Allogeneic stem cell transplantation in the era of novel therapies for acute lymphoblastic leukaemia

Med Clin (Barc). 2019;153(1):28–34

www.elsevier.es/medicinaclinica

Review

Allogeneic stem cell transplantation in the era of novel therapies for acute lymphoblastic leukaemia夽 Pere Barba a,∗ , Izaskun Elorza b a b

Servicio de Hematología, Hospital Universitario Vall d’Hebron-Universitat Autónoma de Barcelona, Barcelona, Spain Unidad de Trasplante de Progenitores Hematopoyéticos Pediátrica, Hospital Universitari Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain

a r t i c l e

i n f o

Article history: Received 31 July 2018 Accepted 9 January 2019 Available online 14 June 2019 Keywords: Allogeneic transplantation Acute lymphoblastic leukaemia Immunotherapy Monoclonal antibodies CAR-T

a b s t r a c t Immunotherapy is changing the treatment of acute lymphoblastic leukaemia (ALL) in adults and children. However, regardless of these new therapies, allogeneic hematopoietic cell transplantation (allo-HCT) still play a key role in the treatment of ALL, although it is uncertain how these new therapies will impact on the transplant procedure and indications. This article reviews the indications of allo-HCT for children and adults diagnosed with ALL, the different sources and conditioning regimens for transplantation as well as the role of measurable residual diseases pre- and post-HCT in the era of the new therapies for ALL. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,

El trasplante alogénico de progenitores hematopoyéticos en la era de las nuevas terapias en la leucemia linfoblástica aguda r e s u m e n Palabras clave: Trasplante alogénico Leucemia linfoblástica aguda Inmunoterapia Anticuerpos monoclonales CAR-T

La inmunoterapia está cambiando profundamente el tratamiento de la leucemia linfoblástica aguda (LLA) infantil y del adulto. Sin embargo, a pesar de todos los avances, el trasplante alogénico de progenitores hematopoyéticos (alo-TPH) sigue siendo un pilar fundamental en su tratamiento. Cómo van a modificar estas nuevas terapias la indicación y el procedimiento de trasplante, resulta todavía incierto. En el presente artículo se discuten las indicaciones de TPH en la LLA infantil y del adulto, las posibles fuentes de donantes y acondicionamiento, así como el papel de la enfermedad residual medible en el contexto de la nueva era de tratamientos en el campo de la LLA. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,

Introduction Allogeneic haematopoietic stem cell transplantation (alloHSCT) offers patients who suffer from acute lymphoblastic leukaemia (ALL) with high risk of relapse better survival compared to conventional chemotherapy.1 The optimisation of the transplant procedure and the greater facility to obtain compatible unrelated donors have meant that this therapy can today be offered to a

夽 Please cite this article as: Barba P, Elorza I. El trasplante alogénico de progenitores hematopoyéticos en la era de las nuevas terapias en la leucemia linfoblástica aguda. Med Clin (Barc). 2019;153:28–34. ∗ Corresponding author. E-mail address: [email protected] (P. Barba). ˜ S.L.U. All rights reserved. 2387-0206/© 2019 Elsevier Espana,

greater number of patients, achieve higher disease-free survival (DFS) results and obtain lower transplant-related mortality (TRM) rates.2 The field of ALL has undergone a real revolution in recent years. A greater biological knowledge of the disease has resulted in the appearance of numerous and innovative treatments, many of them based on immunotherapy.3 These treatments include simple, conjugated or bispecific monoclonal antibodies and chimeric antigen receptor T-cells (CAR-T) for CD19 positive B-precursor ALL. While it seems evident that these new therapies will directly influence the treatment of ALL, indications and implementation of allo-HSCT and current uncertainties regarding how exactly that will occur, far exceeds what we do know for certain. On this basis, the purpose of this review is to summarise what we know about the role of haematopoietic stem cell transplantation (HSCT) in ALL and

P. Barba, I. Elorza / Med Clin (Barc). 2019;153(1):28–34

29

Table 1 Indications of allogeneic transplantation in adult acute lymphoblastic leukaemia depending on the clinical situation according to the European Society for Bone and Marrow Transplantation (EBMT). HLA 10/10a

Alternative donorb

Not recommended

Not recommended

Clinical option

Clinical option

Standard

Standard

Standard

Standard

Standard Not recommended Standard

Standard Not recommended Standard

Ph positive ALL in CR1 with detectable MRD

Clinical option

Clinical option

Ph positive ALL in CR2

Clinical option

Clinical option

Ph positive or negative ALL in refractoriness

Not recommended

Not recommended

Not recommended Standard

Not recommended Clinical option

ALL in CR2

Standard

Clinical option

ALL in CR >2

Standard

Clinical option

Indication Adult patients Ph negative ALL in CR1, good clearance of MRD and no genetic factors of poor prognosis Ph negative ALL in CR1, good clearance of MRD and with genetic factors of poor prognosis Ph negative ALL in CR1, slow clearance of MRD Ph negative ALL in incipient relapse

Ph negative ALL in CR2 Ph negative ALL in refractoriness Ph positive ALL in CR1 without detectable MRD

Paediatric patients Low-risk ALLc in CR1 High riskc ALL in CR1

Observations

In the case of alternative donors, consider the risk of theoretical TRM Try to perform HSCT in negative MRD or at least as low as possible As far as possible, perform some non-toxic treatment to proceed to HSCT in MRD negative

In patients without donor or at high risk of TRM, ABSCT and subsequent maintenance with TKI can be considered. Ideally in a clinical trial If possible, change TKI to deepen the response prior to HSCT Standard, if for some reason HSCT was not performed in CR1

Good results with chemotherapy. Use of all sources and donors. Use the one that is available at the optimum time for the transplant according to the centre’s protocol Try to perform HSCT in negative MRD or at least as low as possible As far as possible, perform some non-toxic treatment to proceed to HSCT in MRD negative

a

Family or unrelated donor. Alternative donor: HLA 9/10, haploidentical or umbilical cord blood. c Categories based on the number of leukocytes at diagnosis, cytogenetics, molecular markers and time to remission. MRD: measurable residual disease; HLA: human leucocyte antigen; TKI: tyrosine kinase inhibitors; ALL: acute lymphoblastic leukaemia; TRM: transplant related mortality; Ph: Philadelphia; CR: complete response; ABSCT: autologous peripheral blood stem cell transplant; HSCT: hematopoietic stem cell transplantation. Authors’ recommendations based on EBMT transplantation indications (Sureda et al. Bone Marrow Transplantation; 2015). b

attempt to predict a possible direction on the positioning of this procedure in the near future, in both adult and paediatric patients.

Transplantation indications The indications for transplantation in adults differ significantly from those of paediatric patients. Because current indications for auto-HSCT in ALL are very residual, we will only discuss indications for allo-HSCT, except when explicitly mentioned. Table 1 shows current indications for allo-HSCT according to the European Bone Marrow Transplant (EBMT) group, while Table 2 contains indications from the PETHEMA group (for adult patients) and SHOPPETHEMA 2013 (for paediatric patients), which are the cooperative groups in Spain.

Adult patients Despite achieving complete remissions in up to 90% of patients, relapses in adult patients are common, affecting up to 50% of patients who do not receive allo-HSCT.4 The prognosis of these relapsed patients is, to date, highly unfavourable.5 This is why alloHSCT remains a fundamental pillar in the treatment of ALL, either for first complete remission (CR1) or in patients with relapsed or refractory disease. Currently, ALL is the second most frequent indication for allo-HSCT in Europe and North America.6

Allogeneic transplantation in first complete remission Several groups analysed the role of allo-HSCT in ALL in first remission (CR1). Most prospective comparative studies were developed in the late twentieth century and were based on an genetic randomisation, so that only patients with a histocompatible donor received allo-HSCT in CR1.1,7 These studies showed that allo-HSCT was effective in reducing the risk of relapse, with greater benefit in standard risk ALL.1 Evidence of the graft versus leukaemia effect in ALL has been reinforced in positive studies with infusion of donor lymphocytes and with the association of graft versus host disease (GvHD) development and a lower relapse rate.8 The fact that a significant proportion of patients who did not receive an allo-HSCT in CR1 managed to achieve lasting remissions led several cooperative groups to improve the selection criteria of candidate patients. These studies, many based on treatment protocols inspired by paediatric regimens, found that patients with a good clearance of measurable residual disease (MRD) could achieve durable remissions during treatment (usually weeks 4–6 and weeks 16–18) without an allo-HSCT in CR1.4 MRD can be determined through detection of leukaemic phenotype by flow cytometry and/or determination of immunoglobulin receptors/T cell by PCR techniques. The sensitivity of PCR techniques is higher than that of cytometry, although both have been shown to be feasible in clinical practice with high concordance between results.9 On this basis, the current trend in most European cooperative groups is to reserve allo-HSCT in CR1 for at-risk patients, mainly those with poor clearance of MRD and/or with genetic criteria of poor prognosis at diagnosis, such as t(9;22) (q34q11), low hypodiploidy/almost

30

P. Barba, I. Elorza / Med Clin (Barc). 2019;153(1):28–34

Table 2 Indications for allogeneic transplantation in acute lymphoblastic leukaemia in highrisk adult (PETHEMA AR-2011 Protocol) and paediatric patients (LAL/SHOP-Pethema 2013 Protocol). Adult patients First referral No cytological complete remission after induction (day +28) or complete remission with MRD > 10−3 measured by flow cytometry MRD > 10−4 measured by flow cytometry after block B3 consolidation Emergence of positive MRD at some point in the follow-up beyond block B3 consolidation Second referral All patients who are transplant candidatesa Paediatric patients First referral No cytomorphologic complete remission after induction A (day +33), confirmed by flow cytometry MRD > 10−2 after induction A (day +33) and MRD > 10−3 at day +78 (prior to consolidation or at block HR-1) At t(4;11) with MRD > 10−3 at day +78 (prior to block HR-1) In hypodiploidy (< 44 chromosomes) with MRD > 10−3 at day +78 (prior to block HR-1) In T-ALL with poor response to prednisone and MRD > 10−3 at day +78 (prior to block HR-1) In HR patients if MRD is persistently positive > 10−4 (after third block HR-3) Second referral Relapse of ALL phenotype T Early medullary relapse of precursor-B ALL (<36 months from diagnosis) Early extramedullary relapse of precursor-B ALL (<18 months from diagnosis) Late relapse of precursor-B ALL with poor response to chemotherapy a This is a recommendation. The protocol does not specifically include patients in CR2. HR: high risk; MRD: measurable residual disease; ALL: acute lymphoblastic leukaemia.

aneuploidy and complex karyotype. At the molecular level, deletions of IKZF-1, rearrangements of KMT2A, alterations of CRLF-2 and of the RAS pathway (KRAS, NRAS and PTPN1), as well as Philadelphia-like subtype (in which some of the mentioned alterations are included) also suggest a bad prognosis.10 In T-ALL, the absence of NOTCH-1 mutations and deletions of CDKN2A/B are also considered to have poor prognosis.3 However, there is no consensus on whether these changes should mean, by themselves, indication for transplantation in Ph negative B-ALL. Classic clinical prognostic factors, such as leukocytosis or CNS infiltration, are not considered, by themselves, criteria to indicate allo-HSCT, since genetics and MRD are attributed a greater risk of relapse and, therefore, indication of HSCT.11 Allogeneic transplantation in second complete remission Currently available data show that the prognosis of patients with relapsed ALL is very unfavourable. Although these patients are likely to achieve a second complete remission (CR2) (30–50%),5 successive relapses are very common, which is why allo-HSCT is considered the only curative option for these patients after reaching a complete remission (CR). Paediatric patients Current chemotherapy protocols offer paediatric patients with ALL an 80% chance of recovery.12 The group of patients with highrisk, refractory or in early spinal relapse ALL (10% of all cases) have a DFS of less than 40% and are considered candidates for allo-HSCT.13 High-risk patients are considered those who do not achieve remission with induction treatment, those who have detectable MRD after induction, and in whom a positive MRD is detected during

treatment. MRD thresholds and the moment it is assessed vary according to the different study groups.12–14 Allogeneic transplantation in first complete remission The factors determining which patients are assigned to a more or less intense treatment group and indication of allo-HSCT in CR1 are clinical presentation, genetics and response to treatment.12 The indication for transplantation in CR1 is reserved for patients who have responded poorly to treatment or a persistence of MRD. Study moments and MRD thresholds have been agreed on that predict a high risk of relapse and which are used for the indication of transplant. Slow responders, assessed at day seven and 14, can be rescued with intensive treatment in 70% of cases; however, those who do not achieve remission on day 28 have a 40% DFS, making them candidates for allo-HSCT in CR1.13 In late moments of treatment, postconsolidation, patients with positive MRD are considered suitable candidates for allo-HSCT in CR1. Indication for allo-HSCT in CR1 is still being debated in patients with early T-cell precursor ALL, infants under six months with MLL gene rearrangements and patients with hypodiploidy karyotype, since it is disease with high resistance to chemotherapy.15 A summary of the results of allo-HSCT in paediatric patients in CR1 are: an incidence of relapse rate of 10–20%, TRM 10–15% and DFS 65–80%.16 Allogeneic transplantation in second complete remission. Relapse occurs in 15–20% of children who achieve remission after induction. The duration of the first remission influences the likelihood of long-term survival, such that early relapse (within six months after treatment) has less than a 40% survival rate with chemotherapy alone.14 Extramedullary late and early relapses present good DFS results when chemotherapy is associated with local treatment. Allo-HSCT in CR2 mainly benefits children with early medullary relapse and those who, even when late, show poor response to treatment. The results of allo-HSCT in paediatric patients in CR2 are: post-HSCT relapse incidence rate 20–40%, TRM 15–25% and DFS 40–50%.17 Children who receive transplants during successive remissions have very poor results even after receiving allo-HSCT, with a DFS of approximately 30%.14 Conditioning regimes Total body irradiation (TBI) at doses of 12 Gy combined with cyclophosphamide at a dose of 60 mg/kg/day (two days) is considered the standard conditioning regimen for this patient group. The TBI dose is fractionated into six sessions (two sessions per day), as a reduced toxicity is observed in the short- and long-term than when it is administered as a single dose. The survival benefit of radiotherapy in paediatric patients has been demonstrated18 ; however, and despite its wide use, evidence in adults is scarcer.19 Some groups have evaluated other strategies with radiation therapy at lower doses (400 cGy) or without radiation therapy, and their results have been satisfactory and comparable to standard conditioning.20,21 In paediatric patients younger than three, with a higher risk of secondary neoplasms and damage to neurological, endocrine and growth development, radiotherapy is replaced by intravenous busulfan, at a dose according to the patient’s weight and preferably by plasma levels.22 There is evidence that regimens without radiotherapy do not result in a worse control of the central nervous system disease compared to radiation therapy.23 The introduction of reduced intensity (RI) regimens facilitated older patients and those with comorbidities’ access to HSCT. There are no randomised studies analysing the role of RI conditioning in ALL. Retrospective studies have shown that this approach is viable in patients with ALL who are not candidates for alloHSCT with conventional conditioning.24,25 However, some (though not all) retrospective comparative studies have questioned the

P. Barba, I. Elorza / Med Clin (Barc). 2019;153(1):28–34

benefit of RI allo-HSCT in elderly patients, since the decrease in leukaemic relapse offered by allo-HSCT could not be compensated by the increase of the TRM.26 The benefit of RI allo-HSCT in paediatric patients is limited; lower DFS than standard conditioning is offered,27 but this is more an option for patients with accumulated morbidity and/or in second transplants. The introduction in recent years of new drugs in the chemotherapy regimen prior to HSCT should be considered when evaluating possible post-HSCT toxicities. Patients who have received rescue treatment with inotuzumab ozogamicin (InO) prior to transplantation have a higher risk of sinusoidal obstruction syndrome (SOS). In adults, the incidence can reach 11%.28 The risk is especially high in patients receiving two alkylating agents during conditioning, such that avoiding this combination is prudent.29 The use of defibrotide as an SOS prophylaxis has proven useful in paediatric patients at high risk,30 and is currently being investigated in adult patients. The use of SOS prophylaxis in patients previously treated with InO could be considered while waiting for the results of ongoing clinical trials (NCT02851407), although there is not yet any definitive evidence for it. Donor sources and types All progenitor sources (bone marrow [BM], peripheral blood [PB] and umbilical cord blood [UCB]) commonly used for other indications, as well as donor types, have proven to be useful in ALL. The preferred source for paediatric patients is BM, due to its lower incidence of chronic GvHD and long-term TRM compared to PB,31 while in adults the most commonly used source is PB. In the paediatric field, UCB is a progenitor source for approximately 85–95% of patients and has the advantages of rapid accessibility, less restriction due to HLA compatibility, greater ethnic variability and adequate cellularity for paediatric weight.32 Paediatric groups with UCB transplantation experience obtain results similar to BM33 in ALL. UCB has also been used with promising results in adult patients,34 although its use is currently decreasing35 and being substituted by haploidentical transplantation. There is less experience with haploidentical transplantations, especially in a post-HSCT cyclophosphamide modality, but the published data seem satisfactory.36 Experiences in haploidentical transplantation in paediatric patients is mainly based on ex vivo depletion platforms. Currently the depletion of TCR lymphocytes ␣␤ allows infusion of haematopoietic progenitors, NK cells and T lymphocytes ␥␦ with potent anti-infective and antileukaemic activity, reaching immune reconstitution earlier.37 In summary, in light of the published data, the fact that indication for transplantation is for an ALL should not modify the choice of source or type of donor in a particular transplantation centre. Moreover, once the patient is in an optimal situation for the transplant, one should proceed with the best donor available at that time without delaying the transplantation to search for an ideal donor, since this delay could lead to relapse and in turn ineligibility for allo-HSCT. Philadelphia positive B-acute lymphoblastic leukaemia Positive Philadelphia (Ph+) B-ALL is, also from an HSCT perspective, a peculiar entity. Because of its high risk of relapse in patients treated only with chemotherapy and tyrosine kinase inhibitors (TKI), the use of allo-HSCT in CR1 has been established. The majority of studies into adults have shown long-term survival greater than 40% in patients receiving allo-HSCT in CR1.38,39 The role of MRD positive prior to allo-HSCT is also important in B-ALL Ph+, and several studies have shown a worse prognosis in patients receiving allo-HSCT with positive MRD.40,41 In fact, some protocols

31

include an intensification or change of TKI to intensify response prior to transplantation and deepen the clearance of the MRD.38 Using TKI in post-HSCT, either as a universal treatment or as an anticipated treatment in the presence of detectable MRD, is recommended. However, there is no consensus regarding which of these two approaches is best, nor the choice of TKI or the duration of posttransplantation treatment. Importantly, TKIs have a non-negligible toxicity in post-HSCT,42 especially in haematologic patients, so its administration is not recommended for at least the first 30 days after transplantation. Evidence has recently appeared that some patients with Ph+ B-ALL (especially those with complete molecular remission) can achieve durable responses with maintenance using new TKI, preceded or not with auto-HSCT. In this regard, the French group demonstrated an OS of 80% in patients who had received a auto-HSCT and maintenance treatment with imatinib,42 and the Italian group recently showed43 promising long-term survival with chemotherapy and maintenance with ponatinib in elderly patients who were not candidates for allo-HSCT. It may be possible that new TKIs will mean that certain patients with Ph+ B-ALL will not have to undergo allo-HSCT in the future, but such approaches should only be considered under research conditions for now. Outside trail and research contexts, allo-HSCT remains the standard for adult patients in CR1.38 In paediatric patients, Ph positive ALL accounts for only 5% of all ALL. The addition of TKI to conventional chemotherapy has allowed similar results to be achieved in patients with Ph negative and positive ALL,44 such that the indication for allo-HSCT in CR1 is reserved for patients with poor response to first-line treatment.45 In patients with relapsed or refractory Ph positive ALL, responses to new monoclonal antibodies such as blinatumomab or inotuzumab ozogamicin28,43 and with CAR T-cells46 have been described. However, these therapies have not yet modified indication for HSCT in patients with Ph positive ALL and its use is limited to patients with post-transplantation relapse or in a research context, not candidates for transplantation.47

Prognostic factors. The role of measurable residual disease In patients with ALL who are candidates for allo-HSCT, the presence of MRD during the chemotherapy treatment prior to transplantation seems to have an impact on prognosis. Several groups11,48,49 (although not all)50 have demonstrated the importance of this factor, either through flow cytometry or PCR techniques. Specifically, the Italian group demonstrated that patients with MRD > 10−3 at week 16 and/or 22 had worse results after allo-HSCT, with a lower overall survival of 20% and an relapse incidence rate within six years of 64%.11 Others, like the French group, did not observe these differences when they analysed MRD in an earlier period (week six).50 However, in the French study this analysis was not included as a primary objective and performed only in a subset of patients (only 54 patients received allo-HSCT with MRD ≥ 10−3 ), so these results should be interpreted with caution. In children, the impact of MRD prior to transplantation has been shown: a DFS of 20% was observed in patients with MRD > 10−4 and of 74% in those with undetectable MRD by flow cytometry.51 In this study by the EUROCORD group, the development of acute GvHD was associated with a lower risk of relapse, especially in the positive MRD pre-HSCT group. Given that the positive MRD pre-HSCT group had a lower DFS than those in the negative MRD group, the need to use pre-HSCT immunotherapy treatment was considered,52,53 which could reduce MRD and thus achieve better post-HSCT results. However, there is currently no evidence of whether this strategy is

32

P. Barba, I. Elorza / Med Clin (Barc). 2019;153(1):28–34

more effective than performing a direct allo-HSCT with detectable MRD. Regarding post-HSCT MRD, its usefulness as a predictive factor of relapse has been demonstrated. A study by the international BFM group showed that detection of MRD measured by flow cytometry after transplantation had an 87% success rate of predicting leukaemic relapse within two months.54 The determination of chimerism is complementary to the study of post-transplant MRD and the absence of a complete donor chimaera has been associated with an increased risk of relapse.55

Relapse after allogeneic transplantation If paediatric patients who relapse after allo-HSCT go into remission and reach a second HSCT, they have an DFS of 30%.56 As mentioned, the most important prognostic variable of DFS in a second HSCT is the duration of the first remission.14 Other better DFS factors include the absence of MRD and not having presented GvHD during the first HSCT. Survival results after a second HSCT do not include the group of patients who do not reach a second HSCT. Approximately 30% of the patients who relapse pass away from refractory disease or due to the high toxicity associated with the aggressiveness of the rescue treatments, given that they are often patients with frequent morbidities and accumulated toxicity. Recent studies suggest that certain paediatric patients with early relapse post-HSCT, comorbidities or persistence of MRD would be candidates for immunotherapy before a second HSCT or even as replacement therapy for HSCT.57 Clinical trials have shown that therapy with CAR-T anti-CD19 is very effective in children with CD19+ ALL who have relapsed after allo-HSCT, achieving complete remissions with a seemingly lower toxicity than conventional treatments, especially in patients with low tumour load.53 Treatment with blinatumomab or InO for patients with postHSCT relapse may be another alternative therapy to traditional chemotherapy.28,58

Future perspectives in the era of new treatments Immunotherapy is changing the way we treat ALL. Whether these advances will lead to changes in indications or even in conditioning treatments for these patients is still to be seen. Some recent studies have suggested46 that certain therapies, especially CART, might replace HSCT and lead to a decrease in transplantations to treat this disease. In this sense, long-lasting remissions have been observed in patients with relapsed ALL after administering CAR T-cells, even without a subsequent allo-HSCT.59 Conversely, these new tools may improve the treatment of patients who are refractory or relapsing and allow allo-HSCT to treat patients who are unable to be treated with HSCT. In addition, CAR-T can clarify the presence of MRD with a much lower toxicity than conventional chemotherapy and treat the patient with allo-HSCT and with lower morbidities and, therefore, lower toxicity. The new monoclonal antibodies, such as blinatumomab or InO, among others, have shown the ability to induce complete quality responses, with very low or even undetectable MRD, in a percentage of patients significantly higher than conventional chemotherapy,58,60 although these responses are usually shortlived and a subsequent allo-HSCT is required. Whether these and other monoclonal antibodies in first-line treatment can reduce relapses to initial treatment and thus decrease the number of patient candidates for transplantation is yet to be confirmed. Finally, it is important to note that most treatments based on immunotherapy today are only effective against B-lineage ALL. This

is why there are not as many prospects for changes in HSCT indication for T-ALL, at least in the short term. Conclusions Despite all the advances in the management of patients with ALL, allo-HSCT remains a fundamental pillar of treatment. HSCT achieves lasting responses in patients with clinical and biological characteristics of poor prognosis and in patients with relapse or refractory disease. The continuous optimisation of the procedure, improvements in the selection of transplantation candidates, the greater availability of donors at the optimal time (thanks, mainly, to haploidentical transplants) and the use of therapies to prevent relapse of the underlying disease, should all facilitate further improvement of the prognosis of these patients beyond what we have already seen in the last decades in paediatric patients and, to a lesser extent, in adult patients. Patients with positive MRD prior to transplantation may be candidates for immunotherapy with CAR-T or monoclonal antibodies with the objective of improving DFS. Another group that can benefit from these therapies is those patients who relapse after an allo-HSCT, especially those that present early relapse and/or associate morbidities and/or refractory disease. The intention of immunotherapy in these cases is to control the disease with as little toxicity as possible, and in some cases to achieve prolonged remissions, when faced with the impossibility of performing a second HSCT. And the possibility that these therapies in themselves may be curative for certain patients is currently under study. Funding PB received funding from the Carlos III Institute of Health FIS16/01433 project and a PERIS 2018–2020 grant from the Generalitat de Catalunya (BDNS357800). Conflict of interest PB has received funding for advice and/or travel from Amgen, Pfizer, Novartis, Jazz Pharmaceuticals and Shire, without affecting the content of this review. IE declares no conflict of interest. References 1. Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111:1827–33. 2. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–101. 3. Ribera JM, Vives S. Acute lymphoblastic leukemia in adults: steps ahead. Med Clin (Barc). 2017;149:119–21. 4. Ribera JM, Oriol A, Morgades M, Montesinos P, Sarrà J, González-Campos J, et al. Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol. 2014;32:1595–604. 5. Oriol A, Vives S, Hernández-Rivas JM, Tormo M, Heras I, Rivas C, et al. Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group. Haematologica. 2010;95:589–96. 6. Passweg JR, Baldomero H, Bader P, Bonini C, Duarte RF, Dufour C, et al. Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2017;52:811–7. 7. Cornelissen JJ, van der Holt B, Verhoef GE, van’t Veer MB, van Oers MH, Schouten HC, et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood. 2009;113:1375–82. 8. Terwey TH, le Duc TM, Hemmati PG, le Coutre P, Nagy M, Martus P, et al. NIH-defined graft-versus-host disease and evidence for a potent graft-versus-

P. Barba, I. Elorza / Med Clin (Barc). 2019;153(1):28–34

9.

10. 11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

leukemia effect in patients with acute lymphoblastic leukemia. Ann Oncol. 2013;24:1363–70. Garand R, Beldjord K, Cavé H, Fossat C, Arnoux I, Asnafi V, et al. Flow cytometry and IG/TCR quantitative PCR for minimal residual disease quantitation in acute lymphoblastic leukemia: a French multicenter prospective study on behalf of the FRALLE, EORTC and GRAALL. Leukemia. 2013;27:370–6. Roberts KG. Genetics and prognosis of ALL in children vs adults. Hematology Am Soc Hematol Educ Program. 2018;2018:137–45. Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, et al. Different molecular levels of post-induction minimal residual disease may predict hematopoietic stem cell transplantation outcome in adult Philadelphia-negative acute lymphoblastic leukemia. Blood Cancer J. 2014;4:e225. Schultz KR, Pullen DJ, Sather HN, Shuster JJ, Devidas M, Borowitz MJ, et al. Riskand response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood. 2007;109: 926–35. Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366:1371–81. Sun W, Malvar J, Sposto R, Verma A, Wilkes JJ, Dennis R, et al. Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study. Leukemia. 2018, http://dx.doi.org/10.1038/s41375-018-0094-0 [Epub ahead of print]. Mann G, Attarbaschi A, Schrappe M, de Lorenzo P, Peters C, Hann I, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood. 2010;116:2644–50. Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, et al. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors—the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015;33:1265–74. Eapen M, Raetz E, Zhang MJ, Muehlenbein C, Devidas M, Abshire T, et al. Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood. 2006;107:4961–7. Page KM, Labopin M, Ruggeri A, Michel G, Diaz de Heredia C, O’Brien T, et al. Factors associated with long-term risk of relapse after unrelated cord blood transplantation in children with acute lymphoblastic leukemia in remission. Biol Blood Marrow Transplant. 2017;23:1350–8. Marks DI, Forman SJ, Blume KG, Pérez WS, Weisdorf DJ, Keating A, et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant. 2006;12:438–53. Kröger N, Bornhäuser M, Stelljes M, Pichlmeier U, Trenschel R, Schmid C, et al. Allogeneic stem cell transplantation after conditioning with treosulfan, etoposide and cyclophosphamide for patients with ALL: a phase II-study on behalf of the German Cooperative Transplant Study Group and ALL Study Group (GMALL). Bone Marrow Transplant. 2015;50:1503–7. Kebriaei P, Anasetti C, Zhang MJ, Wang HL, Aldoss I, de Lima M, et al. Intravenous busulfan compared with total body irradiation pretransplant conditioning for adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2018;24:726–33. Gabriel M, Shaw BE, Brazauskas R, Chen M, Margolis DA, Sengelov H, et al. Risk factors for subsequent central nervous system tumors in pediatric allogeneic hematopoietic cell transplant: a study from the center for international blood and marrow transplant research (CIBMTR). Biol Blood Marrow Transplant. 2017;23:1320–6. Hamidieh AA, Monzavi SM, Kaboutari M, Behfar M, Esfandbod M. Outcome analysis of pediatric patients with acute lymphoblastic leukemia treated with total body irradiation-free allogeneic hematopoietic stem cell transplantation: comparison of patients with and without central nervous system involvement. Biol Blood Marrow Transplant. 2017;23:2110–7. Mohty M, Labopin M, Volin L, Gratwohl A, Socié G, Esteve J, et al. Reducedintensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood. 2010;116:4439–43. Marks DI, Wang T, Pérez WS, Antin JH, Copelan E, Gale RP, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood. 2010;116:366–74. Barba P, Martino R, Martinez-Cuadron D, Olga G, Esquirol A, Gil-Cortés C, et al. Impact of transplant eligibility and availability of a human leukocyte antigen-identical matched related donor on outcome of older patients with acute lymphoblastic leukemia. Leuk Lymphoma. 2015;56: 2812–8. Verneris MR, Eapen M, Duerst R, Carpenter PA, Burke MJ, Afanasyev BV, et al. Reduced-intensity conditioning regimens for allogeneic transplantation in children with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2010;16:1237–44.

33

28. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740–53. 29. Kantarjian HM, DeAngelo DJ, Advani AS, Stelljes M, Kebriaei P, Cassaday RD, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol. 2017;4: e387–98. 30. Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012;379:1301–9. 31. Simonin M, Dalissier A, Labopin M, Willasch A, Zecca M, Mouhab A, et al. More chronic GvHD and non-relapse mortality after peripheral blood stem cell compared with bone marrow in hematopoietic transplantation for paediatric acute lymphoblastic leukemia: a retrospective study on behalf of the EBMT Paediatric Diseases Working Party. Bone Marrow Transplant. 2017;52:1071–3. 32. Gluckman E, Rocha V. Cord blood transplantation: state of the art. Haematologica. 2009;94:451–4. 33. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369:1947–54. ˜ 34. Pinana JL, Sanz J, Picardi A, Ferrá C, Martino R, Barba P, et al. Umbilical cord blood transplantation from unrelated donors in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2014;99:378–84. 35. Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R, et al. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018;53:1139–48. 36. Srour SA, Milton DR, Bashey A, Karduss-Urueta A, al Malki MM, Romee R, et al. Haploidentical transplantation with post-transplantation cyclophosphamide for high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2017;23:318–24. 37. Airoldi I, Bertaina A, Prigione I, Zorzoli A, Pagliara D, Cocco C, et al. ␥␦ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-␣␤+/CD19+ lymphocytes. Blood. 2015;125:2349–58. 38. Ribera JM, García O, Montesinos P, Brunet S, Abella E, Barrios M, et al. Treatment of young patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia using increased dose of imatinib and deintensified chemotherapy before allogeneic stem cell transplantation. Br J Haematol. 2012;159:78–81. 39. Bassan R, Rossi G, Pogliani EM, di Bona E, Angelucci E, Cavattoni I, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol. 2010;28:3644–52. 40. Lussana F, Intermesoli T, Gianni F, Boschini C, Masciulli A, Spinelli O, et al. Achieving molecular remission before allogeneic stem cell transplantation in adult patients with philadelphia chromosome-positive acute lymphoblastic leukemia: impact on relapse and long-term outcome. Biol Blood Marrow Transplant. 2016;22:1983–7. 41. Nishiwaki S, Imai K, Mizuta S, Kanamori H, Ohashi K, Fukuda T, et al. Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ ALL: a study from the adult ALL WG of the JSHCT. Bone Marrow Transplant. 2016;51:43–50. 42. Tanguy-Schmidt A, Rousselot P, Chalandon Y, Cayuela JM, Hayette S, Vekemans MC, et al. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant. 2013;19:150–5. 43. Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795–802. 44. Rives S, Camós M, Estella J, Gómez P, Moreno MJ, Vivanco JL, et al. Longer followup confirms major improvement in outcome in children and adolescents with Philadelphia chromosome acute lymphoblastic leukaemia treated with continuous imatinib and haematopoietic stem cell transplantation. Results from the Spanish Cooperative Study SHOP/ALL-2005. Br J Haematol. 2013;162:419–21. 45. Biondi A, Schrappe M, de Lorenzo P, Castor A, Lucchini G, Gandemer V, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012;13:936–45. 46. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59. 47. Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018;19:240–8. 48. Bar M, Wood BL, Radich JP, Doney KC, Woolfrey AE, Delaney C, et al. Impact of minimal residual disease, detected by flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia. Leuk Res Treatment. 2014;2014:421723.

34

P. Barba, I. Elorza / Med Clin (Barc). 2019;153(1):28–34

49. Zhou Y, Slack R, Jorgensen JL, Wang SA, Rondon G, de Lima M, et al. The effect of peritransplant minimal residual disease in adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2014;14:319–26. 50. Dhédin N, Huynh A, Maury S, Tabrizi R, Beldjord K, Asnafi V, et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood. 2015;125:2486–96. 51. Elorza I, Palacio C, Dapena JL, Gallur L, Sánchez de Toledo J, Díaz de Heredia C. Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia. Haematologica. 2010;95:936–41. 52. Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;13:1522–31. 53. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48. 54. Bader P, Kreyenberg H, von Stackelberg A, Eckert C, Salzmann-Manrique E, Meisel R, et al. Monitoring of minimal residual disease after allogeneic stemcell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial. J Clin Oncol. 2015;33:1275–84.

55. Bader P, Kreyenberg H, Hoelle W, Dueckers G, Handgretinger R, Lang P, et al. Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stemcell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol. 2004;22:1696–705. 56. Kuhlen M, Willasch AM, Dalle JH, Wachowiak J, Yaniv I, Ifversen M, et al. Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial. Br J Haematol. 2018;180:82–9. 57. Yaniv I, Krauss AC, Beohou E, Dalissier A, Corbacioglu S, Zecca M, et al. Second hematopoietic stem cell transplantation for post-transplantation relapsed acute leukemia in children: a retrospective EBMT-PDWP study. Biol Blood Marrow Transplant. 2018;24:1629–31642. 58. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–47. 59. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17. 60. Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13:403–11.