Autologous Stem Cell Transplantation for Acute Lymphocytic Leukemia in Adults

ADVANCES IN THE TREATMENT OF ADULT ACUTE LYMPHOCYTIC LEUKEMIA, PART I1

0889-8588/01 $15.00

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AUTOLOGOUS STEM CELL TRANSPLANTATION FOR ACUTE LYMPHOCYTIC LEUKEMIA IN ADULTS Thomas G. Martin, MD, and Charles A. Linker, MD

Acute lymphocytic leukemia (ALL) is predominantly a childhood disorder with approximately 4000 to 5000 new cases diagnosed in the United States each year. In adults, ALL accounts for approximately 15% to 20% of all acute leukemias, and the incidence increases with age. ALL is a heterogeneous disorder, and response to therapy can vary dramatically depending on the clinical features present at diagnosis. The prognosis is generally much better in children than adults. Following treatment with modern chemotherapy, more than 60% of children enjoy long-term disease-free survival.6* 73 In contrast, only 20% to 38% of adults 21, 49, 51, 53, 6o The inferior results achieve long-term disease-free ~urvival.~, in adults using conventional chemotherapy have led many centers to investigate the use of bone marrow transplantation (BMT) in adults with ALL. This article evaluates past results and the current role of autologous stem cell transplantation in adults with ALL. Future strategies aimed at improving survival following autologous BMT (autoBMT) are also presented. Acute lymphocytic leukemia in adults is rare, and few large prospective trials have evaluated the use of autologous transplantation. Most studies have combined children and adults, standard-risk and high-risk patients, and patients with disease in remission and relapse.

From the Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (TGM); and the Department of Adult Leukemia and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California (CAL) HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 15 NUMBER 1 * FEBRUARY 2001

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This variability in patient groups across studies complicates the assessment of individual therapeutic techniques. Also, transplantation therapy in adults is center specific, and substantial differences exist in regards to preferred preparative chemotherapy, purging strategies, and posttransplantation maintenance therapy. This article attempts to make transplant treatment recommendations in light of these limitations. PROGNOSTIC FACTORS

Standard postremission therapy for adults with ALL includes multiple cycles of intensive combination chemotherapy. Despite this intensive therapy, many adult patients eventually relapse. Investigators have attempted to identify the prognostic factors that predict a poor response to standard therapy. These unfavorable risk factors could then be used to identify patients who may benefit from early high-dose therapy. Although many adverse prognostic factors have been reported, the most common include older age, high white blood cell (WBC) count at diagnosis, longer time to complete remission (CR) (>4 weeks), and abnormal cytogenetic features, mainly t(9,22) and t(4,11).27,45, 50, M, Other frequently reported adverse prognostic features are central nervous system involvement or extramedullary leukemia, hepatosplenomegaly, lymphadenopathy, and the null phenotype.2l’23, 70, Favorable prognostic features in adults include a low white blood cell (WBC) count at diagnosis, T-cell or mature B-cell phenotype, rapid achievement of CR, and younger

Age

Older age is associated with lower CR rates, increased relapse rates, and decreased overall survival in patients with ALL.27The exact age at which adult patients become high risk remains controversial. Several autologous transplant studies have included adults older than 14,20, or 35 years as high risk and have offered transplantation to these adults in first CR. This age variability makes interpretation and comparison of the studies difficult. Overall, most studies consider an age older than 30 or 35 years as high risk. White Blood Cell Count

An elevated WBC count at diagnosis is associated with decreased overall survival, especially in B-lineage disease. Most studies define a WBC count greater than 30,OOO/pL as high risk, although levels greater than lO,OOO/pL, 20,00O/pL, and lOO,OOO/pL have also been reported. A WBC count greater than lOO,OOO/pL is a dire adverse factor in 8-lineage disease and few patients survive long term. In T-cell disease, the WBC

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count is less important, and even those with WBC counts greater than 100,000/ FL can have favorable outcomes with intensive chemotherapy.60 Phenotype

Treatment of T-cell ALL in adults with high-dose cytarabine and cytoxan has changed the prognosis so that T-cell immunophenotype is now considered favorable.58Those individuals with a mediastinal mass and age younger than 30 years seem to have the best prognosis. Adverse prognostic factors in T-cell disease include a WBC count greater than lOO,OOO/pL, more than 2 cycles to achieve remission, and an early T-cell phenotype (CD2 neg). Overall, approximately 20% of adults have Tcell disease. Cytogenetics

Karyotype is the most important prognostic factor for adults with ALL.14 The cytogenetic features associated with the worst prognosis include the Philadelphia chromosome (Ph) (t(9,22)) and t(4,11).87In a French study involving 143 adult patients with t(9,22 ) or t(4,11), fewer than 10 patients experienced long-term survival.38The Ph chromosome confers a dismal prognosis in children and adults. Fewer than 5% of children have Ph+ ALL; however, the incidence increases to more than 30% in adults.77Adultsolder than age 60 may have an incidence as high as 50%.58 Newer molecular-based detection methods suggest that the BCWABL gene rearrangement may be even more prevalent than previously estimated.62As improved molecular techniques evolve, it may be found that age per se is less important as a prognostic factor because of the high incidence of chromosomal abnormalities that accompany aging. Response to Therapy

The most important treatment-dependent variable is the time to achieve CR following induction therapy. Patients who require more than 4 weeks to achieve CR have an increased risk of disease relapse and decreased overall survival. The importance of this effect may be related to the intensity of the induction regimen, with patients failing to achieve remission following intensive chemotherapy at highest risk. Patients who never achieve CR have an extremely poor prognosis. Risk Stratification in Adults

A uniform mechanism for stratifying adults with ALL into risk groups is not available. One possible risk stratification schema is pre-

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sented in Table 1. One major goal in the treatment of adult ALL is to develop a risk-adapted approach capable of appropriately assigning risk groups to conventional or high-dose treatment strategies. Adult patients with low-risk features have an excellent prognosis and are routinely treated with conventional chemotherapy. In contrast, adults with one or more high-risk features have a poor response to standard chemotherapy. In a large prospective study from Germany, the reported 5-year disease-free survival for adults with one or more adverse factors ranged from 11% to 33Y0.~”In many studies, these high-risk patients have been considered for high-dose therapy in first CR. Randomized trials are needed to evaluate the efficacy of autologous transplantation versus conventional chemotherapy in these high-risk patients. CHOICE OF TRANSPLANTATION PROCEDURE

Many factors must be considered when selecting a specific therapy for adult patients with ALL, including age, performance status, risk stratification, disease status, and donor availability. In addition, the type of transplant procedure must be selected. A variety of transplant options exist, including HLA-identical sibling transplantation, allogeneic transplantation (alloBMT)from a mismatch related or unrelated donor, umbilical cord blood (UCB) transplantation, and autologous transplantation. There are few prospective trials comparing these options. Attal and colleagues4 compared HLA-identical sibling transplantation with autoBMT in 120 adults in first CR. The 3-year probability of disease-free survival was significantly higher in the allograft recipients (68% versus 26%), suggesting an advantage to alloBMT. Other studies have demonstrated comparable results among HLA-identical alloBMT and autoBMT.”, 55, 76 Autologous transplantation has also been compared with unrelated alloBMT. In these studies, unrelated alloBMT is associated with increased treatment-related mortality from infection and graft-versus-host disease, whereas autoBMT is associated with increased relapse. The effects seem to offset one another, resulting in similar disease-free survival.18,86 Only a few umbilical cord blood transplantations have been reported for adults with ALL. The low number of stem cells in each UCB

Table 1. PROGNOSTIC GROUPS FOR ADULT ALL

Low Risk = Favorable 1. Time to CR <4 weeks 2. No adverse cytogenetics 3. T-lineage disease, age <30 years OR 4. Early B-lineage disease with WBC count <30,00O/fiL and age <30 years

High Risk = Unfavorable

1. Adverse cytogenetics t(9,22) or t(4,11) 2. Time to CR >4 weeks 3. B-lineage disease with WBC count >lOO,OOO/p,L at diagnosis

CR = complete remission; WBC = white blood cells.

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unit limits the use of UCB transplantation in adults. Newer strategies, including ex vivo expansion of UCB, are needed before this strategy can gain widespread use in adults. Overall, when an HLA-identical related donor is available, most centers prefer allogeneic transplantation. When an identical sibling donor is not available, significant variability exists among transplant centers in regards to the next favored transplant option. Autologous transplantation has several important advantages. The patient’s own stem cells are used for hematopoietic reconstitution; therefore, there are virtually no donor-related limitations. The preparative chemoradiotherapy is better tolerated, resulting in lower treatment related morbidity and mortality. Because immune reconstitution is more rapid after autoBMT, there are fewer posttransplant infections. Also, autoBMT can be performed in older patients. Disadvantages include the lack of graft-versus-leukemia effect, potential leukemia cell contamination of the autologous marrow, and limited ability to eliminate minimal residual disease (MRD) after transplantation. Current strategies are aimed at improving purging techniques, strengthening preparative therapy, and developing posttransplant adjuvant therapy to eliminate MRD and decrease disease relapse. PREPARATIVE THERAPY FOR AUTOLOGOUS TRANSPLANTATION IN ACUTE LYMPHOCYTIC LEUKEMlA

A clearly superior preparative regimen for autologous transplantation in adult ALL has not been identified. The optimal regimen should probably be more intensive than that used in allogeneic transplantation to compensate for the lack of graft-versus-leukemia effect and the relative drug resistance of high-risk ALL. Until now, preparative therapy for autoBMT has, in general, been adapted from alloBMT trials and has included total body irradiation (TBI) with high-dose chemotherapy. Cyclophosphamide was originally used in Seattle and remains the most frequently used approach.81Other chemotherapy agents used with TBI have included et~poside,’~ high-dose cytosine arabinoside,” cytosine arabinoside plus cytoxan;6 high-dose melphalan, cytosine arabinoside plus melphalan,’9, 25 and cyclophosphamide plus melphalan.40A variety of doses and schedules of TBI have been attempted; however, fractionated TBI is currently preferred over single dose because of reduced toxicity to normal cells.17,24 Several centers have attempted to increase the intensity of preparatory therapy to improve the antileukemic response. At the University of California San Francisco Medical Center, Linker and colleagues59have used an intensified regimen, including fractionated TBI (1320 cGy), etoposide (60 mg/kg), and cytoxan (100 mg/kg). This regimen has been given with peripheral blood stem cells (PBSCs) and has been well t0lerated.5~Martin et a161 have also used TBI (1440 cGy) plus etoposide and cytoxan with acceptable toxicity.

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Intensification has resulted, however, in increased toxicity and mortality in other autoBMT 79 Several centers are currently focusing on adding immunotherapeutic agents to preparatory therapy for ALL. Radiolabeled immunoconjugates, monoclonal antibodies, or immune toxins may add significant antileukemia activity without enhancing toxicity. Preliminary results from these trials should be available soon. PURGING OF MALIGNANT CELLS FROM THE AUTOLOGOUS MARROW GRAFT

The goal of autoBMT is to use myeloablative chemoradiotherapy to eradicate host leukemic cells. For this strategy to be successful, the leukemia cells must be sensitive to cytotoxic therapy, and the autologous marrow that is collected and reinfused must be free of contaminating leukemia cells. Data from identical twin transplantations suggest that myeloablative therapy can eliminate host leukemic cells. Gale and colleague~ reviewed ~~ the results from 24 patients with ALL receiving highdose therapy with syngeneic bone marrow support in first CR. The 3year probability of leukemia-free survival was 57%, and the relapse rate was only 36%. These results demonstrate the potent antileukemic effects of myeloablative therapy and suggest that reinfusion of contaminating cells may be responsible for the increased risk of ALL relapse following autoBMT. Using sensitive detection methods, many studies have documented contaminating leukemia cells in bone marrow samples obtained from patients with ALL in CR.31,89, 91 In some studies, the extent of leukemia cell contamination has been directly correlated to disease relapse following autoBMT.", 82, 83 One solution is to use purging techniques to eliminate residual leukemia cells in the harvested marrow. A variety of purging strategies exist, but the optimal approach has not been defined. Unfortunately, there are no randomized or comparative trials evaluating individual purging techniques. Most purging strategies have incorporated immunotherapeutic techniques. Several monoclonal antibodies that target cell surface antigens on ALL cells are available for purging. For example, antibodies against CD9, CD10, CD19, CD20, and CD24 have been used for B-cell ALL and antibodies against CD2, CD3, CD5 and CD7 have been used for T-cell ALL. The antibodies themselves are not sufficiently cytotoxic; consequently, complement is routinely added to enhance immune-mediated cytotoxicity. Antibodies can also be linked to physical particles (i.e., plastic or magnetic beads) to allow cell separation or to immunotoxins to enhance leukemia cell killing. One advantage of immunologic-mediated cell killing is that the leukemic cells are selectively destroyed without damaging normal marrow stem cells. Chemotherapeutic purging involves the exposure of autologous bone marrow to chemotherapy in vitro followed by reinfusion of viable

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cells. The cyclophosphamide derivatives, mafosfamide and 4-hydroperoxycyclophosphamide (4-HC), have been used most frequently.', 41, 42 These cell-cycle dependent agents are effective at eliminating leukemic cells, but they also damage normal cycling hematopoietic progenitor cells. This damage results in delayed engraftment and increased posttransplantation transfusion requirements and infections. Most studies using chemotherapeutic purging have used bone marrow rather than peripheral blood stem cells. Whether the use of peripheral blood stem cells can hasten engraftment following chemotherapy-based purging remains unknown. Some centers have attempted to combine immunologic and chemotherapeutic strategies to enhance the antileukemic activity of purging?" 82 Uckun et a P autografted 14 patients with high-risk T-cell ALL using bone marrow purged with anti-T-cell immunotoxins and 4-HC.84A leukemia progenitor cell (LPC) assay and a sensitive fluorescence-activated flow cytometric assay were used to detect minimal residual disease in the remission marrow and to evaluate the efficacy of purging. A range of 0.8 to greater than 3.4 logs of residual LPC was eliminated from the autograft after combined immunochemopurging. The authors found, however, that high numbers of LPC in the remission marrow were predictive of relapse whereas the number of LPC remaining after purging was not. The data suggest that disease relapse results from increased tumor burden in the host and inefficient pretransplant preparative chemoradiotherapy rather than ineffective purging. Similar results in other trials have led some investigators to question the need of purging in ALL and suggest that efforts should be directed at improving prepara64 Several other purging techniques have been evaluated tive including ex vivo marrow incubation with interferon or interleukin-2 (IL-2), marrow exposure to hyperthermia, and in vitro long-term culture of harvested marrow.6, 47 One potential deleterious effect of purging is the removal of immunocompetent autologous cells. Antibody-mediated purging will eliminate nonleukemic autologous T or B cells, and these cells may be important for autologous antileukemic immunity after transplantation. The removal of these cells may contribute to increased disease relapse. There does not seem to be greater risk of infection after transplantation in antibody-purged marrow autografts than in unpurged marrow autografts. Gene therapy may help to delineate the relative importance of preparative chemoradiotherapy versus purging in ALL.71Purged autologous stem cells can be labeled with a variety of genes, and at relapse the leukemia cells can be evaluated for the presence of these transferred genes. Their presence would suggest ineffective purging, and their absence would suggest chemoradiotherapy resistance. In acute myelogenous leukemia (AML), gene marking studies have demonstrated the contribution of reinfused leukemia cells to disease relapse.16Overall, the clinical value of purging in ALL is unproven. More effective pretrans-

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plant conditioning therapy and the use of gene marking may help to define the future role of purging in adult ALL. STEM CELL SOURCE FOR TRANSPLANTATION

Most studies investigating autoBMT in adults with ALL have used pelvic bone marrow as the source of hematopoietic stem cells. More recently, studies have investigated the use of PBSCs. Powles et aF8 reported faster neutrophil and platelet engraftment after transplantation using PBSCs mobilized with granulocyte colony-stimulating factor (GCSF) than after transplantation using pelvic bone marrow. Purging was not performed in this study but patients were given posttransplant maintenance chemotherapy and it was well tolerated. Patients who received PBSCs were able to start maintenance chemotherapy earlier than those who received bone marrow. Linker and c011eagues~~ have also used PBSCs. In this study, PBSCs were collected after administration of high-dose cytarabine and etoposide chemotherapy. The chemotherapy served as an in vivo purge, and collected cells also underwent in vitro purging with anti-T or anti-B cell antibodies and complement. Most patients experienced rapid neutrophil and platelet engraftment, and no unforeseen toxicity was encountered. Longer follow-up is needed to assess the efficacy of this strategy. More studies investigating PBSC transplantation together with chemotherapeutic purging with or without immunologic purging are necessary. Data regarding leukemia cell contamination following PBSC or pelvic bone marrow collection are limited, and whether one source is better remains unknown. Atta et aP compared residual leukemia cell contamination and purging efficacy in bone marrow versus PBSCs in patients with Ph + ALL. They performed semiquantitative polymerase chain reaction (PCR) assays to identify residual Ph+ cells before and after immunologic purging. Overall, they found more residual leukemia cells, approximately 2 to 3 log, in bone marrow than in PBSCs. Although purging was more efficacious with bone marrow, the absolute number of leukemia cells was higher in bone marrow than in PBSCs. These data together with the rapid engraftment following PBSC transplantation support the use of PBSCs in future adult ALL trials. RESULTS

Many small, single institution studies have evaluated autoBMT in adults with ALL. The results are variable, and transplant success seems dependent on the adverse features present at diagnosis and the disease status (i.e., first CR, second CR, relapse, or refractory) at time of transplant. Registry data strongly support the importance of pretransplant disease status on posttransplant relapse and survival (Fig. 1).The results

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3

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Years 100

n

Not in remission (n = 45)

80.

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P = 0.0001

CR2+ (n = 241)

60 1

CR1 (n = 172)

0

"Q B

1

2

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4

Years

Figure 1. A, Probability of leukemia-free survival (LFS) after autotransplantation for ALL. 13, Probability of relapse after autotransplantationfor ALL. CR = complete remission. (Data registered with the International Bone Marrow Transplant Registry (IBMTR), 1991-1 997.)

from the most important trials in regards to remission status are reviewed later. Comparative Trials Involving Autologous Transplantation in Adults

Few studies have compared autoBMT with alloBMT in adults with ALL. As discussed earlier, Attal and colleagues4conducted a prospective

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trial involving 120 adults with ALL in first CR. Patients with an HLAidentical sibling received alloBMT (genetic randomization), and all others were treated with autologous transplantation. The 3-year diseasefree survival was significantly higher in the allogeneic transplant group (68% versus 28%; P = 0.001), and relapse rates were significantly higher in the autoBMT group. Vey et alS compared results from 63 patients undergoing allogeneic (n = 34) or autologous (n = 29) transplantation in first CR. The 6-year disease-free survival and relapse rates for allogeneic and autologous transplant recipients were 62% versus 27% (Pc0.06) and 10% versus 65% (P= <0.05), respectively. Other studies have not demonstrated a sigruficant advantage to allogeneic transplant. Blaise and colleagues11reviewed the results of 47 patients receiving autologous or allogeneic transplantation in first CR. Autologous transplantation was associated with an increased risk of disease relapse (52% versus 5%; P <0.01), but disease-free survival was comparable (40% versus 71%; P = not significant [NS]). A similar retrospective study from Minnesota demonstrated higher relapse rates in autologous transplant recipients and comparable 4-year disease-free survival (20% for autoBMT versus 27% for alloBMT; P = NS).= These retrospective comparisons are hampered by the fact that the indication for transplant varies or is unknown; consequently, it is difficult to draw definitive conclusions. Overall, most centers prefer matched-sibling alloBMT rather than alloBMT because of the potential benefit of graft-versus-leukemia effect. Several studies have compared autoBMT with intensive postremission chemotherapy?, 69 Fi&e et a P reported the largest randomized prospective trial comparing autoBMT with consolidation chemotherapy in adults with ALL in first CR. The estimated 3-year disease-free survival rates were similar in both groups, and there did not seem to be any advantage in receiving autologous transplantation. A subset analysis including only patients with poor prognostic factors also failed to demonstrate any benefit for autologous transplantation. Late relapses (>36 months) were predominantly found in the intensive chemotherapy arm. The results support the use of intensive chemotherapy as consolidation in all adults with ALL and reserving autoBMT for disease relapse. There were several significant flaws to this study, however. First, a substantial number of patients experienced disease relapse before transplantation (i.e., patients received three postremission chemotherapy cycles before transplantation). This finding raises the question whether autoBMT performed earlier in the disease course (i.e., after one cycle of consolidation chemotherapy) would have been more efficacious. Second, only two thirds of the patients allocated to the BMT arm actually underwent transplantation. If only those who received the BMT procedure are included, the 3-year disease-free survival is 51% (versus 39% for the entire BMT group and 32% for the chemotherapy group). Overall, it is difficult to draw conclusions from current data, and more studies are needed to clarify this controversy. A trans-Atlantic effort between the Eastern Cooperative Oncology Group and the Medical Research Council in Britain is currently comparing alloBMT, autoBMT, and conventional chemotherapy.” Patients are

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being stratified by adverse features, and are being placed into treatment groups at the time of first remission to avoid selection biases. The time allowed between remission and transplantation has been rigorously defined to allow for reliable comparisons among groups. The results of this study may facilitate the assignment of treatment strategies to adults with ALL according to risk stratification. Autologous Transplantation in First Complete Remission

The use of autoBMT in adults with ALL in first CR remains controversial. The results from 11 contemporary publications are depicted in Table 2 . The studies differ in patient characteristics, conditioning therapy, purging techniques, posttransplant maintenance therapy, and length of follow-up. This variation makes comparison between studies difficult. The best results using autoBMT have been reported by Simonsson et al.78Patients received TBI-based conditioning therapy, and all marrow grafts were purged with antibodies and complement. Although the actuarial leukemia-free survival was 659'0, follow-up was short (16 months), and additional patients are likely to relapse. The largest reports are from Gorin et a143 and Fi2re et al.34 In these reports, including more than 325 patients, the disease-free survival and relapse rates are approximately 40% and 55%, respectively. Gorin et a1 described two major prognostic factors for survival after autoBMT: the length of time to remission and the time interval between onset of CR and BMT (Fig. 2 ). Powles and colleagues'j8reported results in 50 adults receiving highdose melphalan alone or melphalan with TBI and unpurged PBSCs or bone marrow. After hematologic recovery, patients were given oral maintenance chemotherapy for 2 years. The authors credited the use of maintenance chemotherapy after autoBMT for the low relapse rates (31%) and improved disease-free survival (53%) at 5 years. Gilmore et a139reported results from 27 adult patients with poor-risk ALL receiving TBI-based conditioning and immunologic purging. The leukemia free survival at 7 years was only 32% and risk of relapse was 67%. The authors concluded that autoBMT may not offer a significant advantage to these high-risk patients. Vey et alas reported on 36 patients treated with TBI and immunologic purging. The low disease-free survival of 26% and increased relapse rate of 65% led the investigators to recommend new therapeutic approaches for autologous transplantation. Overall, autoBMT for adults in first CR is investigational, and patients receiving autoBMT should be treated in randomized, peer-reviewed clinical trials. Autologous Transplantation for Second or Greater Remission

Adult patients who relapse after primary chemotherapy for ALL have an extremely poor prognosis. Although many patients will achieve

Auto Auto Auto Auto Auto Auto Auto Auto Auto Auto Auto

Fiere 1993” G o M 199043 Tiley 199380 Blaise 19971° Powles 199568 Simonsson 198978 Doney 199328 Carey 199lZ0 Deliliers 199326 Gilmore 199139 Vey 1994=

95 233 38 28 50 21 10 13 7 27 34

N

+

TBI + Ct TBI/Mel TBI Ct TBI + Ct TBI/MelorCyt

m1/m

TBI/Cyt MR TBI/Mel TBI/Cyt Me1 L TBI

TMT

15-50 1-55 3-41 16-57 15-58 3-55 2-45 18-51 16-39 11-45 16-59

Age (Y)

MoAB/CT Variable MoAB (11) None MoAb (7) MoAB + C’ MoAB + C’ None None MoAB + C’ MoAB/CT

Purging

A NR HR A A HR HR A HR HR A

R

4% NR 18% 4% 16% 5% 20% 0% 0% 8% 6%

TRM

57% 53% 35% 57% 31% 28% 30% 46% 43% 67O/o 65%

RR

39% (3y) 41% (>3 y) 50% (4 y) 43% (3 y) 53% 65% (1 y) 50% (2 y) 48% (2.5 y) 57% 32% (7 y) 27%

DFS

4 NR 4.5 6 5 NR 6.6 7 10 6 5.5

rn

BMT = bone marrow transplantation; N = number in study; Auto = autologous BMT; TMT = conditioning therapy; TBI = total body irradiation; Ct = cytoxan ? Ara-C or VF-16; Cyt = cytoxan; Me1 = melphalan; MR = multiple regimens; Me1 2 TBI = melphalan alone or with TBI; MoAB = monoclonal antibodies; CT = chemotherapy; Variable = multiple purging regimens; MoAB + C’ = monoclonal antibodies with complement; R = risk category; A = all risk groups; HR = high risk; TRM = treatment-related mortality; RR = relapse rate; DFS = disease-free survival; NR = not reported; T I = time from remission to BMT in months.

BMT

Author, Year

Table 2. AUTOLOGOUS BONE MARROW TRANSPLANTATION FOR ACUTE LYMPHOCYTIC LEUKEMIA IN FIRST COMPLETE REMISSION

-

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29M(n=35)

7-9M (n=41)

3

4-6M (n=102)

1 OS2T U

I

0

1-3M (1145)

P
EBMT 02/89 1

1

20

1

1

40

1

1

I

60 Months

I

80

I

I

100

I

I

120

Figure 2. Autologous bone marrow transplantation in ALL in first complete remission. Influence of the interval from remission to transplant on disease-free survival. M = months; EBMT = European Group for Blood and Marrow Transplantation. (From Gorin NC, Aegerter B, Auvert B: Autologous bone marrow transplantation (ABMT) for acute leukemia in remission: An analysis on 1322 cases. Leukemia 4:3, 1990; with permission.)

a second or greater remission following salvage therapy, the remission duration is usually short, and few patients experience long-term sur~ i v a 1Bone . ~ ~ marrow transplantation offers the best chance for durable survival. Relapse patients with an HLA-identical sibling should receive alloBMT. Patients without available related donors are good candidates for autoBMT or alternative donor transplantation. The results of seven clinical trials involving adults with ALL past first relapse receiving autoBMT are depicted in Table 3. The mean disease-free survival and relapse rates are 25% and 63%, respectively. These results are inferior to those reported for patients receiving autoBMT in first CR (see Table l), but compare favorably with survival rates for relapse patients receiving salvage chemotherapy. For relapse patients lacking HLA compatible donors, autoBMT seems reasonable. Randomized trials comparing autoBMT to salvage chemotherapy in relapse ALL are needed before definitive conclusions can be made. Autologous Transplantation for Relapse or Refractory Adult Lymphocytic Leukemia

Few studies have attempted to use autoBMT for adults with relapse or refractory ALL. The major limitations are drug resistance in the

Auto Auto Auto Auto Auto

Auto Auto

Mehta 199763 Simonsson 198978 Doney 199328 Soiffer 199379 Deliliers 1993*"

Gorin 199043 Uckun 199282

205 14*

23' 32 52 22 13

N

TBI/Mel TBI/MR TBI/Ct TBI / Cyt TBI + Ct Ara-c, cyt Variable TBI/ Ara-C

TMT

1-55 4-36

5-37 3-25 2-46 18-54 10-39

Age (year)

+C +C +C

Variable MoAb + 4-HC

MoAB MoAB MoAB MoAB None

Purging ~

NA 7%

35% 5% 8% 18% 0%

TRM

70% 71%

51% 56% 69% 60% 61%

RR

27% (>3 y) 21% (3.5 y)

26% (10 y) 32% (1 y) 21% (2 y) 20% 31%

DFS-5 y

NA 2.4

NR 3.9-4 NR NR

Mean Log Kill

BMT = bone marrow transplantation; N = number in study; Auto = autologous BMT; TMT = conditioning therapy; TBI = total body irradiation; Ct = cytoxan i afa-C or Vetoposite P-16; Cyt = cytoxan; Me1 = melphalan; MR = multiple regimens; Me1 ? TBI = melphalan alone or with TBI; MoAB = monoclonal antibodies; CT = chemotherapy; Variable = multiple purging regimens; MoAB + C = monoclonal antibodies with complement; R = risk category; A = all risk groups; HR = high risk; TRM = treatment-related mortality; RR = relapse rate; DFS = disease-free survival; NR = not reported; Mean log kill = response to purging in log fold reduction in tumor cells; NA = not applicable. *Included some first remission patients.

BMT

Author, Year

Table 3. AUTOLOGOUS BONE MARROW TRANSPLANTATION FOR ACUTE LYMPHOCYTIC LEUKEMIA IN SECOND OR SUBSEQUENT REMISSION OR RELAPSE

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leukemia cell clones, the lack of significant graft-versus-leukemia effect, and the inability to collect uncontaminated stem cells. Doney et alZ8 reported on 27 patients with relapse ALL undergoing autologous transplantation in Seattle. Patients received TBI-based preparative therapy, and marrow samples underwent immunologic or chemotherapeutic purging. The 1- and 2-year disease-free survival rates were 8% and O%, respectively. Consequently, autologous transplantation for relapse or refractory disease cannot be recommended at this time. Improvements in preparative chemotherapy, purging, and the treatment of minimal residual disease posttransplant are needed before significant advances can be made. Autologous Transplantation for Patients with t(9,22) and t(4,ll) Adult Lymphocytic Leukemia

The Ph chromosome confers a dismal prognosis for patients with ALL, and few patients, if any, are cured with combination chemotherapy.32,35 Most investigators agree that alloBMT in first CR is the treatment of choice. For patients lacking an HLA-matched sibling, unrelated donor transplantation or mismatch-related donor transplantation are reasonable options. The graft-versus-leukemia effect probably plays a significant role in curing patients with Ph+ ALL. Several small studies have evaluated the role of autologous transplantation in Ph+ ALL. Arico and colleagues2 used autoBMT in 25 children and young adults with Ph+ ALL. Only 6 of 25 patients achieved disease-free survival. Dunlop et a130 treated 20 Ph+ adult patients with autoBMT. The reported 3-year probabilities of relapse and disease-free survival were 66% and 26%, respectively. The authors commented that relapses beyond 3 years were seen and that better strategies for Ph+ ALL are needed. Martin and colleagues61treated 36 patients using single or double autoBMT strategies. The relapse rate reached 8O%, and the event-free survival was only 18%. Fiere and colleagues33reported no survivors out of nine, patients treated with autologous transplantation in first CR. Morishima et alG reported on four patients treated with autologous transplantation in first CR. Patients received conditioning with TBI, cytarabine, and cyclosphosphamide, and marrow grafts were purged with antibodies and complement. PCR analysis for minimal residual disease after purging showed no evidence of residual disease. At the time of reporting, three out of four patients remained in continuous CR 77, 29 and 26 months after autoBMT. Altogether, autoBMT in Ph+ ALL is rarely successful, and most patients succumb to disease relapse. Strategies aimed at decreasing relapse are needed. Tyrosine kinase (TK) inhibitors directed against the BCR-ABL gene product have been administered effectively to Ph + patients with chronic myelogenous leukemia.29In vitro, the TK inhibitor STI571 has demonstrated antiproliferative effects against Ph ALL cells. Studies are cur-

+

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rently underway to evaluate the in vivo role of STI571 in Ph+ ALL. TK inhibitors may be effective during induction therapy, purging, or as postremission maintenance therapy for Ph + ALL. Studies are needed to evaluate the most effective use of these BCR-ABL-targeted agents in adult ALL. Patients with the t(4,ll) translocation also have a poor prognosis.14,87 Although there are limited data, most centers would recommend alloBMT in first CR. As with Ph + ALL, patients without a suitable donor would be candidates for experimental therapies including AD transplantation and autologous stem cell transplantation. Only a handful of autologous transplantations for t(4,ll) have been reported. AUTOLOGOUS VERSUS ALTERNATIVE DONOR TRANSPLANTS

It is unclear whether autologous or alternative donor transplantations should be pursued in patients with relapsed ALL who lack an HLA-identical sibling donor. Patient age, the presence of cytogenetic abnormalities, and the expertise of the transplant center should all be considered when determining the optimal transplantation approach. Patients older than age 55 have a high incidence of treatment-related morbidity and mortality after alloBMT and likely should be treated with autologous transplantation. Patients with abnormal cytogenetic features or persistent leukemia should likely receive an alternative donor transplantation. In patients younger than age 55 with normal cytogenetics, the data are inconclusive and either treatment can be pursued. All patients should be treated on peer-reviewed investigational protocols and the expertise of the transplant center should be considered. ANTILEUKEMIA THERAPY AFTER AUTOLOGOUS TRANSPLANTATION

To improve survival after autoBMT, novel strategies aimed at treating minimal residual disease and preventing disease relapse are needed. Several centers are investigating the use of posttransplantation chemotherapy or immunotherapy as treatment for minimal residual disease. As discussed earlier, Powles et a P administered standard oral methotrexate and 6-mercaptopurine for 2 years following autoBMT. The therapy was well tolerated despite compromised marrow reserve. The authors attributed their low relapse rate (32%)to maintenance therapy and recommended that a large randomized trial be performed. Other centers are focusing on immunotherapy after transplantation. The graft-versus-leukemia effect is an important component of allogeneic transplantation. The immune mechanisms responsible for graft-versusleukemia have not been well characterized. Consequently, investigators have attempted to induce an autologous graft-versus-leukemia with

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cyclosporine,5*,90 immunomodulatory cytokines such as IL-2 and interferon,56 and immunostimulants such as l i n ~ m i d e .Administration ~~ of IL-2 after autoBMT has hastened recovery of CD3+ T cells, natural killer cells, and lymphokine-activated killer cell activities.12,48 Leukemiaspecific immune responses have not been demonstrated, however, and one recent study failed to show an improvement in disease-free survival with posttransplantation IL-2 administration.1° Antitumor responses have been noted in patients with solid tumors receiving IL-2 with in vitro generated lymphocyte-activated killer cells.74Studies using this strategy for hematopoietic malignancies are currently being conducted. Immunotherapy using IL-2 with mismatched allogeneic peripheral blood lymphocyte infusions has also been evaluated after autologous transplantation. In a preliminary report from Europe, 16 patients were treated with gradual increments of donor mismatch-related lymphocytes and IL-2. Six patients developed acute graft-versus-host disease and two patients died from graft-versus-host disease. The authors concluded that allogeneic lymphocytes successfully induced graft-versus host disease and that further studies were needed to identify the optimal timing, schedule, dose, and antileukemic effect of alloreactive mismatched cells.67 Monoclonal antibodies and immunotoxins are also under investigation for use after autoBMT in adult ALL. These molecules target antigens expressed on leukemia cells and not on normal hematopoietic stem cells. These molecules do not cause marrow suppression and consequently are ideal agents for use after autoBMT. These molecules can be used alone or in combination with other antibodies, IL-2, interferon, LAK cells, or chemotherapy. The effects of these agents may be additive or synergistic; consequently, they may improve treatment of minimal residual disease and prevent disease relapse after autoBMT. TREATMENT OF RELAPSE FOLLOWING AUTOLOGOUS BONE MARROW TRANSPLANTATION

The optimal management of patients who relapse after autoBMT is controversial. The overall prognosis is poor, and few patients achieve long-term survival. Patients who have experienced longer remission duration (i.e./ >6 months) are more likely to respond to salvage chemotherapy and may be candidates for a second bone marrow transplantation.66For patients with an HLA-matched related or unrelated donor, a second allogeneic transplant is reasonable. Those patients without an available donor usually are treated with conventional chemotherapy although a second autoBMT is also possible. A recent study from the European Group for Blood and Marrow Transplantation reported 2-year leukemia-free survival rates of 27% and 35% for relapsed leukemia patients undergoing second alloBMT and autoBMT, respectively.” Treatment-related mortality was high at 51% for allograft recipients and 27% for autograft recipients at 2 years. A high treatment-related mortality

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has been reported in other second transplant studies leading many investigators to recommend avoiding second transplantations in acute 1e~kemia.I~ The advent of nonmyeloablative allogeneic transplantation offers a potential new strategy for second transplants. Nonmyeloablative allogeneic transplantation may result in less treatment-related mortality and improved survival. This strategy relies on the graft-versus-leukemia effect of donor immune cells. Formal investigations are needed to evaluate nonmyeloablative allogeneic transplantation in adult ALL. Monoclonal antibody or immunotoxin therapy may also demonstrate some benefit in patients relapsing after transplantation. These agents may be used alone or together with salvage chemotherapy or second transplantation.

SUMMARY Autologous bone marrow transplantation remains an investigational treatment for adult ALL. Despite many anecdotal studies showing efficacy, the rarity of ALL has prevented the large randomized trials necessary to confirm effectiveness. Candidates for autoBMT include adult patients in first CR with adverse risk factors and all patients who have experienced disease relapse. It remains debatable which preparative regimen is optimal, whether purging is necessary, or if chemotherapy or immunotherapy administered after transplantation can decrease disease relapse. Overall, every effort should be made to enter ALL patients on well-designed randomized multi-institutional trials. These trials should compare autologous transplantation to newer more intensive chemotherapy regimens and should take into account the heterogeneity of ALL. A quality of life analysis should be performed as one high-dose treatment may be less toxic and better tolerated than multiple cycles of consolidation chemotherapy. Strategies aimed at enhancing an autologous graftversus-leukemia effect after transplantation may enhance long-term survival. Many more studies are needed to further define the optimal role of autoBMT in adult ALL.

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Address reprint requests to Thomas G. Martin, MD Department of Blood and Marrow Transplantation M. D. Anderson Cancer Center 1515 Holcombe Boulevard, Box 243 Houston, TX 77030