Allogeneic Transplantation for Pediatric Acute Lymphoblastic Leukemia: The Emerging Role of Peritransplantation Minimal Residual Disease/ Chimerism Monitoring and Novel Chemotherapeutic, Molecular, and Immune Approaches Aimed at Preventing Relapse Michael A. Pulsipher,1 Peter Bader,2 Thomas Klingebiel,2 Laurence J. N. Cooper3 Although improved donor sources and supportive care have decreased transplantation-related mortality over the past decade, relapse remains the principal cause of failure after allogeneic transplantation for high-risk pediatric acute lymphoblastic leukemia (ALL). Emerging tools of minimal residual disease (MRD) and chimerism monitoring before and after transplantation have defined those children at highest risk for relapse and provide the opportunity for intervention to prevent relapse. Specific methods aimed at decreasing relapse include the use of intensive treatment before transplantation to increase the percentage of patients undergoing the procedure with negative MRD, optimal transplantation preparative regimens, and posttransplantation interventions with targeted or immunologic therapy. Early data demonstrate decreased relapse with the use of sirolimus for all types of ALL and imatinib for ALL with the Philadelphia chromosome (Ph1 ALL) after transplantation. Patients with increasing chimerism or MRD have been shown to benefit from early withdrawal of immune suppression or donor lymphocyte infusion. Finally, various targeted immunologic therapies, including monoclonal antibodies, killer cell immunoglobulin-like receptor mismatching, natural killer cell therapy, and targeted T cell therapies, are emerging that also could have an affect on relapse and improve survival after transplantation for pediatric ALL. Biol Blood Marrow Transplant 15: 62-71 (2009) Ó 2009 American Society for Blood and Marrow Transplantation
KEY WORDS: Pediatric Allogeneic Transplantation, Acute Lymphoblastic Leukemia, Minimal Residual Disease, Immunotherapy
INTRODUCTION Intensive, risk-based chemotherapy approaches cure more than 80% of children with acute lymophoblastic leukemia (ALL) [1-3]. Studies have identified several cytogenetic and response-based risk factors associated with poor outcome that can be defined at presentation
From the 1Division of Hematology/BMT, Primary Children’s Medical Center, University of Utah School of Medicine, Salt Lake City, Utah; 2Department of Stem Cell Transplantation, Children’s Hospital of the J.W. Goethe University, Frankfurt, Germany; and 3Division of Pediatrics, MD Anderson Cancer Center, Children’s Cancer Hospital, Houston, TX. Financial disclosure: See Acknowledgments on page 69. Correspondence and reprint requests: Michael Pulsipher, MD, Huntsman Cancer Institute, University of Utah/Primary Children’s Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132 (e-mail:
[email protected]). 1083-8791/09/151S-0001$36.00/0 doi:10.1016/j.bbmt.2008.11.009
62
or after relapse [4]. Although allogeneic transplantation has been shown to benefit many children with these risk factors, relapse rates after such transplantation remain high, especially for the highest-risk disease states (eg, very early relapse, CR31) [5,6]. Recently, the persistence of minimal residual disease (MRD), measured by flow cytometry or molecular methods, has been used to further identify poor outcomes from chemotherapy [7-9]. Preliminary studies have suggested that a similar link exists between outcome and MRD values before transplantation [10,11]; larger studies should more fully illuminate the predictive power of pretransplantation MRD in the next few years. These tools have spurred investigation into the use of approaches before and after transplantation to achieve and sustain MRD negativity. Such approaches include intensive chemotherapeutic blocks using promising new agents before transplantation and such therapies as imatinib and sirolimus after transplantation. Other approaches include withdrawal of immune suppression and donor lymphocyte infusion
Biol Blood Marrow Transplant 15:62-71, 2009
(DLI) in selected patients with MRD or persistent chimerism and immune-based treatments, such as antibody and cellular therapies. Emerging evidence suggests that improved outcomes after transplantation for pediatric ALL will be seen in the next few years as clinicians (1) define very-high-risk patients early and perform transplantation when performance scores are high, (2) minimize disease burden before transplantation with cytotoxic and targeted agents, (3) use total body irradiation (TBI)-based regimens that decrease the risk of relapse for the patients at greatest risk, and (4) closely monitor patients with MRD and/or chimerism after transplantation, treating as necessary to minimize the risk of relapse. INDICATIONS FOR ALLOGENEIC TRANSPLANTATION IN PEDIATRIC ACUTE LYMOPHOBLASTIC LEUKEMIA Indications for transplantation for pediatric ALL have varied through the years, based on improvements in chemotherapy and outcomes for different risk groups. Although international groups vary somewhat, the Children’s Oncology Group (COG) Acute Lymphocytic Leukemia and Hematopoietic Stem Cell Transplant Committees currently recommend allogeneic transplantation for the indications outlined in Table 1. Indications for transplantation at first complete remission (CR1) will be modified as the data mature regarding the predictive power of MRD (COG
Table 1. COG Indications for Transplantation in ALL Remission Status CR1
CR2
CR3
Indication Alternative or sibling donors: Ph+ patients requiring transplantation Extreme hypodiploidy (< 44 chromosomes or DNA index < 0.81) 11q23 (MLL) plus slow early response (M2/ M3 at day 14 or MRD > 0.1% at day 29) Primary induction failure: M3 bone marrow at day 29 or M2 bone marrow or MRD > 1% at day 29 who then fail after consolidation with M2 or M3 bone marrow or MRD > 1% at day 43 Matched sibling donor only: B-lineage ALL after late bone marrow relapse ($ 36 months from diagnosis) B-lineage ALL in after a very early isolated extramedullary relapse (< 18 months from diagnosis) Alternative or sibling donors: B-lineage ALL after early bone marrowe relapse (< 36 months from diagnosis) T-lineage ALL after bone marrow relapse at any time Ph+ ALL bone marrow relapse at any time T-lineage ALL after very early isolated extramedullary relapse (< 18 months from the initiation of primary chemotherapy) Alternative or sibling donors: Any B- or T-lineage patient with any type of relapse
Allogeneic Transplantation for Pediatric ALL
63
uses flow cytometry, sensitive to 10-4) and gene array profiles. COG investigators presented data at the American Society of Hematology’s 2007 meeting showing outstanding early outcomes using intensive chemotherapy plus imatinib; thus, the role of CR1 transplantation in this group soon may be limited to selected high-risk patients. Transplantation for infant ALL remains controversial; COG investigators have seen improved outcomes for both MLL rearranged and non-MLL–rearranged infants with intensive chemotherapy approaches [12]. Outcomes for the youngest infants with MLL rearrangements remain poor, however, and transplantation has been offered with reasonable rates of cure when remission is obtained [13]. The second complete remission (CR2) indications listed in Table 1 reflect the fact that some patients with late bone marrow relapse and isolated extramedullary relapses can be successfully treated with chemotherapy [5]. But the relatively low morbidity and rates of graft-versus-host disease (GVHD) after matched sibling transplantation, along with reports or equivalent or better outcomes, make transplantation a reasonable option for these patients, especially those who cannot receive salvage chemotherapy of adequate intensity.
INTENSITY OF CHEMOTHERAPY BEFORE TRANSPLANTATION It has been argued that the biology of ALL at relapse determines the outcome, and that patients with sensitive disease will do well and those with resistant disease will do poorly regardless of the pretransplantation chemotherapeutic approach. Recent data from the COG refutes this argument, showing that 71% of patients who achieve CR after induction chemotherapy but have MRD positivity will experience decreased disease burden with subsequent intensive blocks of chemotherapy, with nearly half of them achieving MRD-negative status after 2 consolidation blocks [8]. Because achieving MRD negativity before transplantation improves long-term survival, the major focus in the COG relapsed ALL group is to introduce agents into reinduction protocols that will increase a patient’s chance of becoming MRD-negative before transplantation. Early promising data are emerging with the inclusion of clofarabine and epratuzumab (anti-CD22 antibody) in induction/consolidation approaches [14,15], and protocols including bortezomib and temsirolimus are in the planning stages. Optimal pretransplantation induction regimens for relapsed ALL patients should maximize the number of patients achieving MRD-negative status, while minimizing transplantation-limiting complicatons, such as organ damage and invasive fungal infections.
64
M. A. Pulsipher et al.
Biol Blood Marrow Transplant 15:62-71, 2009
TOTAL BODY IRRADIATION–BASED TRANSPLANTATION REGIMENS FOR ACUTE LYMOPHOBLASTIC LEUKEMIA
PREVENTING RELAPSE WITH TARGETED POSTTRANSPLANTATION THERAPIES The use of cytotoxic therapies to maintain ALL remission after transplantation is infeasible because of hematologic toxicity and abrogation of the graftversus-leukemia (GVL) effect. However, noncytotoxic agents (eg, molecular targeted therapies, immune approaches) can be used successfully to help achieve and sustain remission after transplantation. Two examples with early data are posttransplantation imatinib for Ph1 ALL and sirolimus. Carpenter et al. [18] reported efficacy with acceptable toxicity in early administration of imatinib after transplantation for patients with Ph1 ALL. All 9 of the pediatric patients in their cohort (median follow-up, 1 year) are alive, with 1 relapse. COG investigators found a reasonable toxicity profile with imatinib started 6 months after transplantation, but with some relapses, making the benefits of this approach unclear. Studies evaluating the posttransplantation use of dasatinib and nilotinib are currently underway through the COG and Fred Hutchinson Cancer Research Center in Seattle. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that has been used for more than 15 years as an immunosuppressive agent for solid organ transplantation. Several groups have reported efficacy using sirolimus for GVHD prevention, and because sirolimus has been shown to have a significant antileukemic effect on human ALL in nonobese diabetic–severe combined immune deficiency (NODSCID) models [19], it has been used by COG investigators to both control GVHD and prevent relapse. A pilot study using sirolimus-based GVHD prophylaxis in pediatric ALL has shown lower rates of relapse than expected in all risk groups (Figure 1), and a Phase
CR1 0.8
Cumulative Survival
Fractionated TBI-based preparative regimens, generally containing at least 1200 cGy, have been shown to decrease the risk of relapse in high-risk CR2 ALL transplantation recipients by as much as 27% compared with non-TBI regimens [5]. Relapse can be further decreased by slightly higher doses of TBI (total 1300 to 1400 cGy) or the addition of VP-16 or thiotepa to a 1200-cGy regimen [16]. Although concerns surround the growth and developmental implications of TBI use in infants or children under age 3, several groups have been using this approach with low rates of relapse and acceptable growth and developmental outcomes [17]. Whether TBI is necessary for MRD-negative, intermediaterisk patients, in whom relapse risk is less of an issue, is unknown.
1.0
IR CR2 CR3 0.6
HR CR2 0.4
0.2
0.0 0.00
1.00
2.00
3.00
4.00
5.00
Time from Transplant (yrs) Figure 1. Early outcome data for rapamycin-based GVHD prophylaxis after TBI-based transplantation for ALL (50 patients; median follow-up, 21 months). Two-year event-free survival: CR1, 92% 6 8%; CR2 IR (bone marrow relapse . 36 months from diagnosis), 93% 6 6%; CR2 HR (bone marrow relapse, B cell, \ 36 months from diagnosis, all T cell), 49% 6 14%; CR3, 67% 6 16%.
III trial comparing sirolimus-based GVHD prophylaxis with standard approaches is ongoing. PERITRANSPLANTATION MINIMAL RESIDUAL DISEASE/CHIMERISM MONITORING Analysis of chimerism peritransplantation allows assessment for the rare possibility of imminent graft rejection and also can serve as an indicator for recurrence of underlying malignancy. In addition, characterization of MRD before and after transplantation has defined those patients at greatest risk for relapse. Consecutive posttransplantation MRD monitoring together with chimerism analysis allows the detection of impending relapse in a substantial percentage of children undergoing transplantation for ALL. Consequently, for some groups, these analyses have served as the basis for treatment intervention to avoid graft rejection, maintain engraftment, and treat imminent relapse. DONOR LYMPHOCYTE INFUSION Kolb et al. [20] first described the efficacy of DLI in patients with chronic myelogenous leukemia (CML) relapsing after allogeneic stem cell transplantation. DLI initiated during frank hematologic relapse was found to induce complete remission in 8% of patients with ALL and in 22% of patients with acute myeloid leukemia (AML) [21]. When tumor burden was reduced by chemotherapy before DLI, the rate of complete response was improved significantly (to 33% in ALL and 37% in AML) [22]. These results suggest that immunotherapy provides the greatest benefit to patients with acute
Biol Blood Marrow Transplant 15:62-71, 2009
leukemia after stem cell transplantation when administered before hematologic relapse occurs. Thus, it is desirable to identify those patients at greatest risk for relapse early, to maximize the chance of successful immunotherapy. TECHNIQUES FOR POSTTRANSPLANTATION MONITORING Two different techniques are currently available for posttransplantation surveillance of disease remission: characterization of posttransplantation chimerism and specific detection of MRD. MRD assessment measures the malignant clone directly, whereas chimerism assessment characterizes the origin of posttransplantation hematopoiesis. Over the past decade, methods of detecting MRD and chimerism have improved greatly, with techniques ranging from polymerase chain reaction (PCR) to immunophenotypic analysis (flow cytometry) of aberrant cell surface molecules [23-25]. Chimerism in Leukemia Molecular evidence of persistent or reappearing recipient cells may be a reflection of survival of leukemic cells, survival of normal host hematopoietic cells, or a combination of both. Surviving host hematopoietic cells may in turn facilitate the reemergence of a malignant cell clone by inhibiting immunocompetent donor effector cells. It has been shown that in patients with CML, the reappearance of host hematopoietic cells in the mononuclear cell fraction precedes hematologic relapse [26]; thus, mixed chimerism has been considered to reduce the GVL effect [26,27]. Several early studies left the question of whether patients with acute leukemias and mixed chimerism have an increased risk of relapse unanswered. In the mid-1990s, it was realized that evolution of chimerism is a dynamic process and that chimerism analysis should be done serially in short time intervals. Using short tandem repeat (STR)-PCR– based serial analysis of microsatellite regions identified patients with rapidly increasing mixed chimerism as being at the greatest risk for relapse [22,28-31]. Investigations of subpopulations of patients with acute leukemia indicated a possible difference between adult and pediatric patients. Guimond et al. [32] demonstrated that mixed chimerism in T and natural killer (NK) cell subpopulations is frequently found in pediatric patients with leukemia relapse but not in those in remission, and also not in adult patients with relapse. Studies performed by the German group demonstrated that persistent mixed chimerism in the early posttransplantation period is caused predominantly by normal recipient hematopoietic cells. An increase in recipient chimerism precedes the reappearance of the underlying disease. These findings support the hypothesis that a state of mixed hematopoietic chimerism may reduce the clini-
65
Allogeneic Transplantation for Pediatric ALL
cal GVL effect of alloreactive donor-derived effector cells in patients with acute leukemias and thus facilitate the proliferation of residual malignant cells that may have survived the preparative regimen. Barrios et al. [33] showed that patients with acute leukemias with increasing mixed chimerism have a significantly elevated risk of relapse. Based on the foregoing studies, several trials were initiated to evaluate the efficacy of preventing relapse through preemptive immunotherapy on the basis of chimerism analysis in patients with acute leukemias [29,30]. A German pediatric transplantation group showed that STR-based chimerism analysis performed at regular intervals after transplantation was able to define a subset of children with impending relapse. Furthermore, overt relapse was prevented in a portion of patients by preemptive immunotherapy (withdrawal of immune suppression or DLI) on the basis of increasing mixed chimerism [34]. One challenge of this approach was that it is not possible to define impending relapse in all patients, because the time interval between the conversion of chimerism and relapse can be very short. Chimerism analysis provides information about the alloreactivity and/or tolerance induction of the graft and thus serves as more of a prognostic factor than an indirect marker for MRD. It is important to stress that because of its low sensitivity (about 1%), chimerism analysis is not a reliable means of detecting MRD. Consequently, basing the decision to initiate immunotherapy solely on the results of chimerism testing may result in starting immunotherapy too late. Studies performed by the German group retrospectively investigated the MRD load of patients who received DLI on the basis of increasing mixed chimerism. They found that patients with an MRD load of .10-3 did not benefit from the intervention, but patients with an MRD load \ 10-3 at the start of immunotherapy had a survival rate of just below 40% at 2 years (Figure 2). EFS 1,0 0,9 0,8 0,7 0,6 MRD 10-3; n=7; pEFS = 0.0%
0,2 0,1 0,0 0,0
1,0
2,0
3,0
4,0
Time [Years] Figure 2. The level of MRD at the time point of further immunotherapy determines the success rate for avoiding hematologic relapse in children with ALL after allogeneic stem cell transplantation. Retrospective assessment of quantitative characterization of MRD levels are shown in children with ALL who received preemptive DLI on the basis of increasing mixed chimerism.
66
M. A. Pulsipher et al.
Biol Blood Marrow Transplant 15:62-71, 2009
Minimal Residual Disease
MRD
Chimerism % Donor
A number of retrospective reports have shown that MRD before conditioning is the strongest predictor for relapse posttransplantation [10,11]. The Bristol group showed that patients entering the transplantation with a high MRD load of .10-3 did not survive their disease, whereas a portion of patients with lowlevel disease (\10-3) survived, and MRD-negative patients had the best chance of survival [17]. Using the same semiquantitative technique, a retrospective analysis of German data largely confirmed these results in a series of 45 children. Patients with high-level MRD at the time of transplantation (.10-3) were cured only rarely; however, even in these high-risk patients, additional immunotherapy posttransplantation can eradicate residual disease. As shown in Figure 3, a 15-year-old boy entered transplantation with an MRD load of 1 10-3 before transplantation. After engraftment, he had mixed chimerism, although MRD was undetectable at day 130. Posttransplantation immunosuppression was withdrawn. Because chimerism could not be converted to complete donor status, additional DLI was given. Despite the DLI, MRD began to increase; in response, a second DLI was given 50 days later. As a consequence of these 2 DLI treatments, the patient developed grade I GVHD, followed by a decrease in MRD, and eventually became MRD-negative 3 months after the second DLI (Figure 3). Methods for MRD monitoring in ALL include disease-specific PCR techniques such as T cell receptor (TCR) repertoire or immune globulin gene rearrangements [35,36]. When a disease-specific marker is not available, chimerism analysis in cell subpopulations can be used as a surrogate marker for MRD. Thiede et al. [37] showed that mixed chimerism in CD341 cells is predictive of relapse in patients with AML and ALL in peripheral blood. They noted that increasing autolo-
IMMUNOTHERAPY FOR PEDIATRIC B CELL ACUTE LYMOPHOBLASTIC LEUKEMIA
CSA WD 100 80 60 40 20
DLI
0,1
GVHDI
1E-3 Quantification limit
1E-5
Detection limit -50
0
gous cells within this subset precedes relapse with a median interval of 52 days (range, 12 to 97 days). To enrich this rare subpopulation, however, 50 mL of blood was needed, which limits the applicability of this procedure in pediatric patients. Mattsson et al. [38] performed a prospective analysis in 30 patients with AML and MDS. They evaluated chimerism in CD331, CD71, and CD451 cells and found significantly more relapses in patients whose subpopulations had mixed chimerism compared with those who had complete donor chimerism [38]. In ALL patients, several studies have investigated the impact of mixed chimerism after enrichment of the cell population carrying the leukemic phenotype and found a remarkable correlation between MRD and mixed chimerism in the respective subset [39]. Large studies in ALL patients assessing the predictive value of mixed chimerism in enriched cell populations have not yet been published, however. Serial quantitative analysis of chimerism in whole blood by STR-PCR allows the identification of those patients at greatest risk for relapse. Unfortunately, however, only a percentage of patients who relapse can be detected, because of the often very short time interval between the onset of mixed chimerism and relapse. Therefore, it is essential to that these analyses be performed frequently during the first 100 to 200 days after transplantation, when most relapses occur. Performing chimerism analysis in cell subpopulations can significantly increase the sensitivity of this approach. In this setting, chimerism analysis can be considered a surrogate marker for MRD. Combining chimerism and MRD analysis allows for documentation of engraftment and surveillance of posttransplantation remission status, thus providing a rational basis for individual preemptive immunotherapy strategies to prevent recurrence of the underlying disease.
50
100 150 200 250 300
Time [Days] Figure 3. The course of a 15-year-old boy with ALL who underwent transplantation in CR2 from a HLA-identical unrelated donor. Cyclosporin was stopped when increasing mixed chimerism developed. Although autologous chimerism decreased, MRD became positive. This led to a DLI of 1 105/kg recipient weight, followed by a second infusion of 1 106/kg after MRD did not disappear. Finally, the patient developed grade I GVHD and become MRD-negative. The patient remains in remission.
Various immune-based therapeutic approaches currently under development may decrease relapse in ALL, especially B-lineage ALL. Over the next decade, the use of these therapies before (to deepen remission) or after (to maintain remission) allogeneic transplantation procedures may produce a cure in patients resistant to cytotoxic chemotherapy without the morbidity associated with GVHD. Antibody-Based Therapies Therapeutic monoclonal antibodies (mAbs) have been developed that target B-lineage cell surface antigens. The COG recently reported that epratuzumab, a humanized mAb targeting CD22 [40], administered in combination with reinduction chemotherapy, resulted in some early responses in children with
Biol Blood Marrow Transplant 15:62-71, 2009
relapsed B-ALL [14]. Anti-CD19 mAb also has shown promise in mice with B-ALL xenografts [41], and early clinical trials using CD19-specific mAb are underway for B-lineage lymphoma. Although targeting CD20 (with, eg, rituximab) typically is not considered for treatment of B-ALL, CD20 is expressed in a subgroup of de novo precursor B-ALL associated with an inferior outcome compared with CD20neg B-ALL [42]. Other mAbs with potential therapeutic efficacy are becoming available for B-ALL, such as targeting HLA DR and BR3, which blocks B cell-activating factor, leading to loss of B cells [43-45]. Combinations of mAbs (eg, anti-CD20 and anti-CD22) or mAbs with chemotherapy may be used to improve therapeutic potential for B-lineage malignancies [41,46,47]. The therapeutic benefit of mAbs for B-ALL may be further improved when they are used for targeted delivery of radioimmunotherapy [45], conjugated to toxins (eg, recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin) [48-50] or chemotherapy [51,52], or fused to cytokines (immunocytokine) [53]. Instead of conjugating mAbs to toxins, investigators have ‘‘coupled’’ mAbs to T cells. Recently, low doses of a bispecific (BiTE) mAb (blinatumomab, MT103/MEDI-538) with a dual specificity for CD19 on tumor cells and CD3 on unstimulated T cells were found to induce an antitumor response in patients with B-lineage non-Hodgkin lymphoma [54]. This promising therapy also might be applicable to the treatment of pediatric B-ALL [55]. Natural Killer Cells Human NK cells are a subset of CD561 and/or CD161 peripheral blood lymphocytes that lack the TCR (ie, CD3). As part of the innate immune response, NK cells kill tumor cells independent of recognition of the major histocompatibility complex (MHC). The lack of NK cell inhibitory receptor mismatching (eg, killer cell immunoglobulin-like receptors [KIRs] recognizing self-antigens at HLA-A, -B, or -C loci) leads to inefficient killing of autologous tumor cells, which may be overcome by engraftment of allogeneic NK cells that sense missing expression of donor KIR ligand(s) in the recipient and mediate alloreactions [56]. But for adult patients with B-ALL, relapse-free survival after T cell–depleted HLA-mismatched (HLA-haploidentical) hematopoietic stem cell transplantation (HSCT) typically has not been improved by KIR-ligand mismatches between donor and recipient [57]. This may reflect the presence of inhibitory MHC molecules on B-ALL blasts and/or inherent deficient NK cell activation [58,59]. Recent data suggest that pediatric patients with B-ALL treated with high proportions of alloreactive NK cells may be sensitive to NK cell alloreactivity [60]. To harness potential donor-versus-recipient NK cell alloreacitiv-
Allogeneic Transplantation for Pediatric ALL
67
ity, new investigational treatments (at, eg, M.D. Anderson Cancer Center) are combining haplotypemismatched NK cells and epratuzumab after lymphodepleting chemotherapy given to achieve homeostatic expansion and prevention of immune-mediated rejection of infused allogeneic NK cells. T Cells Approaches to children with high-risk B-ALL undergoing allogeneic HSCT [61], including umbilical cord blood transplantation (UCBT) [62], use immunogenetics to shape the GVL effect mediated by T cells against B-ALL [56,63,64]. For example, HLA matching and mismatching can be used to reduce GVHD, and may improve the GVL effect after UCBT [65]. In addition, genotyping of unrelated hematopoietic stem cell donors outside the MHC loci (eg, absence in the recipient of single-nucleotide polymorphisms of the nucleotide-binding oligomerization domain 2/caspase recruitment domain 15 gene) can positively affect immune function, leading to improved prognoses for patients with acute leukemias, especially ALL [66]. Other donor–recipient factors besides immunogenetics can influence the GVL effect. A recent retrospective analysis provided preliminary evidence that persistent microchimerism of maternal cells in individuals leads to improved relapse-free survival (due to decreased GVHD) when the mother is preferentially used as the haploidentical hematopoietic stem cell donor. This is especially true for malignancies that are not susceptible to NK cell alloreactivity. The beneficial effect of donor sex in haplotype-mismatched parent-to-child HSCT is added to, and as pronounced as, the survival advantage associated with haploidentical HSCT from NK cell alloreactive donors for NK-sensitive diseases (eg, AML, pediatric ALL) [1]. The benefit of a T cell response against B-ALL also is seen in data demonstrating rapid lymphocyte recovery after chemotherapy or HSCT [67,68]. DLIs, which are readily available, contain T cells with a polyclonal TCR repertoire and haves been given to recipients with relapsed B-ALL [69,70], but DLI toxicities of acute or chronic GVHD or marrow aplasia often outweigh the antitumor effect. However, combining DLI with small molecules (eg, imatinib or nilotinib) after lymphodepleting chemotherapy [71,72], intrabone injections [73], graded doses of lymphocytes, DLI from granulocyte colony-stimulating factor–mobilized donors with immunosuppression [74,75], or depleting T cell subsets [76] may be justified in clinical trials, because curative options are rarely available for B-ALL that relapses early (eg, less than 6 months) after allogeneic HSCT [77-81]. To improve the therapeutic index of DLI, investigators from around the world have transduced T cells to express thymidine kinase (TK) derived from herpes simplex virus [82,83]. In the event of toxicity, conditional
68
M. A. Pulsipher et al.
Biol Blood Marrow Transplant 15:62-71, 2009
Immunotherapies for B-ALL Antibody Unconjugated Conjugated Bi-specific
Lymphocyte Allogenic T cells recognizing tumor by endogenous αβ TCR T cells recognizing tumor by introduced CAR Haploindetical NK cells
Vaccine Dendritic cell Autologous tumor rendered immunogenic
Figure 4. Immunotherapeutic Approaches Currently Being Investigated for ALL
ablation of the TK1 T cells can be achieved using ganciclovir. To improve specificity, allogeneic CD81 and CD41 T cells that recognize tumor-associated antigens (TAAs) in context of MHC through endogenous ab TCR have been selectively propagated to target B-lineage antigens, such as intracellular HB-1 [84]. Others have enriched T cells reactive to minor histocompatibility antigens that are present on recipient blasts, but not normal donor hematopoietic cells [85-88]. Immune tolerance typically precludes the ability of autologous T cells to recognize TAAs in the context of MHC in B-ALL. In addition, antigen-specific T cells may not be able lyse B-ALL blasts. Consequently, many investigators have redirected T cell specificity through the genetic introduction of chimeric antigen receptors (CARs) that recognize CD19 expressed on B-ALL, including cancer stem cells [89] and normal B cells [90-92]. Phase I trials are now reporting on the safety and feasibility of this gene therapy approach, and clinical trials of nextgeneration CARs and gene-transfer approaches for BALL are being planned [93]. Vaccines MHC class I and II molecules on allogeneic B-ALL blasts can directly present TAAs to donor-derived CD81 and CD41 T cells, respectively. For example, the leukemia-associated Wilms’ tumor antigen (WT1) is immunogenic, raising the possibility that WT1 vaccines can be used to augment immunity [94,95]. In addition, fusion genes, such as BCR-ABL in P1 B-ALL, may serve as a neoantigen that can be targeted by tumor-specific T cells [96]. B-ALL blasts generally lack costimulatory molecules, such as CD80/CD86, to complete a fully competent T cell activation signal. To augment the immune response, investigators have explored active immunization for B-ALL using autologous dendritic cells pulsed with peptides from TAAs derived from B-ALL [97,98]. Alternatively, autologous tumor cells themselves, possibly infused with accessory
cells such as skin fibroblasts, can be genetically modified to enforce expression of costimulatory molecules, such as CD40 ligand (and interleukin-2), to serve as a source of antigen-presenting cells [99,100]. FUTURE OF IMMUNOTHERAPY FOR PEDIATRIC ALL Despite the irony that a dysregulated immune response to infection early in life may lead to childhood B-ALL [101], pediatric oncologists now have many opportunities to manipulate the immune system (Figure 4) to achieve a lasting anti-B-ALL effect. Immunotherapy may be more effective during a MRD state after bone marrow transplantation, and allogeneic transplantation offers an opportunity to target specific minor histocompatibility antigens or to use KIR antigen mismatching to direct immune reactions to cancer cells. To move immune-based treatments into widespread practice, cooperative groups and biopharmaceutical companies need to emphasize the systematic testing of promising immunotherapies in children with high-risk or relapsed B-ALL, and pediatric oncology fellowships need to incorporate a thorough understanding of the immune system into their training programs. This approach will help build a future in which immunotherapies can be designed rationally and combinations of therapies can be delivered to improve overall survival and decrease the cost of survivorship of pediatric B-ALL. CONCLUSION As chemotherapy for ALL in children improves, the patients with ALL who benefit from transplantation will have a disease that is largely resistant to cytotoxic approaches. Minimizing the disease burden, administering optimal regimens, closely following patients with MRD techniques, and treating when necessary with targeted and immune-based approaches may
Biol Blood Marrow Transplant 15:62-71, 2009
decrease relapse and improve survival. As these approaches improve, children unable to obtain remission who currently benefit little from transplantation approaches also may experience improved survival. ACKNOWLEDGMENTS Financial disclosure: Dr Bader’s studies of MRD/ chimerism have been supported by the Wilhelm Sander Stiftung, Mu¨nchen, Germany and the Deutsche Krebshilfe, Bonn, Germany.
REFERENCES 1. Gaynon PS, Trigg ME, Heerema NA, et al. Children’s Cancer Group trials in childhood acute lymphoblastic leukemia, 19831995. Leukemia. 2000;14:2223-2233. 2. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998;339:605-615. 3. Schrappe M, Reiter A, Zimmermann M, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM Study Group from 1981 to 1995. Leukemia. 2000;14:2205-2222. 4. 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 children: an evidence-based review. Biol Blood Marrow Transplant. 2005;11:823-861. 5. Eapen M, Raetz E, Zhang MJ, et al. Outcomes after HLAmatched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood. 2006;107:4961-4967. 6. Woolfrey AE, Anasetti C, Storer B, et al. Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood. 2002; 99:2002-2008. 7. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood. 2008;111: 5477-5485. 8. Raetz EA, Borowitz MJ, Devidas M, et al. Reinduction platform for children with first marrow relapse in acute lymphoblastic lymphoma. J Clin Oncol. 2008;26:3971-3978. 9. Flohr T, Schrauder A, Cazzaniga G, et al. Minimal residual disease–directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOPBFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008;22:771-782. 10. Bader P, Hancock J, Kreyenberg H, et al. Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL. Leukemia. 2002;16:1668-1672. 11. Knechtli CJ, Goulden NJ, Hancock JP, et al. Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia. Br J Haematol. 1998;102:860-871. 12. Hilden JM, Dinndorf PA, Meerbaum SO, et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group. Blood. 2006;108:441-451. 13. Eapen M, Rubinstein P, Zhang MJ, et al. Comparable long-term survival after unrelated and HLA-matched sibling donor hematopoietic stem cell transplantations for acute leukemia in children younger than 18 months. J Clin Oncol. 2006;24:145-151.
Allogeneic Transplantation for Pediatric ALL
69
14. Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Group Pilot Study. J Clin Oncol. 2008;26:3756-3762. 15. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006;24:1917-1923. 16. 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;12:438-453. 17. Sanders JE, Im HJ, Hoffmeister PA, et al. Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia. Blood. 2005;105:3749-3756. 18. 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;109:2791-2793. 19. Brown VI, Fang J, Alcorn K, et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7–mediated signaling. Proc Natl Acad Sci U S A. 2003;100:15113-15118. 20. Kolb HJ, Mittermuller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76:2462-2465. 21. Collins RH Jr., Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15: 433-444. 22. Bader P, Holle W, Klingebiel T, et al. Mixed hematopoietic chimerism after allogeneic bone marrow transplantation: the impact of quantitative PCR analysis for prediction of relapse and graft rejection in children. Bone Marrow Transplant. 1997; 19:697-702. 23. Bader P, Niethammer D, Willasch A, et al. How and when should we monitor chimerism after allogeneic stem cell transplantation? Bone Marrow Transplant. 2005;35:107-119. 24. Chung NG, Buxhofer-Ausch V, Radich JP. The detection and significance of minimal residual disease in acute and chronic leukemia. Tissue Antigens. 2006;68:371-385. 25. Szczepanski T, Orfao A, van der Velden VH, et al. Minimal residual disease in leukaemia patients. Lancet Oncol. 2001;2: 409-417. 26. Roux E, Abdi K, Speiser D, et al. Characterization of mixed chimerism in patients with chronic myeloid leukemia transplanted with T-cell–depleted bone marrow: involvement of different hematologic lineages before and after relapse. Blood. 1993;81:243-248. 27. Roux E, Helg C, Chapius B, et al. Mixed chimerism after bone marrow transplantation and the risk of relapse. Blood. 1994;84: 4385-4386. 28. Fernandez-Aviles F, Urbano-Ispizua A, Aymerich M, et al. Serial quantification of lymphoid and myeloid mixed chimerism using multiplex PCR amplification of short tandem repeat-markers predicts graft rejection and relapse, respectively, after allogeneic transplantation of CD341 selected cells from peripheral blood. Leukemia. 2003;17:613-620. 29. Formankova R, Sedlacek P, Krskova L, et al. Chimerismdirected adoptive immunotherapy in prevention and treatment of post-transplant relapse of leukemia in childhood. Haematologica. 2003;88:117-118. 30. Gorczynska E, Turkiewicz D, Toporski J, et al. Prompt initiation of immunotherapy in children with an increasing number of autologous cells after allogeneic HCT can induce complete donor-type chimerism: a report of 14 children. Bone Marrow Transplant. 2004;33:211-217. 31. Ramirez M, Diaz MA, Garcia-Sanchez F, et al. Chimerism after allogeneic hematopoietic cell transplantation in childhood acute lymphoblastic leukemia. Bone Marrow Transplant. 1996; 18:1161-1165.
70
M. A. Pulsipher et al.
32. Guimond M, Busque L, Baron C, et al. Relapse after bone marrow transplantation: evidence for distinct immunological mechanisms between adult and paediatric populations. Br J Haematol. 2000;109:130-137. 33. Barrios M, Jimenez-Velasco A, Roman-Gomez J, et al. Chimerism status is a useful predictor of relapse after allogeneic stem cell transplantation for acute leukemia. Haematologica. 2003;88: 801-810. 34. Bader P, Kreyenberg H, Hoelle W, et al. Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem cell transplantation: possible role for preemptive immunotherapy? J Clin Oncol. 2004;22:1696-1705. 35. Gabert J, Beillard E, van der Velden VH, et al. Standardization and quality control studies of ‘‘real-time’’ quantitative reversetranscriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia: a Europe Against Cancer program. Leukemia. 2003;17:2318-2357. 36. van der Velden VH, Hochhaus A, Cazzaniga G, et al. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia. 2003;17:1013-1034. 37. Thiede C, Lutterbeck K, Oelschlagel U, et al. Detection of relapse by sequential monitoring of chimerism in circulating CD341 cells. Ann Hematol. 2002;81(Suppl 2):S27-S28. 38. Mattsson J, Uzunel M, Tammik L, et al. Leukemia lineagespecific chimerism analysis is a sensitive predictor of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome after allogeneic stem cell transplantation. Leukemia. 2001;15:1976-1985. 39. Winiarski J, Mattsson J, Gustafsson A, et al. Engraftment and chimerism, particularly of T- and B-cells, in children undergoing allogeneic bone marrow transplantation. Pediatr Transplant. 1998;2:150-156. 40. Dijoseph JF, Dougher MM, Armellino DC, et al. Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. Leukemia. 2007;21:2240-2245. 41. Stanciu-Herrera C, Morgan C, Herrera L. Anti-CD19 and anti-CD22 monoclonal antibodies increase the effectiveness of chemotherapy in pre-B acute lymphoblastic leukemia cell lines. Leuk Res. 2008;32:625-632. 42. Thomas DA, O’Brien S, Jorgensen JL, et al. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood. 2008. Aug 14. [Epub ahead of print]. 43. Gudowius S, Recker K, Laws HJ, et al. Identification of candidate target antigens for antibody-based immunotherapy in childhood B-cell precursor ALL. Klin Padiatr. 2006;218: 327-333. 44. Lin WY, Gong Q, Seshasayee D, et al. Anti-BR3 antibodies: a new class of B-cell immunotherapy combining cellular depletion and survival blockade. Blood. 2007;110:3959-3967. 45. Pagel JM, Pantelias A, Hedin N, et al. Evaluation of CD20, CD22, and HLA-DR targeting for radioimmunotherapy of B-cell lymphomas. Cancer Res. 2007;67:5921-5928. 46. Leonard JP, Coleman M, Ketas J, et al. Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin’s lymphoma. J Clin Oncol. 2005; 23:5044-5051. 47. Qu Z, Goldenberg DM, Cardillo TM, et al. Bispecific antiCD20/22 antibodies inhibit B-cell lymphoma proliferation by a unique mechanism of action. Blood. 2008;111:2211-2219. 48. Kreitman RJ, Pastan I. Immunotoxins in the treatment of hematologic malignancies. Curr Drug Targets. 2006;7: 1301-1311. 49. Messmann RA, Vitetta ES, Headlee D, et al. A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(1), CD22(1) B cell lymphoma. Clin Cancer Res. 2000;6:1302-1313.
Biol Blood Marrow Transplant 15:62-71, 2009
50. Schwemmlein M, Stieglmaier J, Kellner C, et al. A CD19specific single-chain immunotoxin mediates potent apoptosis of B-lineage leukemic cells. Leukemia. 2007;21:1405-1412. 51. Cheng WW, Allen TM. Targeted delivery of anti-CD19 liposomal doxorubicin in B-cell lymphoma: a comparison of whole monoclonal antibody, Fab´ fragments and single- chain Fv. J Control Release. 2008;126:50-58. 52. Sapra P, Moase EH, Ma J, et al. Improved therapeutic responses in a xenograft model of human B lymphoma (Namalwa) for liposomal vincristine versus liposomal doxorubicin targeted via anti-CD19 IgG2a or Fab´ fragments. Clin Cancer Res. 2004;10:1100-1111. 53. Singh H, Serrano LM, Pfeiffer T, et al. Combining adoptive cellular and immunocytokine therapies to improve treatment of B-lineage malignancy. Cancer Res. 2007;67:2872-2880. 54. Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell–engaging antibody. Science. 2008;321:974-977. 55. Manzke O, Berthold F, Huebel K, et al. CD3xCD19 bispecific antibodies and CD28 bivalent antibodies enhance T-cell reactivity against autologous leukemic cells in pediatric B-ALL bone marrow. Int J Cancer. 1999;80:715-722. 56. Velardi A. Role of KIRs and KIR ligands in hematopoietic transplantation. Curr Opin Immunol. 2008;20:581-587. 57. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-2100. 58. Pfeiffer M, Schumm M, Feuchtinger T, et al. Intensity of HLA class I expression and KIR-mismatch determine NK-cell mediated lysis of leukaemic blasts from children with acute lymphatic leukaemia. Br J Haematol. 2007;138:97-100. 59. Romanski A, Bug G, Becker S, et al. Mechanisms of resistance to natural killer cell–mediated cytotoxicity in acute lymphoblastic leukemia. Exp Hematol. 2005;33:344-352. 60. Moretta A, Locatelli F, Moretta L. Human NK cells: from HLA class I–specific killer Ig-like receptors to the therapy of acute leukemias. Immunol Rev. 2008;224:58-69. 61. Schrauder A, von Stackelberg A, Schrappe M, et al. Allogeneic hematopoietic SCT in children with ALL: current concepts of ongoing prospective SCT trials. Bone Marrow Transplant. 2008; 41(Suppl 2):S71-S74. 62. Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369:1947-1954. 63. Lanino E, Sacchi N, Peters C, et al. Strategies of the donor search for children with second CR ALL lacking a matched sibling donor. Bone Marrow Transplant. 2008;41(Suppl 2):S75-S79. 64. Rutten CE, van Luxemburg-Heijs SA, Griffioen M, et al. HLA-DP as specific target for cellular immunotherapy in HLA class II–expressing B-cell leukemia. Leukemia. 2008;22: 1387-1394. 65. Barker JN. Umbilical cord blood (UCB) transplantation: an alternative to the use of unrelated volunteer donors? Hematol Am Soc Hematol Educ Program. 2007;2007:55-61. 66. Mayor NP, Shaw BE, Hughes DA, et al. Single nucleotide polymorphisms in the NOD2/CARD15 gene are associated with an increased risk of relapse and death for patients with acute leukemia after hematopoietic stem cell transplantation with unrelated donors. J Clin Oncol. 2007;25:4262-4269. 67. De Angulo G, Yuen C, Palla SL, et al. Absolute lymphocyte count is a novel prognostic indicator in ALL and AML: implications for risk stratification and future studies. Cancer. 2008; 112:407-415. 68. Gassas A, Ishaqi MK, Afzal S, et al. Outcome of haematopoietic stem cell transplantation for paediatric acute lymphoblastic leukaemia in third complete remission: a vital role for graft-versus-host-disease/graft-versus-leukaemia effect in survival. Br J Haematol. 2008;140:86-89. 69. Levine JE, Barrett AJ, Zhang MJ, et al. Donor leukocyte infusions to treat hematologic malignancy relapse following allo-
Biol Blood Marrow Transplant 15:62-71, 2009
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82. 83.
84.
SCT in a pediatric population. Bone Marrow Transplant. 2008; 42:201-205. Loren AW, Porter DL. Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation. Bone Marrow Transplant. 2008;41:483-493. Miller JS, Weisdorf DJ, Burns LJ, et al. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood. 2007;110:2761-2763. Symons HJ, Levy MY, Wang J, et al. The allogeneic effect revisited: exogenous help for endogenous, tumor-specific T cells. Biol Blood Marrow Transplant. 2008;14:499-509. Miyake T, Inaba M, Fukui J, et al. Prevention of graft-versushost disease by intrabone marrow injection of donor T cells: involvement of bone marrow stromal cells. Clin Exp Immunol. 2008;152:153-162. Huang XJ, Liu DH, Liu KY, et al. Modified donor lymphocyte infusion after HLA-mismatched/haploidentical T cell–replete hematopoietic stem cell transplantation for prophylaxis of relapse of leukemia in patients with advanced leukemia. J Clin Immunol. 2008;28:276-283. Huang XJ, Wang Y, Liu DH, et al. Modified donor lymphocyte infusion (DLI) for the prophylaxis of leukemia relapse after hematopoietic stem cell transplantation in patients with advanced leukemia: feasibility and safety study. J Clin Immunol. 2008;28:390-397. Smetak M, Kimmel B, Birkmann J, et al. Clinical-scale singlestep CD4(1) and CD8(1) cell depletion for donor innate lymphocyte infusion (DILI). Bone Marrow Transplant. 2008;41: 643-650. Alyea EP, Soiffer RJ, Canning C, et al. Toxicity and efficacy of defined doses of CD4(1) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood. 1998; 91:3671-3680. Klingebiel T, Bader P. Delayed lymphocyte infusion in children given SCT. Bone Marrow Transplant. 2008;41(Suppl 2): S23-S26. Shimoni A, Kroger N, Zander AR, et al. Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias. Leukemia. 2003;17: 290-297. Tiribelli M, Sperotto A, Candoni A, et al. Nilotinib and donor lymphocyte infusion in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph1 ALL) relapsing after allogeneic stem cell transplantation and resistant to imatinib. Leuk Res. 2008. Leuk Res. 2008 May 7. [Epub ahead of print]. Yoshimitsu M, Fujiwara H, Ozaki A, et al. Case of a patient with Philadelphia-chromosome-positive acute lymphoblastic leukemia relapsed after myeloablative allogeneic hematopoietic stem cell transplantation treated successfully with imatinib and sequential donor lymphocyte infusions. Int J Hematol. 2008. Oct;88(3):331-5. Epub 2008 Aug 12. Onodera M. Gene and cell therapy for relapsed leukemia after allo-stem cell transplantation. Front Biosci. 2008;13:3408-3414. Traversari C, Marktel S, Magnani Z, et al. The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies. Blood. 2007;109:4708-4715. de Rijke B, Fredrix H, Zoetbrood A, et al. Generation of autologous cytotoxic and helper T-cell responses against the B-cell leukemia–associated antigen HB-1: relevance for precursor B-ALL–specific immunotherapy. Blood. 2003;102: 2885-2891.
Allogeneic Transplantation for Pediatric ALL
71
85. Akatsuka Y, Kondo E, Taji H, et al. Targeted cloning of cytotoxic T cells specific for minor histocompatibility antigens restricted by HLA class I molecules of interest. Transplantation. 2002;74:1773-1780. 86. Griffioen M, van der Meijden ED, Slager EH, et al. Identification of phosphatidylinositol 4-kinase type II beta as HLA class II–restricted target in graft-versus-leukemia reactivity. Proc Natl Acad Sci U S A. 2008;105:3837-3842. 87. Rosinski KV, Fujii N, Mito JK, et al. DDX3Y encodes a class I MHC–restricted H-Y antigen that is expressed in leukemic stem cells. Blood. 2008;111:4817-4826. 88. Warren EH, Vigneron NJ, Gavin MA, et al. An antigen produced by splicing of noncontiguous peptides in the reverse order. Science. 2006;313:1444-1447. 89. le Viseur C, Hotfilder M, Bomken S, et al. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell. 2008;14:47-58. 90. Brentjens RJ, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res. 2007;13:5426-5435. 91. Marin V, Dander E, Biagi E, et al. Characterization of in vitro migratory properties of anti-CD19 chimeric receptor-redirected CIK cells for their potential use in B-ALL immunotherapy. Exp Hematol. 2006;34:1219-1229. 92. Serrano LM, Pfeiffer T, Olivares S, et al. Differentiation of naive cord blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy. Blood. 2006;107: 2643-2652. 93. Singh H, Manuri PR, Olivares S, et al. Redirecting specificity of T-cell populations for CD19 using the Sleeping Beauty system. Cancer Res. 2008;68:2961-2971. 94. Rezvani K, Brenchley JM, Price DA, et al. T-cell responses directed against multiple HLA-A*0201–restricted epitopes derived from Wilms’ tumor 1 protein in patients with leukemia and healthy donors: identification, quantification, and characterization. Clin Cancer Res. 2005;11: 8799-8807. 95. Rezvani K, Yong AS, Savani BN, et al. Graft-versus-leukemia effects associated with detectable Wilms’ tumor 1–specific T lymphocytes after allogeneic stem cell transplantation for acute lymphoblastic leukemia. Blood. 2007;110:1924-1932. 96. Kessler JH, Bres-Vloemans SA, van Veelen PA, et al. BCRABL fusion regions as a source of multiple leukemia-specific CD81 T-cell epitopes. Leukemia. 2006;20:1738-1750. 97. Mami NB, Mohty M, Chambost H, et al. Blood dendritic cells in patients with acute lymphoblastic leukaemia. Br J Haematol. 2004;126:77-80. 98. Pospisilova D, Borovickova J, Polouckova A, et al. Generation of functional dendritic cells for potential use in the treatment of acute lymphoblastic leukemia. Cancer Immunol Immunother. 2002;51:72-78. 99. Biagi E, Dotti G, Yvon E, et al. Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor-reactive cytotoxic T lymphocytes. Blood. 2005;105:2436-2442. 100. Rousseau RF, Biagi E, Dutour A, et al. Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood. 2006; 107:1332-1341. 101. Roman E, Simpson J, Ansell P, et al. Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol. 2007;165:496-504.