Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

CHAPTER 10

Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia L.M. POON  •  PARTOW KEBRIAEI MD

INTRODUCTION Acute lymphoblastic leukemia (ALL) is a neoplasm originating from B or T lymphocyte precursors which undergo malignant transformation. ALL accounts 10% of all leukemia cases in adults and an annual incidence of 1.7 per 100,000 men and women per year.1 Unlike the dramatic advances made in the treatment of childhood ALL with 5-year survival at more than 90%,2 therapeutic progress for adult ALL remains considerably inferior, with only 30%–40% patients achieving long-term leukemia-free survival.3–6 Although complete remission rates are high (80%–90%) with modern induction regimens,4,6 the major barrier to improved results in adult ALL treatment remains the high relapse rates after first complete remission (CR1). Allogeneic transplantation remains the most effective modality for consolidation and prevention of relapse. Unfortunately, the efficacy of allo-HCT is balanced by significantly higher acute and long-term toxicity, with allo-HSCT.7 Thus, identifying prognostic markers which could help determine the appropriate timing of allo-HCT in the treatment algorithm of ALL is paramount to ensure optimal utilization of this treatment modality. This decisionmaking algorithm is made more complicated in the current treatment landscape of ALL. Advances include the increasing use of alternative donor transplants and reduced intensity-conditioning regimens which have increased the accessibility of allogeneic transplantation versus the advent of pediatric chemotherapy protocols and incorporation of novel agents into ALL treatment protocols which have improved cure rates in adult ALL and brought into question the adverse prognosis of some traditional high-risk factors for ALL. In this chapter, we aim to focus on the role of allo-HCT for adult ALL in CR1 and beyond based on a risk-oriented paradigm, which takes into account the increasing utilization of minimal residual disease (MRD) monitoring. We also explore advances in the field of allo-HCT including the use of alternative donors and the development of reduced intensity

conditioning regimens and their impact on the ALL treatment algorithm.

Allo-HCT in CR1 for Ph-Negative ALL After achieving complete remission with induction therapy, consolidation options include continued chemotherapy or allogeneic transplantation. Historically, the role of allo-HCT for ALL in CR1 has been controversial. Conventional adverse prognostic factors identified have included white blood cell (WBC) counts, age >40 years, immunophenotype, cytogenetics, and postinduction treatment response. What constitutes a high WBC count appears dependent on the ALL subtype, with a WBC count greater than 30,000/μL for B-lineage ALL and greater than 100,000/μL for T-lineage ALL predicting for poorer prognosis. Increasing age has also been shown to portend a worse prognosis with OS ranging from 34% to 57% for patients aged less than 30 years compared with only 15%–17% for patients older than 50 years.8 With regards to immunophenotype, T lineage ALL also appears to have better outcomes than B lineage ALL, whereas among T lineage ALL, patients with cortical T ALL appeared to have the best outcomes.9 In contrast, a recently recognized subtype of T-ALL/LBL derived from thymic cells at the early T-cell precursor (ETP) differentiation stage has been found to be associated with poor outcomes especially when treated with conventional adult regimens.10,11 Specific cytogenetic abnormalities have also been found to have a major impact on prognosis. Some well-accepted adverse prognostic cytogenetics include the Ph chromosome, t(4; 11) (q21; q23), as well as t(8; 14) (q24.1; q32), complex karyotype defined as >5 chromosomal abnormalities, or low hypodiploidy/near triploidy.12–14 Finally, the achievement of CR and time to CR after induction therapy also carries significant prognostic implications, with patients who require more than 4 weeks to achieve a CR having a lower likelihood of being cured.

Hematopoietic Cell Transplantation for Malignant Conditions. https://doi.org/10.1016/B978-0-323-56802-9.00010-9 Copyright © 2019 Elsevier Inc. All rights reserved.

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Although stratification for high-risk disease has varied between the different studies, historically, most of the early studies carried out based on biologic randomization, including the French LALA-8715 and LALA94,3 as well as the GOELAL02 trial,16 have shown a survival advantage for patients with adverse prognostic factors who were treated with allo-HCT compared with adult ALL chemotherapy regimens. The French LALA-8715 which looked at 257 ALL patients in CR1 in a biologic randomization fashion and with an intention to treat analysis showed that patients with adverse prognostic markers who had an HLA-compatible donor had a significant survival advantage compared with patients without a donor (5-year OS 44% vs. 20%). In a follow-up study, the LALA94 trial,3 which stratified only high-risk patients with donors to allo-HSCT, a similar survival advantage was again seen in the patients with donors. (5-year leukemia-free survival [LFS] 45% in those with donors compared with 23% for those without). Similar findings were also demonstrated by the GOELAL02 trial16 in which almost twofold improvement in OS was seen in the group with available donors (6-year OS 75% vs. 39%). Even among the trials that were not able to demonstrate overall survival benefit for the high-risk group assigned to allo-HCT, it was clear that the relapse rates in the allo-HCT arms were superior compared with the chemotherapy or ASCT arm suggesting that the conflicting results were due to the high nonrelapse mortality in the high-risk groups, abrogating the overall survival benefits from allo-HCT rather than the lack of efficacy of the graft-versus-leukemia effect.17,18 Table 10.1 summarizes some of the largest prospective trials looking at upfront transplantation for standard and high-risk ALL based on a donor versus no-donor analysis. As pediatric regimens for treating ALL gains wider acceptance in recent years, however, the continued relevance of these traditional risk factors as decisionmaking tools for allo-HCT have been challenged. Instead, markers like disease response and minimal residual monitoring (MRD) has shown promise and may trump these conventional markers, changing the decision-making paradigm for allo-HCT for ALL. As MRD is inherently a response-based assessment, it may serve as an in vivo test for chemosensitivity and disease biology that pretreatment markers along may not be able to help. More recent reports have also suggested that MRD stratification may be combined with molecular subtyping to provide better risk stratification. In a recent study by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL),19

522 transplant-eligible Ph-negative ALL patients (aged between 15–55 years) who were stratified as high risk based on at least one traditional adverse risk factor and who were treated with a pediatric-intensive chemotherapy regimen, were evaluated. No relapse-free or overall survival benefit was demonstrated in the allo-HCT (N = 282, either with a 10/10 matched related [matched RD] or unrelated donor [MUD], n = 231, or a 9/10 MUD or umbilical cord blood [UCB] transplant, n = 51), compared to the chemotherapy arm (N = 240). Of note however, postinduction MRD of >10(-3) and presence of the IKZF1 deletion were able to identify a subgroup of particularly high risk of relapse who would benefit from allogeneic stem cell transplantation (allo-SCT) in CR1. Importantly, these markers were found to be better for risk stratification than analysis of pretreatment characteristics alone. This finding that has also been supported by similar results from other large cooperative group studies. Though using different technical aspects for MRD quantification, different protocol designs and selection criteria for MRD-directed therapy, the Spanish PETHEMA group20 and North Italian Leukemia group (NILG)21 have also shown that MRD negativity identifies a low-risk group of patients for whom chemotherapy-alone approaches alone may be associated with prolonged disease-free survival. Within the NILG, Bassan et al. performed an MRD-oriented therapy for Ph-negative patients (excluding those with the t(4; 11) translocation) and were able to identify a low-risk MRD-negative population, with bone marrow relapse rates of less than 20%, and DFS nearly 80%, in whom SCT in CR1 was unnecessary. Similarly, the PETHEMA group demonstrated that in high-risk patients (based on pretreatment characteristics) with rapid MRD clearance, avoiding HCT was safe, with 5-year DFS and OS of 55% and 59%, respectively, from chemotherapy alone. Of note, in both the studies, multivariate analysis showed that the pattern of MRD clearance was the most significant prognostic factor for CR duration and OS, as compared to classic risk factors. Moving forward, MRD is likely to play a more pertinent role in the allo-HCT decision-making algorithm, superseding conventional pretreatment risk factors. More work is however necessary in determining the optimal MRD method and appropriate time points for testing before MRD can be incorporated into riskadapted therapies. 

Allo-HCT in CR1 for Ph-Positive ALL Historically, the prognosis of patients with Ph+ ALL has been poor with long-term DFS rates of 10%–20%.22 In the preimatinib era, allo-HCT has been standard of care

CHAPTER 10  Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

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TABLE 10.1

Prospective Trials of Upfront Allo-HSCT Versus No Allo-HSCT for Standard-Risk and High-Risk ALL in the Pre-MRD and MRD Era PROSPECTIVE DONOR VERSUS NO-DONOR STUDIES IN STANDARD-RISK AND HIGH-RISK ALL 5-YEAR OVERALL SURVIVAL % NO DONOR

Study

Accrual Period

Patients, n

Donor, Allo-HSCT

Overall

Chemo

AutoHSCT

P Value

SR: N = 161

51

45

DNS

DNS

NS

HR: N = 96

44

20

DNS

DNS

0.03

SR: N = 562

62

52

56

46

0.02

HRb: N = 465

41

35

31

37

NS

SR: N = 138

69

49

NA

49

0.05

HR: N = 119

53

41

NA

41

NS

HRb

45

23

DNS

DNS

0.007

Other Findings

Pre-MRD Era LALA-8715

1986–1991

MRC/ ECOG17

1993–2006

HOVON trials48

1992–2005

LALA-943,a

1994–2002

N = 259

MRD Era GRAALL, 2003/200519

2003–2011

HRb: N = 522

3-year OS: (donor allo-HCT group): 70% 3-yr OS: HR, 0.76 (95% CI, 0.57 to 1.02) was not significantly improved in the SCT group

P = .07

47% of cases MRDneg at 6 weeks after induction. Allo-HSCT was associated with longer RFS in patients MRDpos >10–3 after induction (hazard ratio, 0.40) but not in good MRD responders

GMALL 06/09 and 07/0392

1999–2009

HRb/SR with MRD-positive wk 16, N = 580

5-year leukemia-free survival for SR/ HR patients with MRDpos at week 16 (N = 120): 44% (allo-HSCT) versus 11% (no allo-[HCT)

P < .001

Allo-HSCT benefit in both high and standard risk with MRDpos. No alloHSCT benefit in MRDneg group.

Auto-HSCT, autologous stem cell transplant; DNS, data not stated; HR, high risk; LFS, leukemia-free survival; MRD, minimal residual disease; MRDneg, negative minimal residual disease; MRDpos, positive minimal residual disease; NA, not applicable; NS, not significant; OS, overall survival; SR, standard risk. a5-year leukemia-free survival. bHigh risk excluding Ph-positive ALL cases.

for consolidation, with 30%–65% long-term survival for patients transplanted in CR1.23–25 In the post-TKI era, the incorporation of imatinib into standard ALL therapy has resulted in significantly improved remission induction rates, as well as improved depth of remissions,26–29 enabling more HSCT in CR. Three-year OS rates of between 50% and

65% have been reported in patients transplanted with myeloablative conditioning26,30–32 in this setting. With the improved outcomes in the post-TKI era, a number of questions have arose about the use of alloHCT and role of maintenance TKI after allo-HCT, as well as the role of auto-HCT in patients with good MRD response and who are without a donor. 

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Question 1: Is Transplant Mandatory for all Ph-Positive ALL Patients? Before the development of tyrosine kinase inhibitors (TKIs), Philadelphia-positive ALL carried a poor prognosis even with allo-HCT.25,33 The incorporation of TKIs into chemotherapy regimens has led to improved response rates and depth of responses and allowed more patients to be able to undergo allo-HCT with better remission states. With TKIs/chemotherapy allowing complete molecular remission in a significant subset of patients, there has been debate in recent years whether allo-HCT is still

mandatory. Table 10.2 summarizes some of the largest prospective studies looking at allo-HCT for Ph-positive ALL in first remission. Although allo-SCT is still regarded as the best treatment option for patients with Ph-positive ALL in CR1, the long-term results of regimens combining chemotherapy with TKIs suggest the possibility of long-term survival in a proportion of patients who do not undergo a transplant This concept was first inspired by a study from the Children’s Oncology Group which reviewed pediatric patients with ALL treated with imatinib and chemotherapy.34,35 Patients with matched related donors were offered allo-HCT. In the long-term

TABLE 10.2

Prospective Studies of Upfront Allo-HSCT in Ph-Positive Patients in the TKI Era

Study MRC/ ECOG38

GRAALL, 200539

SWOG, 080540

MDACC group93

Accrual Period 2003–2014

2006–2011

2009–2013

2011–13

Patients, n

CR Rates

Percentage Undergoing Allo-HSCT in CR1

UKALL chemoregimen + imatinib; allo-HSCT if donor

N = 175

92%

46%

4-yr OS, 38% overall; 4-yr EFS, 33% overall.

4-yr OS 50% for the per-protocol allo-HSCT versus 19% in those who achieved CR but did not undergo allo-HSCT

Randomization to induction regimen: VCR/Dex + imatinib ×28 days (arm A) versus HyperCVAD + imatinib ×14 days (arm B); allo-HCT or autoHCT based on donor availability if patients achieved MMR after cycle 2

N = 268

98% arm A versus 91% arm B; (MMR 66% v. 65%)

77% (63% allo-HSCT, 14% autoHSCT)

5-yr OS 46%; 5-yr EFS 37%; no differences between induction arms

Significant benefit to allo-HSCT in RFS and OS; no benefit in MRDneg patients

HyperCVAD + dasatinib; allo-HSCT if donor

N = 94

88%

49%

3-yr EFS, 54% overall; 3-yr EFS, 76% for alloHSCT

Landmark analysis 175 days after CR: significantly better RFS (P = 0.037) and OS (P = 0.036)

HyperCVAD + ponatinib; No planned alloHSCT

N = 37

97%

24%

2-yr EFS 80%; 2-yr OS 81%

No benefit to alloHSCT at median 26 months followup; all allo-HSCT in MRDneg state

Regimen

Outcomes

Allo-HSCT Effect in CR Patients

CR, complete remission; Dex, dexamethasone; EFS, event-free survival; MMR, major molecular remission; MRD, minimal residual disease; Neg, negative; OS, overall survival; RFS, relapse-free survival; VCR, vincristine.

CHAPTER 10  Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia follow-up, there was no superiority in the DSF between the matched related donor allo-HCT arm and the chemotherapy plus imatinib-alone arm (5-year DFS 65% vs. 70%). However, this study cannot be considered definitive, given the small number of patients in both the arms (28 treated with imatinib and 21 patients received sibling-donor BMT), as well as a high nonprotocol MUD allo-HCT rates. In the adult population, there has been conflicting results. The ALL202 trial from the Japanese Adult Leukemia Study Group reported on 80 patients who received a combination of imatinib and chemotherapy.31 Of these patients, 31 did not undergo allo-HCT. Outcomes among the chemotherapy-only versus the allo-HCT group were similar, albeit with short followup data. In contrast data from the MD Anderson cancer centre (MDACC) demonstrated that patients <40 years old who underwent allo-HCT showed a trend toward improved survival compared with patients treated with second-generation TKIs/chemotherapy, though statistical significance was not reached, likely due to the limited patient numbers.36,37 The UKALLXII/ECOG2993 trial reported on patients treated with imatinib added to standard BFM-type induction chemotherapy.38 Transplant patients had significantly better overall survival (50% vs. 19%), event-free survival (46% vs. 14%), and relapse-free survival compared to the nontransplant patients (69% vs. 18%), though there were differences between the transplant versus nontransplant group suggesting potential selection biases affecting study results. The GRAALL group showed that allo-HCT was associated with a significant benefit in relapse-free survival (RFS) (hazard ratio [HR], 0.69 [95% confidence interval (CI), 0.49–0.98]; P = .036) and OS (HR, 0.64 [95% CI, 0.44–0.93]; P = .02) in their population of patients who were younger than 60 years and received imatinib-based therapy.39 Interestingly, however, patients who achieved a molecular CR did not benefit from allo-HCT in terms of RFS, whereas those who had MRD did. Most recently, a multicenter US intergroup trial40 showed superior RFS and OS for the transplanted patients, after induction with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) and dasatinib. These findings suggest second-generation TKIs may not be potent enough to eliminate the need for alloHCT; however, MRD monitoring may select a small subgroup of patients who have excellent long-term outcomes even without allo-HCT in first remission. These results are further supported by the studies from the MDACC in their cohort of patients41,42 treated with TKIs and hyper-CVAD regimen, where achievement of at least a major molecular response (MMR) was found to be independently prognostic for improved survival.

163

In addition, patients who achieved a complete molecular remission (CMR) (defined as absence of BCR-ABL1 transcripts with a sensitivity of 0.01%) by 3 months had an excellent long-term survival even without allo-HCT, with a 4-year OS rate for patients achieving CMR by 3 months of 66%, and a median OS of 10 years. Moving forward, prospective trials using MRD-based risk stratification for patients with Ph-positive ALL are important to elucidate the optimal postremission management of these patients and to assess the appropriate time points for MRD assessments. 

Question 2: Is Posttransplant TKI Maintenance Necessary? Given the efficacy of TKIs and the continuing risks of relapse after allo-HCT, an important issue is the role of TKIs maintenance after transplantation. In patients who turn MRD-positive after allo-HCT, TKI may help convert some to molecular remission, allowing prolonged disease-free survival.43 In patients who are MRD negative, however, the use of TKI remains unclear given the limitations in the literature with a paucity of prospective studies and conflicting results from retrospective studies, most of which have small patient numbers. In one of the largest retrospective studies of 113 patients with Ph-positive ALL undergoing alloHSCT, neither TKI use before HSCT nor after HSCT was found to significantly impact transplant outcomes in univariate or multivariate analyses.44 The GMALL performed a prospective multicenter randomized trial of prophylactic versus MRD-triggered imatinib after alloHCT.45 Incidence of molecular recurrence after alloHCT was significantly reduced compared with imatinib given at detection of MRD (40% vs. 69%, respectively, P = .046). The probabilities of ongoing remission, DFS, OS, and EFS were 82.6%, 69.4%, 77.3%, and 62.5%, respectively, with no statistically significant difference between study arms. There was however premature discontinuation of imatinib in the majority of patients due to poor tolerability, and the numbers in both the arms were small (N = 26 and 29). Liew et al. performed a meta-analysis of the published studies comparing the outcomes of patients after allo-HSCT who did or did not receive TKIs.46 This looked at 346 patients who received a TKI after alloSCT and 1095 patients who did not. There were no differences in relapse-free survival or overall survival in both the arms. Although the result from this meta-analysis needs to be interpreted with caution given the heterogeneity between the studies, these overall findings do suggest that TKIs might not be necessary and highlights the need for larger prospective controlled studies to address this issue.

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In patients who become MRD positive after alloHSCT, posttransplant TKI appears beneficial, being able to convert some of them to molecular remission and allow prolonged disease-free survival. Until then, a panel of experts from the Acute Leukemia Working Party of the European Society for Blood and Marrow transplantation has prepared a consensus statement to guide the use of TKIs after allo-HCT.47 Some key points of this recommendation include: 1 All Ph-positive ALL patients are candidates for TKI use after allo-HCT. 2 Patients with detectable MRD after allo-HCT should be started on TKI treatment as soon as possible. 3 For patients who are MRD negative after allo-HCT, both a prophylactic and preemptive strategy are valid options. 4 For patients transplanted in CR1, TKIs should be given for 12 months of continued MRD negativity, whereas if transplanted in CR2, TKIs should be continued indefinitely. 

Question 3: Is There a Role for Autologous HCT for Ph-Positive Patients? In patients with Ph-negative ALL, most of the studies using biologic randomization to compare autologous HCT (autoHCT) or chemotherapy versus allogeneic transplantation have found that for high-risk patients, allo-HCT led to superior DFS and OS compared with autologous HSCT or chemotherapy,3,15–17,48 with no significant difference between chemotherapy and autologous HSCT.3,15 In the MRC/ECOG trial25 with the largest number of patients randomized to autologous versus chemotherapy (456 patients), the eventfree survival of the autologous arm was significantly lower, and the relapse risk was significantly higher than that of chemotherapy. Thus, currently, there does not appear to be any benefit for autologous HSCT in the treatment of Ph-negative ALL. In contrast, for Ph-positive ALL patients, there have been data suggesting a potential role for auto-HCT in these patients, especially those with MRD negativity at the time of transplant. The EBMT compared the outcomes of auto-HCT for Ph ALL, before and after the use of TKIs in 177 patients, and showed an improvement in overall survival and leukemia-free survival (LFS) in those transplanted in the TKI era.49 Among the subgroup of 22 patients actually treated with TKIs and being in complete molecular remission at the time of auto-HCT, the LFS at 3 years was 65%. Similar results have been shown in other retrospective studies looking at auto-HCT in Ph-positive patients, especially in the setting of MRD negativity. 

ALLOGENEIC HSCT BEYOND CR1 The outcome of patients with relapsed refractory ALL is dismal, with complete response rates to salvage therapy ranging from 40% to 45% and overall survival being usually less than 10%.50–53 A number of multicenter trials have characterized prognosis and outcome of patients with ALL after relapse and shown that in patients with CR2, allo-HCT offers the best chance for potential cure. Data from the MRC UKALL12/ECOG2993 trial52 showed that in patients with relapsed disease, 5-year survival after HSCT ranged from 15% to 23% depending on donor type (15% for autograft, 16% for MUD, 23% for MRD) and was significantly better than chemotherapy (4%) (P < .05). Similar findings were reported by the GMALL as well as the LALA and PETHEMA group.53–55 Gokbuget et al. reported outcomes of 547 ALL patients in first relapse.53 Three-year OS was 38% for the patients who underwent transplantation, whereas none of the nontransplantation patients had long-term survival. In an analysis of 421 patients previously treated on LALA-94, who had disease relapse, CR2 was attained in 44% of patients, but the 5-year OS was again significantly better in the subset that was able to receive allo-HSCT (25% vs. 7% for the whole group).54 Oriol et al. reported on the outcome of 263 adults with relapsed ALL, all of whom were previously treated on four consecutive PETHEMA trials with similar induction therapies.55 Forty-five percent of patients achieved a second remission, and best outcome was noted for patients younger than 30 years with a long first remission duration transplanted in CR2, with an OS of 38% at 5 years. Significantly, outcomes of allo-HCT in CR2 are much poorer than those of allo-HCT performed in CR1 in all the studies, hence underscoring the importance of identifying high-risk patients who should be transplanted in first remission. Many patients with relapsed and refractory disease do not reach allo-HCT stage, either due to treatmentrelated toxicities of salvage treatment which precludes subsequent transplantation or persistently refractory disease.56 The treatment-related mortality associated with salvage chemotherapy in this setting may be as high as 20%.57 Given these risks, some have argued that for patients with low-to-moderate disease burden and an available donor, reinduction chemotherapy may be omitted in preference for immediate allo-HCT. Terwey et al. performed one of the largest retrospective review addressing this and was able to show a 5-year OS rate of 47% in 19 patients with relapsed or refractory disease who received an allo-HSCT without prior reinduction chemotherapy, a result that was superior to the group that had received prior reinduction

CHAPTER 10  Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia chemotherapy (5-year OS: 18%).58 It should be noted that the patients who went transplantation immediately had very low tumor burden and that such results are not universally shared with other similar results suggesting that allo-HCT in CR2 is superior to alloHCT in active disease.59,60 The EBMT recently reviewed the results of patients with ALL transplanted in refractory disease and developed a prognostic score for LFS in this patient group.61 Use of TBI and infusion of a female hematopoietic cells into male recipients were associated with improved outcomes. Patients with both the factors have a 5-year OS of 57% compared with patients with no prognostic factors present. Although this scoring system requires validation, it does provide a basis for future studies. Until more prospective data are available, recommendations regarding reinduction chemotherapy versus upfront transplant in patients with refractory disease or early relapse will have to be individualized depending on the patient, their disease behavior, and the availability of donors. 

OPTIMAL CONDITIONING AND DONOR SELECTION FOR ALLO-HCT FOR ALL From the data discussed, it is evident that there are patients for whom an allo-HSCT would allow best chances for long-term disease control. However, only about 30% of patients, however, will have a matched sibling donor. In addition, the toxicities associated with a myeloablative regimen limit its use to younger patients without comorbidities. The development of reduced-intensity conditioning (RIC) regimens and use of alternative donor allo-HSCTs increase the accessibility of this modality to patients who might need it most.

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regimens given its ability to cross the blood-brain barrier. A recent matched pair analysis from the EBMT62 found that thiotepa conditioning was associated with higher relapse rates compared with Cy/TBI arm (HR = 1.78; 95% CI, 1.07–2.95; P = .03) but equivalent 2-year PFS and OS and supports the use of thiotepa-based conditioning as a valuable alternative to TBI-based conditioning. 

Choice of RIC The data for RIC for ALL are less mature than those for AML. Two large observational database retrospective registry studies from the EBMT and CIBMTR63,64 have demonstrated the feasibility and efficacy of RIC for ALL. The optimal RIC conditioning also remains unclear with various regimens reported from various centers.65–68 Importantly, most studies for RIC have shown that outcomes of patients transplanted in CR1 appear to be superior than those transplanted beyond CR1 (45% vs. 28% in CIBMTR study and 51% vs. 33% in the EBMT group). In contrast, patients transplanted with active disease did poor suggesting a limited role for RIC allo-HSCT for ALL not in CR.69 Although awaiting more data from randomized studies, RIC HCT should be considered for ALL patients in CR1 with higher NRM risks, in the absence of clinical trials. In contrast, for younger patients without comorbidities with higher risks of relapse (e.g., disease in CR2 and beyond), MA conditioning should still be considered. 

Alternative Donors Only about one-third of patients who need a transplant will have a sibling donor. For others, alternative donors including matched unrelated, cord blood, and haploidentical donors have been investigated. 

Choice of Myeloablative Conditioning

MUD Transplants

Myeloablative conditioning for ALL has generally included total-body irradiation (TBI) or busulfan. Given the ability of TBI-based myeloablative regimens to eradicate the leukemia cells in sanctuary sites, cyclophosphamide and TBI remain the preferred MA regimen for ALL. The frequent immediate and late complications such as azoospermia, diabetes, hypertension, as well as late secondary malignancies of TBI, however, has led to continued development of novel radiation-free myeloablative regimens, using busulfan as a backbone, to improve outcomes. These are associated with encouraging rates of PFS and OS as well as acceptable toxicity profiles and are reasonable alternatives to TBI-based regimens. In addition, in recent years, thiotepa has been added to these conditioning

Prospective studies comparing allo-HSCT to chemotherapy have been based on the availability of a matched sibling donor. However, with the availability of allele-level HLA typing and improved supportive care over time, the safety of MUD transplants has improved, and there are increasing data suggesting comparable outcomes for MUD compared with sibling transplants. Some important studies include the following: (1) a multicenter retrospective review from Germany and Sweden that reported no significant difference in 5-year DFS in 221 patients with high-risk ALL that underwent an HLA-matched versus an HLA unrelated alloHSCT (42% vs. 45% at 5 years for patients in CR1);70 (2) Data from the Japanese registry that showed lower NRM (14% vs. 24% at 4 years, P = .0002), higher relapse

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rates (32% vs. 22% at 4 years, P = .03), and no difference in OS (65% vs. 62% at 4 years, P = .19) between the sibling and MUD transplants; and (3) Data from the CIBMTR on 672 ALL patients, which found no difference in leukemia-free survival between MUD and sibling allo-HSCT.1 There have also been several other single-center studies which have reported their experience with MUD transplants for ALL and demonstrated comparable disease-free and overall survivals as compared with sibling transplants.71,72 For patients without MUD donors, cord blood and haploidentical transplants are alternatives. 

UCB Transplants Unlike sibling and MUD transplants, cord blood transplants allow for greater HLA disparity and hence matches are easier to find. The largest data sets supporting the use of UCB transplantation for ALL comes from registry data. In one of the largest studies, Eapen et al. reported data from 1500 patients from the CIBMTR and EBMT73 and showed that LFS for UCB transplants was comparable with that after a 8/8 or 7/8 allele-matched peripheral blood stem cells (PBSC) or bone marrow transplantation, though NRM was higher after UCB transplantation than 8/8 allele-matched PBPC recipients (HR, 1.62; 95% CI, 1.18–2.23; P = .003) or bonemarrow transplantation (HR, 1.69; 95% CI, 1.19–2.39; P = .003).73 Recent publications from the University of Minnesota74,75 and Fred Hutchinson Cancer Research Center (FHCRC)76 have also compared UCB transplants with alternative donor sources specifically for patients with ALL and found similar PFS and OS among the groups. Interestingly, results from the FHCRC have also suggested that for patients with MRD positivity, UCB transplants were associated with lower relapse rates than MUD transplants. Overall these findings suggest that for adult patients with high-risk ALL, UCB transplants are an acceptable alternative and have comparable outcomes to a well-matched unrelated donor. 

Haploidentical Transplants Another alternative door option is that of haploidentical transplantation. This has been increasingly used since haplo-donors are virtually available for all patients, and it allows almost all patients to undergo an allo-HCT if needed. Early use of haploidentical transplantation involved mainly T-cell depletion of the graft associated with higher incidences of graft failure and slow immune recovery and infective complications. In the last decade, there has been an increasing use of unmanipulated grafts with in vivo T-cell depletion using either the John Hopkins method using posttransplant cyclophosphamide77,78 or the Beijing hospital

strategy of intensive antithymocyte globulin (ATG)based immunosuppression.79,80 Using a T-cell depletion strategy, Ciceri and colleagues reported a leukemia-free 2-year survival rate of 13% for patients with high-risk ALL undergoing haploidentical transplantation in first complete remission, 30% for those undergoing HSCT in second or further complete remission, and 7% in those undergoing HSCT in nonremission.81 The Beijing group recently compared outcomes of haploidentical (N  =  103) with matched sibling donor allografts (N = 83) in a cohort of high-risk Ph-negative ALL patients in CR1 (N = 210).79 At 3 years, cumulative incidence of relapse (18 vs. 24%; P = .30), NRM (13 vs. 11%; P = .84), DFS (68 vs. 64%; P = .56), and OS (75 vs. 69%; P = .51) were similar between both the groups. In recent years, there have also been a number of multicenter or registry data specifically reviewing outcomes of posttransplant cyclophosphamide for ALL. In recent multicenter retrospective study by Srour et al.,82 outcomes of 109 adults with ALL receiving haploidentical transplant with posttransplant cyclophosphamide were reported. Effective disease control and safety profile in concordance with outcomes of matched related and MUD transplants were demonstrated, including an encouraging DFS of 52% at 3 years. Similarly the EBMT published their data specifically looking at the use of unmanipulated haploidentical stem cell transplantation in 208 patients with ALL transplanted in EBMT centers from 2007–2014 (57% using posttransplantation cyclophosphamide and 43% using ATG plus standard prophylaxis).83 No difference was found in the outcomes between the two types of graft versus host prophylaxis though there was a trend toward increased NRM in the ATG group. Patients transplanted in CR1 had a 3-year OS of 52% which appears comparable with results reported for matched related and MUD transplants, whereas patients transplanted with active disease did poorly with only a 5% OS at 3 years. Overall these findings suggest that for adult patients with high-risk ALL, haploidentical transplants are a valid alternative donor option; though for patients with active disease, given the poor outcomes, efforts should be made to achieve disease remission before transplantation. 

ADVANCES IN THE FIELD OF ALL Novel ALL Entities and Role of Allo-HCT for These Entities In recent years, there have been 2 new distinct subsets of ALL identified with distinctive clinical behavior and prognosis, immunophenotype, as well as gene expression signatures.

CHAPTER 10  Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia These include the early T precursor acute lymphoblastic leukemia (ETP-ALL) and the Philadelphia-like ALL (Ph-like ALL). For transplant physicians, it is important to know about these new entities and how to incorporate transplantation into the treatment algorithm for these entities.

Early T precursor ALL ETP ALL is a leukemia derived from thymic cells at the early T precursor differentiation stage.10 These leukemic cells are believed to have a unique genetic makeup with multilineage pluripotency and characteristics of myeloid progenitors as well as hematopoietic stem cells at both the immunophenotypic and genetic level.84 In the WHO 2016 classification, ETP ALL is recognized as a new provisional entity, defined based on immunophenotype with expression of CD7 but lacking CD1a and CD8 and with positivity for 1 or more of the myeloid/stem cell markers CD34, CD117, HLADR, CD13, CD33, CD11 b, or CD65.85 The prognostic significance of ETP ALL remains conflicting and appears to depend on the treatment provided. The use of a paediatrics-based approach with treatment intensification based on MRD appears to be able to abrogate the prognostic significance of ETP ALL. Favorable long-term outcomes have been seen in ETP ALL patients in the Children’s Oncology Group and Medical Research Council Working Party on Leukaemia in Children UK National Acute Lymphoblastic Leukaemia 2003 study despite higher MRD rates after induction. In contrast, in ETP patients treated in the MD Anderson Cancer Centre with a mainly adulttype chemotherapy, outcomes appeared to be poorer than those of the patients with other T ALL subtypes.11 More studies in this field will allow us to better determine the optimal management of this ALL subtype and whether there is a role for upfront allogeneic transplantation versus using a pediatric protocol in this disease entity. 

Philadelphia-like ALL (BCR-ABL–like ALL) Ph-like ALL is a novel entity first described by Mulligan et al. from the Children’s Oncology group and St Jude’s children’s hospital86 and by den Boer et al. from the Netherlands,87 which had a gene expression profile that was very similar to Ph-positive ALL. Of note, this entity is found to be associated with a variety of genomic alternations that activate kinase and cytokine receptor signaling, including JAK/STAT signaling, as well as FGFR1, IL2RB, PDGFRA, and the RAS signaling pathway among others. In addition, this entity was also found to be associated with high frequency of deletions of the IKZF1 gene

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which encodes IKAROS, the lymphoid transcription factors.86–88 More studies are currently underway to identify options to improve outcomes in these patients including ways to more rapidly identify this entity, as well as studies of clinical or prognostic markers that can identify subsets who would benefit from the addition of tyrosine kinases to treatment regimens. The role of allo-HCT in improving outcomes of this high-risk ALL subset remains unclear and will also be an area of further research. 

Incorporation of Novel Agents into the Treatment Algorithm of ALL After many decades of little progress of new drugs, in recent years, there has been a rapid development of several immune-based therapies which has shown significant promise both as single agents as well as in combination with chemotherapy, for the treatment of ALL. Of these, the 2 leading compounds, inotuzumab and blinatumomab, have been recently approved by the FDA in the setting of relapsed refractory ALL. Blinatumomab is a bi-specific T cell–engaging construct with dual specificity against CD19 and CD3, hence bringing cytotoxic T cells to close proximity with CD19 ALL cells and optimizing cell killing. It was first investigated with patients in CR1 with MRD positivity with encouraging results but has since been extensively investigated in the relapsed refractory setting where it has been shown to have superior outcomes than current standard of care chemotherapy (SOC). An open label multicenter clinical trial (TOWER NCT02013167) compared blinatumomab to SOC in 405 patients with relapsed refractory ALL89 and showed a statistically significant improvement in overall survival for patients treated with blinatumomab compared with SOC (HR, 0.71; 95% CI: 0.55–0.93; P = .012). Median survival was also improved in the blinatumomab arm (7.7 months, 95% CI: 5.6–9.6) compared with that in the SOC arm (4.0 months, 95% CI: 2.9–5.3). The results of this trial led to approval for blinatumomab in the United States in 2014. Blinatumomab is currently also being investigated as maintenance therapy after allogenic transplantation. In addition, a US Intergroup (E910) is currently also assessing chemotherapy with and without blinatumomab in adult patients with newly diagnosed ALL. Inotuzumab, a monoclonal antibody against CD22 and linked to calicheamicin, has also recently received approval for the treatment of ALL in the relapsed refractory setting, based on results from the randomized INO-VATE ALL (NCT01564784) trial90 Of the initial 218 randomized patients, the rates of complete remission were significantly higher in the inotuzumab group (80.7% vs. 29.4%, P < .001).

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Progression-free survival was also improved in the inotuzumab group (median 0.0 months vs. 1.8 months; HR, 0.4; P < .001), but responses appear shortlived and allo-HCT appears still necessary to consolidate clinical responses. Importantly, however, the use of inotuzumab has been associated with higher risks of venoocclusive disease (VOD) subsequently in patients undergoing allo-HCT, and in a series of 23 patients receiving an allo-HCT after salvage therapy with inotuzumab, Kebriaei et al.91 reported a fatal VOD rate of 19% (n = 5). Of note, 4 of the 5 patients had received two alkylating agents in their conditioning regimen. These findings are a stark reminder to transplanters that novel agents may have an impact on allo-HCT outcomes and that understanding of drug toxicities and careful selection of preparative regimens and avoidance of other concomitant hepatotoxic drugs may be considered to reduce posttransplantation toxicities. There are also currently several other monoclonal antibodies in currently earlier phases of clinical development with promising initial results. In recent years, one of the most exciting developments in the field of ALL treatment has been the development of chimeric antigenic T cells (CAR-T) for the treatment of relapsed refractory B cell malignancies. Currently there are more 240 trials of CAR-T cells worldwide and two CAR-T cells from Novartis and Gilead and KiTE Pharma, targeting the CD19 antigen found on B cells, have been approved for the treatment of B acute lymphoblastic leukemia and diffuse large B cell lymphoma, respectively. With a response rate of more than 80% among patients with relapsed refractory AL treated with the CD19 CART, tisagenlecleucel (Kymriah) from Novartis, the potential of this treatment is immense. However, the high rates of potentially fatal complications such as cytokine release syndrome and neurotoxicity associated with this treatment entity, as well the prohibitive costs of these CAR-T cell therapies have been barriers to the widespread use of this technology. Further work to improve upon the safety and affordability of CAR-T cells is currently ongoing and will hopefully allow this therapy to become a more broadly applicable treatment option. More data and results are needed from ongoing clinical trials to determine the optimal patient population, sequence in treatment, and optimal role of these agents in ALL treatment. In addition, current results suggest that despite the efficacy of novel agents, allo-HCT remains relevant, and more studies will be needed to determine the optimal incorporation of these agents and allo-HCT into the treatment algorithm for ALL. 

Conclusion Allogeneic transplantation is associated with a strong GVL effect and remains an essential tool in the treatment of adult ALL. Despite the development of novel agents as well as pediatric styled protocols for adult patients, it remains a relevant modality of treatment and development of RIC protocols, and increasing use of alternative donors allows allo-HCT to be considered for more patients. A risk-adapted approach is needed for better selection of patients who would benefit from transplantation in CR1, and MRD is likely going to have a key role in this treatment algorithm.

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92. Gokbuget N, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120(9):1868– 1876. 93. Jabbour E, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015;16(15):1547–1555.