Curr Hematol Malig Rep DOI 10.1007/s11899-017-0371-4

ACUTE LYMPHOCYTIC LEUKEMIAS (K BALLEN, SECTION EDITOR)

Who Should Receive a Transplant for Acute Lymphoblastic Leukaemia? Rishi Dhawan 1 & David I. Marks 1

# Springer Science+Business Media New York 2017

Abstract Allogeneic haematopoietic cell transplantation continues to be an important curative therapy for acute lymphoblastic leukaemia (ALL). Traditionally accepted indications for allografting adult ALL patients need reevaluation in light of outcomes with paediatric-like intensive regimens. Minimal residual disease status and oncogenetics can be used for restratification of standard risk patients. A greater body of data on haematopoietic cell transplantation (HCT) outcomes from haploidentical and cord blood donor sources has been generated in recent years. In this review, we describe the indications for allografting adult ALL patients in first complete remission (CR1). Role of minimal residual disease (MRD) in optimising HCT for ALL is delineated. We also discuss how alternative donors, haploidentical and cord blood and reduced intensity conditioning make allografts more accessible to patients with high-risk ALL. Recent data on use of monoclonal antibodies and chimeric antigen receptor (CAR)-modified T cells in adult ALL patients are also reviewed.

Keywords Acute lymphoblastic leukaemia . Allogeneic haematopoietic cell transplantation . Minimal residual disease . Pre-transplant conditioning . Prognostic factors . Monoclonal antibodies This article is part of the Topical Collection on Acute Lymphocytic Leukemias * David I. Marks [email protected] Rishi Dhawan [email protected] 1

Adult BMT Unit, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, England, UK

Introduction Acute lymphoblastic leukaemia (ALL) is an aggressive neoplasm of immature lymphoid cells. It comprises 5% of all the adult lymphoid neoplasms [1]. In addition to blood, bone marrow and lymphoid tissue, it may involve sites such as the liver, testes and central nervous system. While 90% of adults attain remission with standard induction regimens, 30 to 60% relapse. Less than 10% of patients survive for 5 years after relapse [2–7] (Table 1). Recent data shows that paediatric or paediatricinspired regimens have better outcomes in young adults with ALL compared to historical adult ALL regimens [8–10]. Allogeneic haematopoietic cell transplantation (HCT) is the most potent therapy to consolidate remission in ALL [11]. Traditionally, sibling allograft in first complete remission (CR1) has been offered to adult ALL patients with certain adverse risk factors [12–17]. These high-risk factors include age >40 years, a high white blood cell (WBC) count at diagnosis, >4 weeks to achieve CR1 from the start of induction therapy and poor-risk cytogenetic abnormalities [18]. As paediatric regimens for treating adult ALL gain widespread acceptance, the dogma that most of the adult ALL patients need allografts is brought into question. Data from recent trials suggests that traditional poor prognostic markers need reevaluation as decision-making tools for allografting adults with ALL [8, 19••, 20–24]. In this review, we redefine the traditional indications for HCT in adult ALL vis-à-vis recent data on minimal residual disease (MRD) and oncogenetics. We also review transplant-conditioning regimens, donor options and the role of monoclonal antibody constructs in adult ALL patients who need HCT.

Curr Hematol Malig Rep Table 1 Indications for HCT in adult patients with ALL

Indications

Comments

References

• High WBC count at diagnosis

>30 × 109/L in BCP-ALL

[25] [15, 16]

• Poor-risk cytogenetics

>100 × 109/L in T-ALL Ph chromosome

[18]

Indications for HCT in first CR Conventional poor prognostic features • Age >40 years

t(4;11)(q21;q23) t(8;14)(q24.1;q32) Complex karyotype (5 or more chromosomal abnormalities) Low hypodiploidy/near triploidy • Failure to attain CR within 4 weeks of therapy MRD >1 × 10−4 after 2 courses of therapy

Unlikely to work with high levels of MRD i.e. >1 × 10−3

High-risk genetics

Heterogeneity in MRD time points in different trials e.g. post induction vs. post consolidation MRD IKZF1 deletion in BCP-ALL

[21]

Unfavourable NOTCH1/FBXW7; N/K-RAS; PTEN genetics in T-ALL Early T cell precursor ALL

[23, 24]

New ALL subtypes with poor prognosis

[17] [19••, 22, 67]

Ph-like ALL

BCP-ALL B cell precursor acute lymphoblastic leukaemia, CR complete response, MRD minimal residual disease

Current Indications for Allogeneic HCT in CR1 The traditional adverse risk factors for ALL are not synergistic and have a cumulative impact on prognosis. It is difficult to determine the impact of these adverse risk factors on the prognosis individually or in combination. Unlike acute myeloid leukaemia, where individually weighted risk factor-based scores are used as a therapeutic decision-making tool, the traditional risk factors for ALL have not been combined for individualised therapy [25, 26]. The early trials by the Centre for International BMT Research (CIBMTR) and the French Leucémie Aiguë Lymphoblastique de l’Adulte trials, LALA-87 and LALA94, showed a survival advantage for ALL patients with adverse risk factors who were treated on adult intensive regimens [25, 27–29]. However, the newer prospective trials incorporating paediatric induction regimens for adult ALL patients question the ability of the traditional adverse risk factors to identify patients that benefit from HCT. These trials show that response to therapy trumps conventional adverse risk factors [10, 22, 30]. Dhédin et al. recently published their experience with treating 522 transplant eligible adults (15- to 55-year age group) with Philadelphia chromosome-negative ALL in CR1 using paediatric-based Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) trial regimen [19••]. All patients had at least one traditional

adverse risk factor. Of the 282 patients who underwent HCT, 231 patients had either a matched sibling or 10/10 human leukocyte antigen (HLA)-matched unrelated donor (MUD). The rest underwent 9/10 MUD or umbilical cord blood donor transplant. They observed that HCT offered no relapse-free survival (RFS) and overall survival (OS) benefit to the HCT-cohort, defined as transplant eligible by the conventional adverse risk factors. MRD positivity (>10−3 at 6 weeks post induction) and lineage-specific oncogenetic markers (IKZF1 deletion in B-lineage ALL) were able to distinguish patients at high risk of relapse who would benefit from allograft in CR1. Post induction MRD status is a better risk stratification tool compared to conventional high-risk factors. Two caveats apply to the above discussion. While the French studies do demonstrate an improved outcome in adult patients treated with intensive paediatric regimens, they also show that adults >45 years have undue toxicity with these regimens. Secondly, the heterogeneity in MRD data from different trials precludes recommendation for MRD as decision-making tool in daily practice. The UK NCRI UKALL XIV trial is evaluating use of MRD in transplant decision-making. Allogeneic HCT should be considered from the day of the diagnosis in all patients <70 years with ALL to avoid delays in identifying donors and in pre-transplant evaluation [25].

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Ph-Positive Acute Lymphoblastic Leukaemia Around 20–30% of adult ALL patients harbour the adverse t (9;22) translocation, also known as Philadelphia (Ph) chromosome. Its incidence increases with age; 49% of patients over 40 years of age have this cytogenetic abnormality [31]. Phpositivity defines a poor prognostic subgroup in ALL, although the adverse risk is less clear with use of TKI. In the pre-imatinib era, 5-year relapse-free survival (RFS) and overall survival (OS) rates were <20 and <10%, respectively [32]. With the incorporation of tyrosine kinase inhibitors (TKI) in induction regimens, current CR rates are >90%. However, majority of the patients relapse without consolidative allograft [31]. With allogeneic HCT in CR1, the 5-year OS and RFS rates in Ph-positive ALL have increased to 46 and 38%, respectively [33]. The UKALLXII/ECOG2993 study compared outcomes of patients, within the imatinib-treated cohort, who underwent transplant (N = 82) to those who received chemotherapy alone (N = 39). Transplant patients had significantly better OS (50 vs. 19%), event-free survival (EFS) (46 vs. 14%) and RFS (69 vs. 18%) [34]. Hence, allogeneic HCT continues to be the only curative option for Ph-positive ALL, and all fit patients with donors should be offered this intervention. The Eur opea n Society for Blood and M arrow Transplantation (EBMT) has recently reported allogeneic HCT outcomes of a large cohort of Ph-positive patients from the post-imatinib era [33]. On multivariate analysis, matched sibling donor (MSD) transplants had better leukaemia-free survival (LFS) (hazard ratio (HR) 0.65; P = 0.014) and relapse incidence (RI) (HR 0.47; P = 0.001) compared to matched unrelated donor transplants. Donor choice had no effect on OS (HR 0.81; P = 0.27). There was no difference between reduced intensity conditioning (RIC) and myeloablative conditioning regimens with regards to OS (HR 0.95; P = 0.78) and LFS (HR 1.14; P = 0.48). The EBMT study also highlighted the significant effect of post-transplant TKI maintenance on overall survival, leukaemia-free survival and relapse incidence. However, the available comparative studies do not prove that post-transplant TKI improves outcomes. Unlike Ph-negative ALL, where MRD levels are well defined, the MRD levels in Ph-positive ALL patients are less well defined for risk stratification [12, 33, 35, 36]. Recent data shows that RIC approach and allografts from MUD and umbilical cord blood donors are feasible and carry significant survival benefit [33, 34].

Donor Choice The allograft benefits depend on transplant-related mortality (TRM), which in turn is affected by donor stem cell source. In early prospective trials highlighting better

outcomes with HCT in the high-risk ALL subset, randomization was based on sibling donor availability [11, 13, 14]. Apart from benefits of practicability, availability and cost, sibling donor allograft has advantages of decreased relapse incidence, lesser acute graft-versus-host disease (GVHD) and shorter interval between CR1 and transplant. [19••, 25, 33, 37]. However, only a third of the patients have a matched sibling donor [37, 38]. Early studies showed MUD allograft TRM of 40% [27]. With better supportive care and widespread availability of allele-level HLA-matching, the HCT outcome with MUD is now similar to matched sibling donor [37, 39]. In the study by Dhédin et al., MUD HCT in Ph-negative ALL patients in CR1 had 3-year OS of 70% and non-relapse mortality (NRM) as low as 18% [19••]. We recommend allograft in CR1 for all patients who are MRD-positive post induction/early consolidation and for those with high-risk oncogenetic markers, such as BCR/ABL1 translocation, MLL gene rearrangement, hypodiploidy and IKZF1 deletion. The aggressive upfront management in CR1 is justified by post-relapse 5-year survival of less than 10% [4]. We prefer to transplant after the first block of consolidation post remission. This gives time for administration of CNS prophylaxis. For relapsed patients, we prefer to transplant in second complete remission (CR2) at 6 weeks post induction initiation. Donor identification and stem cell procurement are the rate-limiting steps for ALL transplants. Delay in transplant invariably leads to additional consolidative chemotherapy and carries risks of relapse and toxicity. This may further affect transplant eligibility, give rise to complications during the transplant and increase non-relapse mortality [19••]. Hence, referral to the transplant team needs be made close to the diagnosis for the donor search to be timely. For relapsed patients, the short CR2 duration offers a narrow window of opportunity for allograft consolidation [25]. Cord Blood Allografts A third of patients do not have a suitable matched unrelated donor. Cord blood takes shorter search time and allows for greater HLA disparity. Almost all patients have a cord blood unit allograft source. Several retrospective registry-based studies have shown cord blood allograft outcomes to be comparable to MUD allografts [40–42, 43••, 44]. In the CIBMTR study, post-myeloablative conditioning, three-way comparison was made between MUD (7–8/8 HLA-matched peripheral blood or bone marrow) and cord blood allografts. Cord blood allografts were associated with higher incidence of graft failure but less GVHD compared to MUD allografts. There was no difference in TRM, LFS and OS between MUD and cord blood allografts. In a recent retrospective analysis,

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survival and relapse rates with cord blood allografts were found to be similar to those with HLA-matched donor allografts and superior to those with HLA-mismatched donor allografts. Interestingly, cord blood allografts were associated with lower post-transplant relapse rates compared to MUD allografts in patients with pre-transplant minimal residual disease [45].

Haploidentical Donor Allografts Almost all patients have a haploidentical family member as a potential donor. A haploidentical donor is readily available, motivated to donate and unlike cord blood units, provides easy accessibility for post transplant donor-derived cellular therapy. Early trials of haploidentical donor allografts involving ex-vivo T cell depletion were plagued by high transplantrelated mortality (TRM) due to poor immune reconstitution post transplant. New transplant strategies for haploidentical transplant have combined T cell replete allografts with post-transplant cyclophosphamide (PTCy) to eliminate alloreactive T cells while sparing other T cells leading to faster immune reconstitution. This approach is associated with low TRM and GVHD rates. However, early trials with PTCy have used it in combination with reduced intensity conditioning regimens in high-risk patients, and hence, high relapse rates are a major problem [46]. In a CIBMTR study of haploidentical donor allografts with PTCy in acute myeloid leukaemia, RIC was associated with lower non-relapse mortality, high relapse rates and comparable survival compared to myeloablative conditioning [47]. A similar study is needed for ALL patients. Another haploidentical donor transplant strategy developed by Beijing University uses a combination of GCSFmobilized peripheral blood and bone marrow T cell replete allografts together with intensive anti-thymocyte globulin (ATG)-based immunosuppression [48]. 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) [49]. Poor prognostic subgroup was defined as per the conventional high-risk factors. Haploidentical donor allograft patients were significantly younger (median age 26 vs. 38 years; P < 0.001) and had higher incidence of grade 2– 4 acute GVHD (28 vs. 13%; P = 0.008). Grade 3–4 acute GVHD was similar between the two donor groups (6 vs. 2%; P = 0.25). At 3 years, NRM (13 vs. 11%; P = 0.84), chronic GVHD (38 vs. 25%; P = 0.07), cumulative incidence of relapse (18 vs. 24%; P = 0.30), disease-free survival (DFS) (68 vs. 64%; P = 0.56) and OS (75 vs. 69%; P = 0.51) rates were similar between the two groups. The outcomes in this study require confirmation by other groups in different populations.

Conditioning Regimens Myeloablative Conditioning Allogeneic HCT is considered the most potent anti-leukaemic therapy for ALL. In the early studies that showed that HCT in CR1 improves survival in high-risk ALL, majority of patients received myeloablative conditioning [11, 19••, 27, 33]. While there is no ideal myeloablative conditioning regimen for HCT in ALL, cyclophosphamide (120 mg/kg) combined with total body irradiation (TBI) of 12 Gy in six fractions has been considered the standard myeloablative conditioning regimen due to its ability to target extramedullary sanctuary sites like central nervous system sites and testes. A CIBMTR study compared cyclophosphamide and 12-Gy TBI conditioning with the City of Hope group’s regimen, etoposide (60 mg/kg) and TBI of 13.2 Gy in nine fractions. The study showed a survival benefit of etoposide/TBI compared to standard cyclophosphamide/TBI. However, with TBI >13 Gy, outcomes were comparable between both the conditioning regimens [50]. Cyclophosphamide and etoposide have different toxicity profiles. While cardiotoxicity is the major limiting factor for cyclophosphamide, hepatotoxicity and mucositis are the major adverse effects associated with etoposide. Etoposide/TBI is a valid conditioning regimen for fit patients <40 years of age. This regimen has been shown to be particularly advantageous for patients in CR2 [50]. Methotrexate for GVHD prophylaxis accentuates the mucosal toxicity of etoposide. Recombinant human keratinocyte growth factor (palifermin) may ameliorate the severe mucositis associated with this regimen [25]. Busulfan is an effective apoptosis-inducing agent for lymphoblasts as well as for the myeloblasts [51]. Busulfan, in combination with cyclophosphamide, is an attractive alternative to the conventional Cy/TBI regimen for HCT in ALL. Busulfan-based conditioning spares the patients from longterm adverse sequelae of TBI: hypothyroidism, growth impairment, cataracts and late secondary cancers. Busulfan has an added advantage in that plasma drug-level monitoring can accurately target its therapeutic index and prevent over- or under-dosing. Kunter et al. reported the results of fludarabine and pharmacokinetic-targeted busulfan HCT in a retrospective study of 65 ALL patients in CR1 [52]. The outcomes of fludarabine/busulfan conditioning in this study (at 2 years, NRM 14%; RFS 61%; OS 65%; CIR 26%) were comparable to those of the conventional myeloablative TBI-based conditioning. Santrone and Kebriaei have reported similar findings with pharmacokinetic-targeted busulfan in combination with fludarabine [53] and clofarabine [54], respectively. Kebriaei, Marks, et al. in a recent CIBMTR-based retrospective cohort analysis of adult ALL patients undergoing HCT compared the outcomes of TBI-based myeloablative conditioning (N = 819

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Cy/TBI and Etoposide/TBI), with those of busulfan-based myeloablative conditioning regimens (N = 299; busulfan/cyclophosphamide, busulfan/melphalan, busulfan/fludarabine and busulfan/clofarabine). Although they observed a higher incidence of relapse and acute GVHD with busulfan-based conditioning, there was no difference with regards to TRM, chronic GVHD, DFS and 3-year OS between the two myeloablative regimens [55]. Thus, busulfan-based conditioning, with pharmacokinetic monitoring, is a reasonable alternative to TBI-based myeloablative conditioning. Reduced Intensity Conditioning With full-intensity HCT, transplant-related mortality increases with age. In a CIBMTR study on unrelated donor HCT in Phnegative ALL in CR1, the 5-year transplant-related mortality in patients more than 35 years of age was in the range of 33 to 58% [27]. Increased TRM with full-intensity HCT negates the gains in leukaemia-free survival in patients >40–45 years of age. Hence, allograft may not confer a survival benefit in patients beyond this age group [11, 25]. Reduced intensity conditioning (RIC) extends the opportunity of consolidative allogeneic HCT to older patients with high-risk ALL in CR1 who are not eligible for full-intensity HCT [27, 56]. The attenuated intensity of RIC causes less extensive tissue damage and consequent release of pro-inflammatory cytokines thereby decreasing the risk of graft-versus-host disease. Unlike full-intensity conditioning HCT, RIC relies more on graft versus leukaemia (GVL) effect for the curative potential of allogeneic HCT. The caveat is that leukaemia needs to be MRD-negative prior to HCT for the GVL to have a curative effect [25]. Few early studies of RIC HCT demonstrated 2-year OS of 30% and TRM of 4 to 27% in patients with advanced-stage ALL [57–59]. Marks et al. on behalf of CIBMTR examined the influence of conditioning regimen intensity on HCT outcomes in Ph-negative ALL [60]. They compared allograft (sibling or unrelated donor) outcomes of RIC (N = 93) with full-intensity conditioning (N = 1428). Patients receiving RIC were significantly older (median 45 vs. 28 years; P < 0.001). Although 43% of the patients in the RIC group were 50 years or older, there was no significant difference between the two groups in 3-year TRM (P = 0.92). Relapses were nonsignificantly increased in the RIC group (35 vs. 26%; P = 0.08). Age-adjusted survival was similar in both the conditioning groups (38 vs. 43%; P = 0.39). This study demonstrated that RIC allograft could be offered to elderly ALL patients with acceptable TRM and survival. In an EBMT registry-based study, Mohty et al. compared outcomes of 576 ALL patients in CR receiving RIC or fullintensity allografts [61]. All the patients were >45 years of age and received sibling donor HCT. In this study, gains made by RIC in lowering TRM (21 vs. 29%) were lost by increased

relapse rates (47 vs. 31%). Similar to the CIBMTR study, there was no difference in OS and LFS between the two conditioning groups. Full-intensity conditioning HCT should be considered for all fit high-risk ALL patients eligible for transplant as it is supported by robust long-term follow-up data. The lack of long-term relapse-free survival data precludes firm recommendations for RIC HCT. It is possible that late relapses may occur. RIC certainly has a role in consolidative HCT for elderly ALL patients. Retrospective registry-based data suggests that survival and NRM with RIC HCT in this age group is similar to those with full-intensity HCT in younger patients. UKALL 14 is prospectively studying the role of RIC HCT in elderly ALL patients who are otherwise ineligible for full-intensity HCT.

Integrating Novel Therapies Into Transplantation Although CR rates in adult ALL reach 85%, 3-year DFS and OS rates remain dismally low at 45% [62, 63]. Monoclonal antibodies, conjugated, unconjugated and bispecific, and genetically engineered cellular therapy in the form of chimeric antigen receptor (CAR)-modified T cells (CAR Ts) are an exciting advance in targeted immunotherapy against precursor B cell ALL [64, 65]. Pre-transplant Therapy to Improve HCT Outcomes Persistent or relapsed MRD after induction/consolidation chemotherapy in ALL carries an adverse prognosis [21, 22, 30]. It is postulated that adult ALL patients show a slower disease clearance compared to children [66]. In the UKALL XII study, of the 36 patients who received allograft in CR1, 13 were MRD-positive prior to HCT. In the German Multicentre Study Group for Adult ALL (GMALL) study, 21% patients in the standard-risk group and 39% patients in the high-risk group remained MRDpositive after the first consolidation (week 16) [67]. Only 47% of these patients were able to undergo HCT, presumably due to rapidly occurring relapses. Median remission duration in patients with MRD >10–3 was only 4.9 months. MRD response is an important milestone on the road to cure in the modern ALL therapy era. Undetectable or negative MRD prior to HCT carries a low risk of relapse after transplant [25, 68, 69]. Rituximab Around 30–40% of patients with precursor B cell ALL express CD20 at diagnosis. Most of the studies report CD20 expression in ALL as a poor prognostic marker and define its positivity as expression on >20% of the

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lymphoblasts [70–72]. The GRAALL group recently published findings from the multicentre randomized trial on adding rituximab (N = 104) to standard chemotherapy (N = 105) in Philadelphia-negative ALL patients [73•]. Only patients with CD20-positive disease received rituximab. Adding rituximab led to fewer relapses (subdistribution hazard ratio 0.52; 95% CI 0.31 to 0.89; P = 0.02), better EFS (hazard ratio 0.66; 95% CI 0.45 to 0.98; P = 0.04) and similar OS. More patients in the rituximab group underwent allogeneic HCT compared to those in the control group (34 vs. 20). Rituximab addition did carry an OS (74 vs. 63%; P = 0.018) benefit among patients who did not get allograft in CR1. It is possible that receiving ten additional rituximab doses contributed to their OS benefit [74]. Intriguingly, there was no significant difference in MRD response between the two groups. The optimal dose schedule of rituximab in ALL therapy needs to be defined in future studies in order to better determine its impact on post-transplant outcomes. Other studies have shown that incorporating rituximab into the standard ALL chemotherapy may lead to better disease control, decrease MRD and improve HCT outcomes [71, 75, 76].

Topp et al. recently reported a phase 3 randomized trial (TOWER study) comparing blinatumomab (N = 271) with conventional chemotherapy (N = 134) in relapsed or refractory ALL patients [79]. Blinatumomab salvage had higher response rate (46 vs. 28%; P = 0.001) and better survival (median OS 7.8 (95% CI 5.7, 10) vs. 4 months (95% CI 2.9, 5.4; P = 0.011)). Two cycles of blinatumomab cost $178,000 [80]; this may affect access to the drug worldwide.

Blinatumomab

Inotuzumab Ozogamicin

Blinatumomab is a monoclonal antibody with dual specificity against CD3 T cell receptor and CD19 on B cells. It works as a bispecific T cell engager (BiTE) engaging CD3-expressing T cells to lyse CD19-expressing leukaemic cells. In a phase 2 GMALL study involving 21 ALL patients with persistent or relapsed MRD, 80% of the evaluable patients (N = 20) achieved MRD negativity with four or less cycles of blinatumomab monotherapy [77]. Subsequent allograft was offered to all the eligible patients. Nine patients underwent allogeneic HCT. At a median 33-month follow-up, 60% patients were in CR; RFS was 65 and 61% in the transplant and non-transplant subgroups, respectively. Although initial studies evaluated blinatumomab in MRDpositive ALL without overt haematological disease, recent studies have reported its use in overtly relapsed or refractory ALL including post-transplant relapse. In a phase 2 multicentre study, two cycles of blinatumomab led to response in 81 (43%) of the 189 patients with relapsed or refractory ALL including 64 (34%) patients with post-HCT relapse [78•]. Thirty-eight responders had 50% or more blasts in the bone marrow at baseline. Of the 73 patients evaluated for MRD response, 60 (82%) were MRD-negative. Subsequent allograft was performed in 32 (40%) responders including 27 (52%) of the 52 patients who had not been transplanted previously. Cytokine release syndrome, infections and neurological toxicity were the major serious adverse events.

More than 90% of B-lymphoblasts express CD22 glycoprotein on their surface. Inotuzumab ozogamicin is an antiCD22 monoclonal antibody conjugated to the cytotoxic drug calicheamicin. Kantarjian et al. recently compared inotuzumab to standard chemotherapy in relapse or refractory adult ALL as a first or second salvage. The objective complete response rates were significantly better in inotuzumab group (81 vs. 33%; P < 0.001). Patients who responded to inotuzumab achieved flow MRD negativity (78 vs. 28%; P < 0.001), had a longer duration of remission (median 4.6 vs. 3.1 months; P = 0.03) and directly went on to consolidative allograft (41 vs. 11%; P < 0.001). Inotuzumab salvage therapy was associated with longer PFS (median 5 vs. 1.8 months; P < 0.001) and OS (7.7 vs. 6.7 months; P = 0.04; HR 0.77) compared to standard chemotherapy. Hepatic veno-occlusive disease (VOD) was the second most common serious adverse event (11 vs. 1%) after febrile neutropenia (12 vs. 18%) among the patients who received inotuzumab. Myeloablative conditioning was a possible contributory factor to this adverse event as 75% of the patients in this group received this conditioning. Of the 13 patients who received dual-alkylator-based conditioning, 5 developed VOD compared to 1 of the 21 patients who received a single-alkylator regimen. Use of targeted therapy, inotuzumab ozogamicin and blinatumomab, in the management of relapse or refractory adult ALL (including post-HCT relapses) is supported by

Post-transplant Relapse or Refractory Disease Due to modest results of salvage chemotherapy, relapsed or refractory ALL continues to be a major problem. Response rates with novel cytotoxic agents, such as clofarabine, nelarabine and liposomal vincristine are 17, 31 and 21%, respectively [81–83]. Gökbuget et al. evaluated nelarabine salvage therapy in 126 relapsed or refractory T-lymphoblastic leukaemia (T-ALL) patients, including 27 (21%) with post-HCT relapse [84]. One to two cycles of nelarabine led to CR in 36% of the patients. Subsequent allograft was realized in 80% of the responders including 55% with post-HCT-relapsed disease.

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randomized studies. Their response rates and CR durations are superior to those of conventional chemotherapy, including the novel cytotoxic agents. Their different specificities and adverse effect profiles can be exploited in tailoring their use to different clinical settings. Unlike blinatumomab, inotuzumab’s efficacy is not undermined by high disease burden in the bone marrow [78•, 85•]. MRD response following salvage with these antibodies needs to be consolidated with HCT for best long-term outcomes. However, it is unproven that blintumumab given to MRD-positive patients improves subsequent transplant outcomes.

CAR T cells

References Papers of particular interest, published recently, have been highlighted as • Of importance •• Of major importance 1.

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Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells recognise cancer cell in the context of an antibody. They have proved extremely effective against relapsed or refractory BCP-ALL with up to 70–90% response rates reported [86–88]. In vivo persistence of current secondgeneration CAR constructs depends partly on costimulatory domain, which can be either CD28 or 4-1BB. The University of Pennsylvania/Children’s Hospital of Philadelphia group reported 90% complete response rate with their CAR T cells [88]. These CAR constructs use 4-1BB as costimulatory domain and persist for long in vivo, up to 11 months in this study. The majority of the responders had sustained remissions without any further therapy. Investigators at the National Cancer Institute reported 70% complete response rate with their anti-CD19 CAR T cells which use CD28 as costimulatory domain [87]. These CAR T cells have shorter in vivo persistence, 2 months in this study. Almost all the responders in the NCI study received a consolidative allograft. Allogeneic transplantation will remain an important part of the therapy of ALL in adults but the indications remain controversial. The focus now is getting patients to transplant MRD-negative, without undue toxicity. RIC regimens are being investigated in prospective trials with good results. All stem cell sources have been used; there is convincing data for cord blood transplants and emerging data for haploidentical donors. Monoclonal antibodies are an important bridge to HCT. CAR T cells hold promise as definitive treatment for post-HCT-relapsed ALL. Compliance with Ethical Standards

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Conflict of Interest The authors declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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