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Purpose of Review Outcomes for older adults with acute lymphoblastic leukemia (ALL) remain poor, and allogeneic hemato- poietic stem cell transplant (HSCT) remains a potentially curative modality. However, benefits are offset by high rates of non- relapse mortality (NRM) in patients undergoing myeloablative conditioning (MAC) regimens. Reduced intensity conditioning (RIC) regimens can extend this therapy to adults who are unfit for MAC, although at the cost of higher relapse rates. In this review, we discuss evidence to support the usage of RIC regimens, controversies, and potential strategies to improve transplant outcomes going forward. Recent Findings Several novel therapies have recently been approved for the treatment of relapsed ALL and may play an important role in bridging adults with residual disease to RIC transplant. Assessing response to initial therapy via minimal residual disease (MRD) monitoring may determine which patients will derive the most benefit from allogeneic HSCT. Summary Reduced intensity allogeneic HSCT remains a potentially curative therapy that can be offered to older adults however challenges remain. Going forward, MRD testing and novel therapies may help better select which patients should proceed to transplant and assist in getting those patients to transplant with optimally controlled disease. . . Keywords Acute lymphoblastic leukemia (ALL) Allogeneic hematopoietic stem cell transplant (HSCT) Reduced intensity conditioning (RIC) Introduction myeloablative allogeneic HSCT was reported as ranging be- tween 33 and 58% , and is higher for adults with a poor Outcomes for older adults with acute lymphoblastic leukemia performance status . Reduced intensity conditioning (RIC) remain poor, with an estimated 5-year survival of approximately offers the chance to extend a potentially curative strategy and 35–45% . This is in part due to the inability of older adults to graft vs. leukemia effect to older patients without the associated tolerate the intensive therapies used to treat pediatric and young toxicities of a myeloablative regimen. In this article, we will first adult patients [2, 3]. Allogeneic hematopoietic stem cell trans- review the indication for allogeneic hematopoietic transplant in plantation (HSCT) has been shown to improve survival in adults adult ALL, compare outcomes of RIC to MAC conditioning, with ALL as compared to chemotherapy alone [4, 5]; however, review issues related to RIC, discuss unanswered questions and transplant-related mortality (TRM) increases with age. In a controversies in RIC, and discuss potential methods to improve study from the CIBMTR, 5-year TRM in adults undergoing outcomes with RIC. Finally, we will discuss how novel agents recently approved for the treatment of ALL and how they may be combined/sequenced with transplant. This article is part of the Topical Collection on Stem Cell Transplantation The Role of Transplant in Adult ALL * Jessica T. Leonard email@example.com The indications for allogeneic hematopoietic stem cell 1 transplant in CR1 are controversial, with recommendations Center for Hematologic Malignancies, Knight Cancer Institute, from major groups ranging from transplant for all adults Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Mail Code L586, Portland, OR 97239, USA with ALL to recommending this procedure to only those 330 Curr Hematol Malig Rep (2018) 13:329–340 Table 1 High Risk Features in Risk factor Value Acute Lymphoblastic Leukemia Age Age > 35* In general, higher risk with increasing age WBC count B-lineage: WBC > 30 k T-lineage: WBC > 100 k Cytogenetics High risk: t(9;22)** (4;11) t(v; 11q23) any MLL rearrangement t(8;14) t(17;19) Monosomy 7 Low hypodiploidy or near tetraploidy Complex cytogenetics (> 5 chromosomal abnormalities) Intermediate risk: t(1;19) Trisomy 8 or trisomy 21 Deletion 6q Good risk: Hyperdiploidy (51–65 chromosomes) t(12;21)—ETV6-RUNX1 Immunophenotype Poor prognostic markers: B-lineage: CD20 expression*** T-lineage: ETP-ALL Good prognostic marker: T-lineage: cortical phenotype (CD1a) Molecular markers B-lineage: Ph-like ALL (CRLF2, ABL, PDGFR) IKZF1 deletion TP53 mutation Response to Induction therapy Failure to achieve hematologic remission within 4 weeks of induction therapy Adapted from Hematopoietic Cell Transplants – Concepts, Controversies and Future Directions. Cambridge University Press May 2017 *Commonly used cut off however with pediatric inspired regimens being used to the age of 39, would consider increase in age to ≥ 40 **Since the development of the ABL specific kinase inhibitors, many report outcomes of Ph+ ALL as similar to those of patients with Ph− ALL ***The poor prognostic impact of CD20 expression may be overcome with addition of Rituximab to standard chemotherapy with a matched donor available [4, 8–11]. However, for 1 is generally recommended for all “adults” with high-risk those who suffer a relapse the long term overall survival disease. is < 24% [5, 12], stressing the need to identify those who will benefit from transplant early in the disease course. A Defining Adult—Where Do We Draw the Line—the common method is to stratify patients based on risk factors Role of Intensive Chemotherapy in ALL (Table 1), with transplant in CR1 offered to all patients with adverse characteristics. However, more recent evi- The classification for “high risk” includes age, which is cur- dence suggests that conventional high-risk factors may be rently defined as over 35 years. trumped by minimal residual disease (MRD) status (to be Several large retrospective studies have now demonstrated discussed later). Until prospective studies can that adolescent and young adults treated with a pediatric-based clearly define a subset of adults that achieve durable regimen have superior outcomes, upward of 60–70% without long-term remissions without transplant, transplant in CR consolidative allogeneic HSCT [3, 11, 13–15]. Despite the Curr Hematol Malig Rep (2018) 13:329–340 331 retrospective nature of these studies, the current culture has peripheral blood grafts in the RIC group) and more RIC being been to avoid transplant in this age group unless they relapse performed in the recent time period. The authors found that or are persistently MRD positive. A major question/ there was no significant difference between the two groups in controversy in this field is what the upper age limit for these terms of 3-year NRM (MAC 33%, RIC 32%, p = 0.92) and regimens should be, as this limit has ranged between 30 and although there was a trend toward higher risk of relapse in the 60 years in different studies. While one group did report that a RIC group, this was not statistically significant (26% MAC pediatric-based regimen was tolerated up to the age of 50 , vs. 35% RIC, p = 0.08). The age-adjusted overall survival was other groups have found higher rates of toxicity when these also not statistically different (43% MAC vs. 38% RIC, p = regimens are used in patients over the ages of 35–45 [2, 3]. 0.39), suggesting that RIC is a suitable alternative to MAC for Many contemporary prospective trials of pediatric-based reg- older adults. In a multivariate analysis, factors that negatively imens are limiting the upper age limit to < 40 years (CALGB impacted overall survival included Karnofsky performance 10403, Alliance AO41501), and the majority of data regarding status < 80, mismatched-unrelated donors, transplant in CR2 the use of pediatric regimens are in adults up to the age of 30– and age > 30 years. 39. To date, there are limited data to suggest that using “adult” Similar results were seen in a cooperative group study from regimens results in durable remission without the use of trans- the JSHCT . The impact of conditioning regimen on plant, with the possible exception of MRD-guided strategies adults > 45 years of age with both Ph+ and Ph− ALL were (see separate discussion below). For that reason, the current examined. Between the years of 2000–2009, 575 patients (369 NCCN recommendation is that outside of a clinical trial, all MAC, 206 RIC) were identified who met inclusion criteria. adults who are not treated with a pediatric-based regimen There was no statistically significant difference in the 3-year should be considered for allogeneic HSCT in CR1, with the rate of NRM (38% MAC vs. 36% RIC); however, there was a lower age limit being defined by currently available pediatric- higher risk of relapse in the RIC group which did not become inspired protocols. apparent until the third year after transplant (risk of relapse at 1 year 12% MAC vs. 14% RIC; risk of relapse at 3 years 15% MAC vs. RIC MAC vs. 26% RIC, p = 0.008). As above in a multivariate analysis, there was no significant effect of conditioning inten- As younger adults may be treated with chemotherapy alone, sity on 3-year overall survival (51% MAC vs. 53% RIC, p = the transplant-eligible population is thus older and more likely 0.701). Factors associated with a worse outcome in this group to suffer the side effects of myeloablative conditioning. For included HLA-mismatched donors and transplant in CR2. this reason, many groups are offering reduced intensity con- While both of these studies suggest that outcomes with RIC ditioning regimens to their adults who are eligible for trans- are similar to outcomes for MAC in adults, results should be interpreted with caution. The patient populations were hetero- plant. Unfortunately, to date, there have been no prospective studies comparing outcomes of patients with acute leukemias geneous in terms of donor source and GVHD regimens, and who undergo MAC vs. RIC conditioning regimens to deter- although criteria for the definition of RIC were applied, a wide mine whether outcomes are equivalent. However, there are variety of conditioning regimens were used. In addition, dif- several large retrospective cohort reports that have addressed ferences between the groups (older age and more comorbidi- this question [7, 16–18]. As these studies are the basis for ties in the RIC groups, more common use of PBSC source and which we justify reduced intensity conditioning, it is worth more recent transplant) make drawing conclusions difficult. reviewing them in detail. Two additional studies are worth discussion, as they used In a CIBMTR study, Marks et al.  examined the role of more uniform populations. Mohty et al.  on behalf of the the intensity of conditioning regimen on relapse rate, non- EBMT described the effect of conditioning regimen on out- relapse mortality (NRM), and overall survival (OS) in adults comes in adults > 45 years of age with both Ph+ as well as Ph− > 35 years of age with Philadelphia chromosome negative acute lymphoblastic leukemia. This study was limited to pa- ALL. For definitions of RIC, please see Table 2. The majority tients who underwent a matched sibling allogeneic stem cell of patients who underwent MAC received TBI, generally in transplant in a complete remission (CR1 or CR2). A total of combination with cyclophosphamide, and a smaller number 576 patients met the inclusion criteria between the years of had high-dose busulfan-based regimens. Between the years of 1997–2007, of these 449 underwent MAC and 127 underwent 1995–2006, a total of 1428 patients who underwent MAC and RIC. The median age of the RIC group was 56 (45–73) and 93 patients who underwent RIC were identified. As a group, that of the MAC group was 50 (45–68). Other significant patients who underwent RIC were older (45 vs. 28 years), with differences included age of donor (49 years in the MAC group 43% of this group being > 50 years of age. Those that were and 55 in the RIC group, p < 0.001), bone marrow source younger who underwent RIC had a KPS < 80, organ dysfunc- (34% of MAC patients vs. 9% of RIC patients), and female tion or a history of invasive fungal infection. Other differences donor into male recipient (22%of MAC vs. 31% RIC, p = between the two groups included source of graft (more 0.05). In contrast to the study by Marks et al., the authors 332 Curr Hematol Malig Rep (2018) 13:329–340 Table 2 Summary of cooperative studies comparing outcomes with reduced intensity conditioning as compared to myeloablative conditioning in adult ALL Study Years Definition reduced intensity Patient ages Number of Patient characteristics Donor source Outcomes conducted subjects Marks et al. 1995–2006 Busulphan 9 mg/kg or less; melphalan MAC: 28 MAC: Ph− B-ALL, T-ALL Matched sibling, 3-year CIBMTR 150 mg/kg or less; TBI < 500 cGy (16–62) 1428 CR1 or CR2 MUD, MMUD OS: MAC 43%, RIC 38% p =0.39 single dose or < 800 cGy RIC: 45 (17–66) RIC: 93 NRM: MAC 33%, RIC 32%, p =0.86 fractionated; Relapse: MAC 26%, RIC 25%, p = 0.08) fludarabine + low-dose TBI Tanaka et al. 2000–2009 Busulphan 9 mg/kg or less; melphalan MAC: 51 MAC: 369 B-ALL, both Ph+ and Matched sibling, z3-year JSHCT 140 mg/kg or less; fludarabine + (45–70) RIC: 206 Ph−,T-ALL MUD, MMUD OS: MAC 51%, RIC 53% p = 0.701 low-dose TBI RIC: 58 (45–70) CR1 or CR2 NRM: MAC 15%, RIC 26%, p = 0.008 Relapse: MAC 31%, RIC 47%, p < 0.001 MAC: 449 B-ALL, both Ph+ and All donors were 2-year Mohty et 1997–2007 Busulphan 8 mg/kg or less; melphalan MAC: 50 al.EBMT 150 mg/kg or less; fludarabine + (45–68) RIC: 127 Ph− fully matched OS: MAC 45%, RIC 48% p =0.56 low-dose TBI RIC: 56 (45–73) CR1 or CR2 siblings NRM: MAC 31%, RIC 21%, p =0.03 Relapse: MAC 31%, RIC 47%, p < 0.001 Bachanova et al. 2000–2009 Consistent with CIBMTR guidelines MAC: 50 MAC: 130 Ph+ ALL only, all Matched sibling, 3-year CIBMTR, Ph+ above (19–66) RIC: 67 patients MUD, MMUD OS: MAC 35%, RIC 39% p = 0.701 ALL only RIC: 54 (19–69) in CR1 NRM (1-year): MAC 36%, RIC 13%, p < 0.001 Relapse: MAC 28%, RIC 49%, p < 0.058 MAC myeloablative conditioning regimens, RIC reduced intensity conditioning regimens, ALL acute lymphoblastic leukemia Curr Hematol Malig Rep (2018) 13:329–340 333 found that 2-year transplant-related mortality was significant- underwent fludarabine/melphalan conditioning for high-risk ly reduced in the RIC group (29% MAC vs. 21% RIC, p = ALL defined as either over age 50, compromised organ func- 0.03); however, the risk of relapse was significantly higher tion, or prior HSCT. Forty-two percent of the patients were (31% MAC vs. 47% RIC, p < 0.001). However, this translated Philadelphia chromosome positive (Ph+) and three patients into no significant difference in overall survival between the had ALL that was secondary to a prior malignancy. They re- two groups, with the 2-year OS rate being 45% in the MAC ported an impressive 2-year OS of 61.5%, with a 2-year NRM group and 48% in the RIC group (p =0.56). of 21.5%, and a relapse incidence of 21.1% . In another One additional study focused on the effect of conditioning study, a Korean group reported the outcomes of 37 adults aged regimen on Ph+ patients alone. Bachanova et al. [17�� ]on 15–63 with high-risk ALL who underwent FluMel condition- behalf of the CIBMTR compared outcomes of 197 adults ages ing. Patients were defined as high riskiftheywere >50 yearsof > 18 who underwent MAC (130) vs. RIC (67) in first CR. In age, had compromised organ function, or active infection that their analysis, patients were matched for age, donor type, and would preclude them from undergoing myeloablative condi- HCT year. The majority of patients received pre-transplant tioning. Only patients in CR1 and CR2 were included in this TKI, which was similar between the groups. Similar to the study. This group reported similarly impressive outcomes, with study by Mohty, TRM was found to be significantly lower a 3-year OS rate of 64%, 3-year NRM of 17.7%, and 3-year in the RIC when compared to the MAC group (36% MAC relapse rate of 19.7% . These outcomes are significantly vs. 13% RIC, p = 0.001). Additionally, rates of aGVHD were better than those reported by the large cooperative group studies significantly lower in the RIC group (30 vs. 47%, p =0.014). above, and are likely due to the fact that these studies were However, the 3-year relapse rate was higher in the RIC group performed at single institutions, where there was more unifor- (49 vs. 28%, p = 0.058). Factors associated with a higher risk mity in terms of not only conditioning regimen, but also GVHD of relapse in the RIC group included MRD positivity as well prophylaxis and supportive care. This suggests that if condi- as no pre-HCT TKI. Consistent with all other studies, 3-year tions can be optimized and patients properly selected, outcomes overall survival was not significantly different between the for adults with RIC can approach those of the AYA population two groups (39% RIC vs. 35% MAC). treated with a pediatric regimen. Although all groups reported no significant difference in overall survival between myeloablative conditioning vs. re- Disease Status at Time of Transplant—Who may Not duced intensity conditioning, it is interesting to note that in Benefit From RIC Transplant? two of the studies, the differences between rates of TRM and relapse between the myeloablative and RIC groups was more A consistent finding across many of the studies reviewed is that apparent. The major difference in these studies is that some disease status at the time of RIC transplant significantly impacts variables were more uniform, with patients in the Mohty study transplant outcomes. The 3-year relapse rates for patients being limited to those who received sibling donors and patients transplanted in ≥ CR2 or with relapsed/refractory disease have in the Bachanova study being limited to those in CR1. In addi- been reported to be as high as 67%, and 3-year overall survival tion, in the Bachanova study, patients in the RIC vs. MAC is reported as being 20% or less. This still offers an improve- group were further matched in terms of donor source, age, ment in survival as compared to those who do not undergo and comorbidities. This highlights the challenges with allogeneic HSCT after relapse, where survival is < 10%. interpreting results from large retrospective cohorts, as the het- However, the benefit is modest and a thorough discussion of erogeneity of patient populations, donor source, and disease transplant associated morbidity should be had with patients status can confound any true differences between conditioning prior to deciding whether to proceed with transplant at later regimen intensity. Although a randomized trial comparing RIC disease states. One important factor impacting survival in re- to MAC is unlikely to occur, a large, well-designed prospective lapsed patients is the presence of active disease; for those who study of RIC allogeneic HSCT in older adults with ALL would proceed to transplant with disease present survival is < 10%, help delineate the risks and benefits of this transplant strategy. with some groups reporting no long-term survivors for patients who proceed to transplant with active disease [12, 21]. Single Institution Studies of RIC Although myeloablative regimens may offer a chance for sur- vival for these patients , reduced intensity transplant should A number of groups have published single institution studies not be recommended to patients with active disease. reporting their outcomes with reduced intensity conditioning [19–23] (Table 3). Many of these include adults with both Age vs. Performance Status, Which Should Limit Who AML and ALL with only a small number of ALL patients, or Is Eligible for Transplant? look at a variety of conditioning regimens, making results dif- ficult to interpret. However, two are worthy of discussion. In a Many of the cooperative group studies discussed above define study from the City of Hope, 24 patients aged 23–68 years adult as patients over age 18, but what about outcomes when 334 Curr Hematol Malig Rep (2018) 13:329–340 Table 3 Single Institution Studies of reduced intensity conditioning (RIC) regimens in adult ALL Study Regimen Years conducted Patient ages Number of subjects Disease status Donor source Outcomes Stein et al FluMel 2002–2007 23–68 24 Ph+/Ph− Sibling: 8 2year: CR1: 11 MUD: 8 OS 61.5% CR2: 4 MMUD: 6 NRM: 21.5% CR ≥ 3: 4 Relapse: 21.1% Relapsed: 4 Refractory: 1 Cho et al FluMel 2000–2007 15–63 37 Ph+/Ph−T-cell Sibling: 27 3-year: CR1: 30 MUD: 4 OS: 64.1% CR2: 7 MMUD: 6 NRM: 19.7% Relapse: 17.7% Ram et al Flu/TBI 2000–2009 8–69 51 Ph+/Ph− Sibling: 9 3-year: CR1: 25 MUD: 31 OS: 34% CR1, MRD+: 7 MMUD: 11` NRM: 28% CR ≥ 2: 18 Relapse: 40% Persistent disease: 1 Hamaki et al Flu/Bu 2000–2003 17–68 33 CR1: 13 Sibling: 20 3-year: Flu/Bu + ATG CR2: 6 MM sib: 5 progression: 50.9% Flu/Bu + TBI Relapsed: 9 Unrelated: 8 progression-free mortality: 30.4% Flu/Bu +ATG +TBI Refractory: 5 2-year: Flu/Mel OS: 29.7% Cladribine-based Other Massenkeil et al......... Flu/Bu + ATG 1998–2002 19–67 9 Unknown for ALL subset Unknown for ALL subset 3-year: OS: 44% Curr Hematol Malig Rep (2018) 13:329–340 335 we focus on older adults only? A retrospective CIBMTR melphalan, respectively (NRM 18 vs. 23 vs. 23%, p =NS study examined the outcomes of adults over 55 years of age and relapse 48 vs. 55 vs. 45%, p = NS). Absent from all group who underwent reduced intensity conditioning between the studies was reports of CNS/sanctuary site relapse vs. marrow years of 2001–2012 [25�� ]. Two hundred seventy-three pa- relapse, and there have been no prospective trials directly tients were identified, ranging in age between 55 and 72. comparing TBI-based to non-TBI-based RIC regimens. The majority of the patients were in CR1 (71%), with 17% Therefore, the role of TBI in the context of reduced intensity being in CR2 or beyond and 11% with primary induction regimens remains to be defined. failure vs. relapse. Donor source included unrelated donors Another unanswered question concerning reduced intensity (59%) vs. a matched sibling (32%). Fifty percent of patients regimens is how reduced can the intensity be? In a six- had Ph+ disease, and 56% had a KPS of > 90%. Conditioning institution study coordinated by Fred Hutchison cancer center, regimens varied but were consistent with the previously de- adults ages 8–69 years with high-risk ALL underwent condi- scribed CIBMTR definition of reduced intensity. For the tioning with a non-myeloablative regimen that included group as a whole, the 3-year OS was 38% with a 3-year fludarabine 90 mg/m and 2Gy TBI . Patients were defined NRM rate of 25%. Relapse was the leading cause of death as high risk if they were over the age of 50–55, had prior in the group, with 47% of all patients suffering from relapse. myeloablative allogeneic HSCT, or had other comorbidities that When stratified by age (55–60, 61–65 and 66+), those 66+ precluded the use of a myeloablative regimen. Both Ph+ as well had a higher rate of NRM (40 vs. 22–23% for the younger as Ph− patients were included, and disease status at the time of groups, p = 0.07), as well as increased mortality (RR 1.51, transplant ranged from CR1 to >CR3 and patients with 95% CI 1.0–2.29, p=0.05).However,those 66+alsotended relapsed/refractory disease. The 3-year OS in this group was to have a worse KPS (≤ 80) and more comorbidities, and reported as 34%, with a 3-year NRM of 28% and a 3-year KPS ≤ 80 independently was significantly associated with an relapse rate of 40%. However, when limited to patients increased 3-year NRM risk (34%, 95% CI 25–43%). This transplanted in CR1, the 3-year OS rate was 62%. NRM was makes it difficult to discern whether age or performance status not described for the group of patients who underwent trans- contributes more to poor outcomes. Other groups that includ- plant in CR1; however, the 3-year rate of relapse in this group ed younger adults have similarly noted that poor performance was between 15% (Ph−) and 32% (Ph+). Although compari- status is associated with higher NRM and decreased OS [6, 7], sons between studies is challenging given the differences in highlighting the fact that performance status in and of itself is patient populations, it is encouraging to see that outcomes from indeed a risk for poor outcomes. While there are certainly a non-myeloablative conditioning regimen were on par with older adults who proceed to RIC transplant with an excellent those from single-institution RIC studies for patients in CR1. performance status and tolerate the procedure quite well, age may still modify the impact of poor performance status, with Donor and Graft Source, Does it Matter? Enhancing older individuals with a poor KPS being less able to tolerate GVL transplant than younger patients with a poor KPS. Therefore, transplant, even reduced intensity, should be undertaken with Given the higher reliance on the graft vs. leukemia (GVL) effect caution in older patients with concurrent comorbidities and in patients undergoing reduced intensity conditioning prior to poor performance status. allogeneic HSCT, the source of the graft has the potential to significantly impact the risk of disease relapse. Early transplant Questions to Address Going Forward—What Is studies suggested that the best donor source for patients with the Optimal Conditioning Regimen? ALL was a matched sibling, and many trials that stratified to transplant vs. no transplant based on donor availability only One criticism of reduced intensity conditioning is that many considered matched siblings. However, with improvements in regimens do not include TBI, which is thought to reduce the supportive care and higher level HLA matching, outcomes for risk of CNS and sanctuary site relapse . In the CIBMTR adults with ALL who undergo an 8/8 matched unrelated donor review comparing MAC to RIC, the addition of TBI did sig- transplant are equivalent to that of patients who undergo a nificantly lower the risk of relapse; however, this included matched sibling transplant [27–30]. Rates of both acute as well both patients undergoing MAC and RIC, in which the major- as chronic GVHD were higher in the MUD group; however, ity of patients that had received TBI were MAC recipients relapse rates were significantly lower, presumably due to a . In addition, the Fred Hutchison group that reported out- more potent graft vs. leukemia effect. It is possible that in the comes of adults treated with Flu/TBI reported that no patients reduced intensity setting where more of the therapeutic effect is suffered from isolated CNS relapse . When confined to based on graft vs. leukemia, an unrelated donor may provide an just RIC regimens, the EBMT group reported no differences advantage over a matched related donor. Similar findings were in NRM or rate of relapse when comparing low-dose TBI- seen in a single institution study from Dana Farber, which in- based regimens to fludarabine-busulphan to fludarabine- cluded patients with any hematologic malignancy, where 336 Curr Hematol Malig Rep (2018) 13:329–340 outcomes from adults who underwent reduced intensity condi- several groups reporting inferior outcomes for patients that –4 tioning and received a transplant from a matched sibling were enter transplant with MRD of > 10 [31–35]. MRD status compared to outcomes for those who underwent compared out- would be expected to be even more important in the context comes for adults with a variety of hematologic malignancies, of reduced intensity conditioning, where the therapeutic ben- who underwent a matched unrelated donor transplant . efit is derived from the graft vs. leukemia effect rather than by Patients who underwent MUD transplant had lower rates of cytoreduction through a myeloablative conditioning. This was relapse at 2 years (52 vs. 65%, p = 0.005) and superior 2-year demonstrated in the CIMBTR study of reduced intensity con- PFS (39.5 vs. 29%, p = 0.01). Overall survival at 2 years was ditioning in patients with Ph+ ALL, in which patients who not significantly different between the groups, being 56% for were MRD positive pre-transplant had a higher risk of relapse MUD vs. 50% for MRD (p = 0.53). Only seven patients with if they underwent RIC vs. MAC conditioning [17�� ] (61% ALL were included in this study, so it is difficult to say whether RIC vs. 35% MAC, HR 1.97 with 95% CI 1.09–3.57, p = these findings would be pertinent to patients with ALL. In 0.026). Although this direct comparison between MRD posi- addition, given the morbidity associated with GVHD, it is pre- tivity and risk of relapse in RIC vs. MAC conditioning has not mature to recommend that patients who are undergoing RIC been studied in Ph− ALL, it is clear that MRD is a marker for should seek out an unrelated donor. However, going forward worse outcomes after transplant. However, there are many as we learn more about the biology of GVL vs. GVHD and unanswered questions concerning MRD. First, it is unclear have better methodologies to prevent and treat GVHD, the what the optimal time to determine MRD status, with some current paradigm of preferring a matched sibling donor may groups reporting the significance of early MRD clearance [36, come into question, particularly in the context of a reduced 37� ], while others report that early MRD positivity (at week 6) intensity conditioning regimen. is not as predictive of post-transplant outcome as MRD level Peripheral blood stem cells (PBSC) vs. bone marrow (BM) after consolidation at week 16 and/or week 22 . Next, the as a donor source is another factor that may impact outcomes optimal threshold for determining what level of MRD positiv- after reduced intensity conditioning. In a retrospective analy- ity is relevant has not yet been determined. Current protocols –4 sis from the EBMT, outcomes for adult patients with AML define MRD as anything > 10 ; however, with the advent of who underwent reduced intensity conditioning and received commercially available next-generation sequencing (NGS) either PBSC or BM from either matched related vs. matched for all subtypes of ALL through IG and TCR sequencing, it –7 unrelated were compared. In the context of receiving a is possible to detect MRD to less than 1 × 10 . It is not yet matched sibling donor graft, there was no difference in clear whether more sensitivity is better, or whether very low- GVHD or leukemia free survival between patients receiving level disease can still be overcome by even reduced intensity PBSC vs. BM grafts. However, for patients who underwent conditioning regimens. Finally, although blinatumomab was MUD transplant, the group that received PBSC had higher recently shown to improve outcomes when used to treat pa- rates of both acute and chronic GVHD as well as higher tients with MRD positivity (see next section), the number of NRM, but also had significantly lower incidence of relapse patients treated is small and it remains to be see whether . This is in contrast to a retrospective study published by treating a patient who is MRD positive to a deeper level of the CIBMTR, where no difference in rates of NRM, relapse or remission prior to transplant will improves outcomes in the overall survival were found between patients with hematolog- context of reduced intensity conditioning. ic malignancies that underwent PBSC vs. BM transplant . An alternate method to improve transplant outcomes is the In the CIBMTR analysis, however, both related and unrelated use of post-transplant maintenance therapy for high-risk pa- donors were analyzed together. Neither of these studies in- tients. This has already proven to be beneficial for patients cluded patients with ALL, and thus these findings cannot be with Ph+ ALL who are treated with post-transplant TKIs generalized to this population. At the present time, the major- [39–41], and some groups have reported that pre-transplant ity of adults undergoing allogeneic HSCT in the USA receive MRD levels are no longer significant in this patient population PBSC grafts given the ease of collection, although using BM . Whether post-transplant TKI therapy should be admin- as a source is more common in Europe. As we develop better istered prophylactically to all patients undergoing allogeneic treatments for GVHD and are able to lower rates of NRM, HSCT for Ph+ ALL vs. just for those who develop MRD after PBSC may become the preferred source for patients undergo- transplant (i.e., a pre-emptive strategy) is an open area of ing RIC conditioning as a way to enhance GVL. debate, although one small prospective study did show equiv- alent outcomes for patients who received prophylactic vs pre- Strategies to Improve RIC—Pre-transplant MRD emptive therapy . Although there are currently no accept- and Post-transplant Maintenance ed post-transplant therapies for Ph− ALL or T-ALL, post- transplant maintenance therapy is an active area of investiga- Minimal residual disease (MRD) has been shown to be a tion and is a potential strategy to mitigate the high-risk status strong predictor of outcome after allogeneic HSCT, with of patients entering a RIC transplant with MRD. Curr Hematol Malig Rep (2018) 13:329–340 337 Novel Therapies results will help define the optimal usage of blinatumomab as it relates to allogeneic HSCT. Treatment options for patients with relapsed ALL have greatly Inotuzumab ogozamycin is a drug-antibody conjugate that increased in the recent years, with the FDA approval of three combines the toxin calicheamicin with a humanized CD22 new agents in this setting. All therapies are highly effective, antibody. When this antibody binds to B cells, it is rapidly and will thus allow more patients with relapsed disease to internalized, delivering the drug directly to the leukemic attain disease control and proceed to a potentially curative blasts. A phase III trial comparing salvage chemotherapy to allogeneic HSCT. In addition, when effective, all of therapies treatment with inotuzumab also showed promising results, have reported high rates of MRD negativity, and thus could with an overall response rate (CR + CHR + Cri) of 81% as serve as a useful bridge to allogeneic HSCT. compared to 29% in the salvage chemotherapy arm. Of the Blinatumomab is a bispecific T cell engaging antibody responders in the inotuzumab group, 78% achieved a MRD (BiTE) composed of an anti-CD19 antibody connected to an negative status [47� ]. In addition, a greater proportion of pa- anti-CD3 antibody via a non-immunogenic link. It functions tients was able to proceed to allogeneic HSCT in the by bringing cytotoxic T cells in contact with CD19+ cells, inotuzumab arm; 41 vs. 11%. In regard to transplant, however, leading to perforin-mediated lysis of leukemic cells. A ran- inotuzumab carries a risk of developing veno-occlusive dis- domized phase III trial of blinatumomab compared to salvage ease (VOD) for patients who had previously or who subse- chemotherapy for patients with relapsed/refractory ALL quently underwent allogeneic HSCT. The overall risk of VOD showed that 44% of patients in the blinatumomab arm attained for patients treated with inotuzumab was 11%, however for a CR, CRh, or Cri within the first 12 weeks as compared to transplant patients 10/48 developed VOD. The risk appears to 25% in the standard chemotherapy group [43� ]. Seventy-six be higher for patients who underwent conditioning with a percent of the responders in the blinatumomab group achieved dual-alkylator regimen. As there is a newly approved agent a MRD-negative status, as compared to 48% of responders in available for the treatment of VOD (defibrotide) not all cases the chemotherapy group. Response was correlated to percent- were fatal; 2 patients recovered, 4 had ongoing VOD, and 1 age of blasts present in the bone marrow, with 65.5% of pa- died. As the majority of RIC regimens contain only one tients with < 50% bone marrow blasts responding to treatment alkylating agent if any, the hope would be that rates of VOD as compared to 34.4% of those with > 50% marrow blasts. would be small or negligible in this population. However, this Although shown to be superior to chemotherapy, the real ben- remains to be determined. efit of blinatumomab may be in treating patients with low Finally, one of the most exciting new strategies for treating levels of persistent disease to an MRD-negative state. An early relapsed/refractory ALL is genetically engineered T cells, the pilot study of blinatumomab looked at response rate in pa- chimeric antigen receptor T cells (CAR-T cells). In this thera- py, Tcells are harvested from a patient and transduced with the tients with ALL who had persistent MRD after initial therapy or those who became MRD positive after initially attaining receptor for CD19; the Tcells are then able to exert a cytotoxic molecular remission . Sixteen of 20 patients (80%) became effect on cells that highly express CD19 (i.e., leukemic blasts). MRD negative after 1 cycle, and long-term follow-up showed Cells are also transduced with a co-stimulatory domain, either that 33 months and then 5 years, 60 and 50%, or patients 4-1BB or CD28; these “second generation” CAR-Tcells show remained in remission, respectively . Based on these enhanced efficacy and longer duration of persistence after promising results, a recent phase II study investigated the infusion. Responses to CAR-T cells are impressive, with rates use of blinatumomab in patients in a hematologic CR (< 5% ranging between 70 and 94% in very heavily pre-treated pa- blasts) but with persistent MRD positivity (> 1 × 10-3). Both tients [48–52]. As with both inotuzumab and blinatumomab, patients in CR1 but with persistent MRD as well as patients in among patients who responded, the majority, > 80%, attained CR 2-3 with persistent MRD after salvage therapy were in- a MRD-negative status. CAR-T cell therapy does come with a cluded. After a single cycle of blinatumomab, 78% of patients high rate of toxicity, including cytokine release syndrome and became MRD negative, and in a landmark analysis responders neurotoxicity, which has led to a number of deaths. While had a significantly longer relapse free survival (23.6 vs 5.7) FDA approved for patients under the age of 25, results in and OS (38.9 vs 12.5 months) as compared to the non-re- adults have not been as impressive, as the toxicities associated sponders. Seventy four patients underwent allogeneic hsct; with CAR-T cells are not as well tolerated in older individuals of these 49% remain in remission, 15% have relapsed and [53, 54]. In addition to toxicity, relapse is another issue with 18% died in CR. [46��]. Although the benefit of treating CAR-T cells, with the primary mechanism being relapse with MRD pre-transplant to improve RFS and OS has not yet been CD19 negative disease followed by immunologic response to demonstrated in a randomized trial, blinatumomab has now the cells [48, 55, 56]. Although many hope that CAR-T cell become the first agent approved to address MRD positivity. therapy will ultimately replace allogeneic HSCT, much work Ongoing trials incorporating blinatumomab into the in post- remains to be done to enhance durability and better understand transplant setting to prevent MRD emergence are ongoing; and manage the serious toxicities associated with this therapy. 338 Curr Hematol Malig Rep (2018) 13:329–340 Although each of these novel agents represents an important over the age of 45, and thus represent a substantial number step forward for the treatment of patients with relapsed/ of yearly cases. While the introduction of pediatric-based refractory B-ALL, few durable remissions without consolidative treatment regimens has greatly improved outcomes for ado- allogeneic HSCT have been reported. Until we have a better lescents and young adults, likely obviating the need for allo- understanding of which patients may achieve a long-term remis- geneic HSCT for many, the toxicities of these regimens in- sion, and until we can prolong the durability of CAR-T cells, creases substantially over the age of 40–50. For older adult these therapies remain a bridge to allogeneic HSCT. patients, the benefit of myeloablative allogeneic HSCT is outweighed by the risks; however, reduced intensity condi- Moving Away From Transplant (for Some), tioning is a valid option for these patients. Therefore, more MRD-Guided Strategies effort should be made toward optimizing outcomes in the reduced intensity setting. This could include incorporating As mentioned previously, MRD remains a strong predictor of novel agents into upfront treatment of adult ALL to increase outcome in acute lymphoblastic leukemia. Within the pediat- rates of MRD negativity prior to transplant, optimizing con- ric realm, MRD-directed therapy is increasingly being used to ditioning regimens to reduce TRM, optimizing donor selec- intensify or de-escalate therapy . This begs the question, tion to enhance the GVL effect, and using prophylactic or pre- can MRD-directed therapy be used to identify a subset of emptive post-transplant therapies. adults for whom allogeneic HSCT is not necessary? Several large cooperative group studies have attempted an Compliance with Ethical Standards MRD-guided approach in adults, with promising results. In Conflict of Interest Jessica T Leonard has received research grants from three separate studies, the Italian NILG trial, the German Amgen. Brandon Hayes-Lattin declares that he has no conflict of interest. GMALL 07/2003 trial, and the Spanish PETHEMA trial, adult patients were treated with a pediatric inspired regimen Human and Animal Rights and Informed Consent This article does not and then assigned to undergo consolidation with chemothera- contain any studies with human or animal subjects performed by any of py if they were MRD negative or allogeneic HSCT if they the authors. were MRD positive. Although each group used a different Open Access This article is distributed under the terms of the Creative method to measure MRD as well as a different time point to Commons Attribution 4.0 International License (http:// assess MRD, all identified a subset of low-risk, MRD- creativecommons.org/licenses/by/4.0/), which permits unrestricted use, negative patients with relapse rates of < 20–30% without al- distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the logeneic HSCT [5, 31, 39]. However, whether these results Creative Commons license, and indicate if changes were made. can be applied to older adults is not yet clear. There were few adults above the age of 50–55 in these trials, and presumably the promising outcomes in the chemotherapy only group are in part secondary to the pediatric based regimens, which are References not as well tolerated in older adults. There are no data at this time to suggest that “adult” regimens can produce durable Papers of particular interest, published recently, have been remissions without consolidative allogeneic HSCT. In addi- highlighted as: tion, 20–30% of MRD “negative” patients do still relapse, and � Of importance survival for adults transplanted in CR2 is substantially lower �� Of major importance than for those transplanted in CR1 . As we learn more about MRD with time, we may be able to identify a subset 1. Swaika A, Frank RD, Yang D, et al. 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Current Hematologic Malignancy Reports – Springer Journals
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