults and 269 children were autografted in first remission (CR1). The follow-up was 36 months (1-236). The transplant related mortality (TRM) at 5 years was 11% ± 1% in adults and 4% ± 1% in children. The relapse incidences (RI) were 60% ± 2% and 48% ± 3%, respectively. In adults, the LFS and overall survival (OS) were 36% ± 2% and 42% ± 2%; in children the figures were 50% ± 3% and 54% ± 3%, respectively. There was no indication in favor of purging the autograft in vitro; rather, the TRM in adults receiving purged marrow was higher (16% ± 3% versus 7% ± 1%, p = 0.003). Figure 1
shows the LFS of children and adults transplanted in CR1 with peripheral blood stem cells.
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The Italian Association of Paediatric Haemato-Oncology (AIEOP/FONO-TMO) analyzed, retrospectively, 154 children [11] autografted in CR2 (98 patients) or beyond (56 patients). The LFS for those autografted in CR2 was 34.6%. By univariate analysis, two favorable factors were identified: the existence of a single isolated extramedullary relapse as opposed to a full marrow relapse (68.9% versus 18.2%; p < 0.0001) and the use of TBI in the pretransplant regimen (48% versus 15%; p = 0.003). The study supported the effectiveness of ABMT in children with an extramedullary relapse.
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REPORTS FROM COOPERATIVE GROUPS AND SINGLE INSTITUTIONS |
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TopAbstractIntroductionMinimal Residual Disease in...European Registry DataReports from Cooperative Groups...ASCT in ALL with...Conclusion and Future ProspectsReferences |
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The analysis was done in March 1999 with a median follow-up of 10 years. In 572 patients evaluable, the OS at ten years was 27%. The survival rate for the 436 patients achieving complete remission (CR) (76% of the population) was 30%. It was 35.5% in patients younger than 35 years and only 14.5% in those older than 35. By intention to treat, OS at 10 years for patients allografted (below 40 years of age) was 44% versus 11% in the chemotherapy arm (p = 0.009). In the auto BMT trial, also by intention to treat, OS at 10 years was 34% in those autografted versus 29% in the chemotherapy arm (not significant). In patients with standard risk, it was 49% versus 40%, still not significantly different. Interestingly, however, the OS in standard risk ALL was identical (49%) after allografting or autografting, while better results were obtained following allografting than autografting in high-risk patients (44% versus 10%) (Table 1). Again, comparisons were made between allo BMT and CT in the first trial and between ABMT and CT in the second one. Therefore, results given in Table 1 are raw data and no comparison was attempted between allo- and autografting, which would have been possible only within a single trial.
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Seventy-five consecutive ABMT for high-risk ALL were analyzed in Barcelona [13] in relation to marrow purging with a cocktail of mAbs and complement. The LFS at 5 years was 52% and the RI 35% in the 52 patients who received purged marrow. These values were 12% and 86%, respectively, in the 23 who received unpurged marrow (p = 0.02 for LFS; p = 0.005 for RI). The authors concluded on the clinical relevance of BM purging in high-risk ALL autografted in CR1.
In our own team (Saint-Antoine, Paris), the protocol for high-dose consolidation and autografting has been similar for adult patients with ALL and AML [14]. The pretransplant regimen has consisted of cyclophosphamide (120 mg/kg) and fractionated TBI at the total dose of 12 Gy. Marrow has been purged in vitro with mafosfamide either at a dose adjusted to the individual colony-forming units-granulocyte-macrophage (CFU-GM) sensitivity of each patient, as determined on a marrow test sample taken 15 days before harvesting, or at the constant dose of 50 µg/107 mononucleated cells. Forty-six patients, including 11 with the Ph1/bcr-abl or the t(4;11) abnormalities have been autografted in CR1. The median age was 31 years (range, 14-55). The dose of marrow infused in CFU-GM (conventional, agar, no cytokines) was 6.28 x 104/kg (0.15-33) before purging and 0.002 (0-3) postpurging. The LFS at 10 years was 52% ± 8%. All relapses but one have occurred before 28 months (Fig. 2). The only exception was a very late relapse at 8 years. Because results for ALL and AML were identical, a predictive model could be built for both diseases, which indicated that the best prognostic group consisted of patients autografted with the richest marrow (prepurging) submitted to the most aggressive purging leading to the lowest residual CFU-GM dose postpurging [14].
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The experience of the transplant team in Katowice (J. Holowiecki), recently presented at the sixth seminar on the treatment of acute leukemia (Dubrovnik, Croatia, September 16-18, 2001) deserves recognition because of the practicality of the approach: 125 high-risk ALL patients had their marrow harvested in CR and stored mixed with citrate-phosphate-dextrose-adenine anticoagulant-preservative solution (CPDA-1) medium for 72 hours at 4°C (no cryopreservation). The autograft was readministered after a high-dose regimen, the CAV consisting of cyclophosphamide (120 mg/kg total), etoposide (VP16) (800 mg/m2 total), and Ara-C 3 g/m2. The TRM was 3.5% in CR1 and 5.9% in CR2 with a follow-up of 37 months; the LFS at 10 years was 64% and 47%, respectively. The authors conclude that these results compare favorably with those of teams employing more complicated and intensive transplantation procedures.
Children
In a series of 31 consecutive children in CR2 autografted in London [16] with a pretransplant regimen consisting of high-dose melphalan and TBI and unpurged marrow, the LFS at 5 years was 45%. In a series of 55 children in CR2 autografted in Madrid [17] with purged marrow, the LFS was 46% at 5 years. The experience in infants, for whom the prognosis with CT is very poor, is extremely limited. Of interest is that in a series of 26 infants including 15 AML and 10 ALL [18], an LFS of 63% was obtained at 5 years. A single factor was associated with better LFS in multivariate analysis, i.e., an interval from CR1 to autografting of less than 4 months.
Post-Transplant Maintenance
All these studies reflect the resistance of ALL to chemotherapy and high-dose consolidation. Results of all three therapeutic modalities, i.e., conventional chemotherapy, allogeneic, and ASCT, are worse in ALL than in AML. The difficulty of eradicating leukemia in the patient probably also explains the relative inefficiency of the in vitro purging methods we presently use.
Available results favor the use of ASCT in infants and children in second remission. In adults, there is a trend in favor of ASCT for standard risk ALL in CR1. Because ALL is characterized by late relapses, some teams have investigated introduction of maintenance therapy following ASCT. The Royal Marsden team, in particular, has treated a total of 82 adults with ALL in CR1 with a BM (n = 35) or a PB (n = 47) unpurged autograft from July 1984 to September 1999 [19]. The pretransplant regimen consisted of high-dose melphalan (HDM) at 110 mg/m2 and TBI, or HDM alone at a higher dose (200 mg/m2). After hematologic recovery, all patients received maintenance therapy with methotrexate (MTX) and 6 MP alone or combined with monthly courses of vincristine-prednisolone (VP) for 2 years,. Patients receiving HDM at 200 mg/m2 alone had a significantly lower TRM; 6 MP could be started in 72% of the patients at a median of 61 days, MTX in 55% at a median of 111 days, and VP in 39% only at a median of 87 days. As of November 2000, 44 patients were alive in continuous CR1 with a 5-year LFS of 57%. Results were better in non-high-risk patients with an LFS of 80% (versus 35%; p = 0.001), an RI of 14.5% (versus 58.4%; p = 0.002) and an OS of 83% (versus 45%; p = 0.002). Interestingly, patients who received the VP had a lower relapse incidence (30% at 5 years versus 42%), but the difference was not statistically significant. This experience is interesting because it conveys several messages: first, that ASCT in adult ALL can produce acceptable/good outcome; second, that, as already shown for ALL, the best results, in fact, are obtained (not surprisingly) in good-risk patients, so that reserving ASCT for high-risk patients (a natural tendency in most centers nowadays) may well be a false concept; and third, that maintenance therapy post-ASCT is an option to consider more seriously than in AML where late relapses are the exception rather than the rule. Alpha-interferon post-ASCT also has been suggested as efficient in maintaining CR, alone [20] or combined with interleukin-2 (IL-2) [21].
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ASCT IN ALL WITH THE PHILADELPHIA CHROMOSOME; ATTEMPTS AT PURGING THE AUTOGRAFT |
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TopAbstractIntroductionMinimal Residual Disease in...European Registry DataReports from Cooperative Groups...ASCT in ALL with...Conclusion and Future ProspectsReferences |
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In a retrospective study by the EBMT (J.P. Laporte, M. Labopin, unpublished data) on a total of 550 ALL patients with a known karyotype, 73 Ph1+ patients (37 autografts and 36 allografts) were compared with 477 Ph1– patients (195 autografts and 282 allografts). Following autografting in CR1, the LFS at 3 years was 20% versus 56% (p = 0.0009), similar to the results post-allografting with an LFS of 24% versus 61% (p < 0.0001). By pair match analysis, the OS at 3 years (Ph1+ versus Ph1–) was 30% versus 57% (p < 0.0001). Figure 3 shows the latest update on 92 patients autografted in CR1 and 18 in CR2.
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The Frankfurt team has investigated purging and autografting Ph1+ ALL in CR1. Twenty autologous BM and 25 PB grafts were collected from a total of 40 consecutive patients with bcr-abl+ ALL in first (n = 37) or second (n = 3) complete morphological remission and subsequently purged with a cocktail of anti-CD19, -CD10, AB4 mAbs and immunomagnetic beads (IMB) [22]. Residual bcr-abl+ cells before purging were detected in 19 of 20 BM grafts at a median of 4 (range 0-6) logs and in 17 of 25 evaluable peripheral blood stem cell (PBSC) grafts at a median of 1 (range 0-3) log above the limit of detection assessed by a semiquantitative limiting log10-dilution reverse transcriptase-PCR (RT-PCR) (p < 0.0001). IMB purging depleted a median of 2.5 (range 1-4) log of residual bcr-abl+ cells from BM and a median of 1 (range 0-2) log from PBSC grafts, RT-PCR negativity in 1/20 BM, and 12/25 PBSC grafts. BM purging was superior using the triple mAb cocktail, which depleted 2.64 ± 0.4 log (n = 14) compared with 1.6 ± 0.4 log (n = 5) using the mAb cocktail not including AB4 (p = 0.02). They concluded that unpurged BM grafts contain 2-3 log more residual bcr-abl+ cells than unpurged PBSC grafts and that purging efficacy is superior in BM compared with PBSC grafts, but median titers in purged BM grafts still exceeded those in purged PBSC grafts. On a total of 40 patients autografted with BM or PB once or twice, the event-free survival at 3 years ranged between 20% and 30%, with some indication of a better outcome in patients receiving more intense therapy pretransplant and some kind of maintenance (interferon alpha, IL-2) post-transplant. Interestingly, no relapse was observed after 18 months.
One of the most interesting recent experiences is the therapeutic scheme designed by the San Francisco team (Linker, unpublished) for adult patients with very-high-risk ALL, as defined by one of the following three poor-risk criteria: A) presence of the t(9;22), t(4;11), or del 7 chromosome abnormality; B) no CR after the first induction course including vincristin, steroids, daunorubicin, and L-Asparaginase, and C) an initial WBC over 100,000/mm3 for B-ALL. The estimated LFS at 2 years in this poor-risk patient population is around 20% with CT. In this protocol, patients are submitted to a double intensification protocol combining in vivo and in vitro purging. A first intensification is delivered with high-dose Ara-C (16 g/m2) and VP-16 (40 mg/kg), both over 4 days with G-CSF given from day 14 for mobilization. PB collection (already in a way purged in vivo) is then purged in vitro with mAbs and complement, to be later reinfused after a pretransplant regimen consisting of fractionated TBI (1,320 cGy), VP-16 (60 mg/kg), and cyclophosphamide (100 mg/kg). Recovery of polymorphonuclear cells to 1,000/mm3 and platelets to 20,000/mm3 has occurred by days 12 and 27, respectively. Patients have been discharged on day 20. The LFS at 3 years has been reported as high as 46%; obviously, however, the number of patients is still small, and the follow-up has to be increased before a valuable conclusion can be generated.
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CONCLUSION AND FUTURE PROSPECTS |
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TopAbstractIntroductionMinimal Residual Disease in...European Registry DataReports from Cooperative Groups...ASCT in ALL with...Conclusion and Future ProspectsReferences |
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Regarding in vitro purging, in contrast to AML, where there are considerable arguments in favor of purging [1], there is not a single report demonstrating benefit in ALL. Because expression of antigens differs from immature blast cells to the most mature ones, when using mAbs in a lytic complement system, the choice of a cocktail rather than single antibodies has been the logical rule of thumb in the past. However, analysis by DNA chips may soon identify more specific targets in ALL, and this attitude may change in favor of the use of highly specific antibodies if MRD indeed can be monitored this way. Also, drugs such as cyclophosphamide derivatives (4HC and mafosfamide), which have, in fact, a broader killing action may have been insufficiently tested and deserve new interest.
At the moment, future prospects essentially concern the inclusion of the STI571 anti-tyrosine kinase (and others) in the therapeutic scheme. Promising results have been achieved in a phase II study in heavily pretreated patients with relapsed or refractory Ph/bcr-abl+ ALL. Nineteen of 32 patients showed a hematological response, and CR was obtained with STI alone in a quarter of these patients [23, 24]. Several protocols are presently being built, which include treatment by STI before autografting and/or STI maintenance postautografting.
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REFERENCES |
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TopAbstractIntroductionMinimal Residual Disease in...European Registry DataReports from Cooperative Groups...ASCT in ALL with...Conclusion and Future ProspectsReferences |
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This article has been cited by other articles:
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  H. M. Lazarus and S. Luger Which Patients with Adult Acute Lymphoblastic Leukemia Should Undergo a Hematopoietic Stem Cell Transplantation? Case-Based Discussion Hematology, January 1, 2007; 2007(1): 444 - 452. [Abstract] [Full Text] [PDF]
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