Second unmanipulated allogeneic transplantation could be used as a salvage option for patients with relapsed acute leukemia post-chemotherapy plus modified donor lymphocyte infusion

Abstract

Relapse is the main problem after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcome of a second allo-HSCT (HSCT2) for relapse post-HSCT has shown promising results in some previous studies. However, little is known about the efficacy of HSCT2 in patients with relapsed/refractory acute leukemia (AL) post-chemotherapy plus modified donor lymphocyte infusion (post-Chemo+m-DLI) after the first allo-HSCT (HSCT1). Therefore, we retrospectively analyzed the efficacy of HSCT2 in 28 patients with relapsed/refractory AL post-Chemo+m-DLI in our center. With a median follow-up of 918 (457–1732) days, 26 patients (92.9%) achieved complete remission, and 2 patients exhibited persistent disease. The probabilities of overall survival (OS) and disease-free survival (DFS) 1 year after HSCT2 were 25.0% and 21.4%, respectively. The cumulative incidences of nonrelapse mortality on day 100 and at 1 year post-HSCT2 were 7.1%±4.9% and 25.0%±8.4%. The cumulative incidences of relapse were 50.0%±9.8% and 53.5%±9.9% at 1 and 2 years post-HSCT2, respectively. Risk stratification prior to HSCT1 and percentage of blasts before HSCT2 were independent risk factors for OS post-HSCT2, and relapse within 6 months post-HSCT1 was an independent risk factor for DFS and relapse post-HSCT2. Our findings suggest that HSCT2 could be a salvage option for patients with relapsed AL post-Chemo+m-DLI.

Keywords

second hematopoietic stem cell transplantation / acute leukemia / relapse / chemotherapy / modified donor lymphocyte infusion

1 Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains an important strategy for the treatment of acute leukemia (AL) [1–5]. Relapse is still the main problem after allo-HSCT, and it significantly decreases survival [6,7]. The treatment of relapsed AL post-HSCT remains a clinical challenge. Although there is no standard approach for post-HSCT relapse management, significant improvements have been achieved in recent years [8–15], especially with regard to donor lymphocyte infusion (DLI) [9].

More recently, our group developed a novel approach of chemotherapy plus modified DLI (Chemo+m-DLI) for patients who relapsed after allo-HSCT. We found that the 1- and 2-year disease-free survival (DFS) rates in 20 patients who relapsed after allo-transplantation were 60% and 40%, respectively [12]. In addition, for patients relapsing after HSCT1 and who achieved complete remission (CR) after Chemo+m-DLI, minimal residual disease (MRD) and graft-versus-host disease (GvHD)-guided multiple consolidation chemotherapy with Chemo+m-DLI reduced the cumulative incidence of relapse (CIR) and improved the overall survival (OS) and DFS [16]. However, more than 30% of the patients did not respond to Chemo+m-DLI, and 20%–50% of the patients relapsed again after this effective therapy [16–18]. The prognosis for these patients is extremely poor, and their treatment options are limited.

A second allo-HSCT (HSCT2) is another feasible strategy in patients who relapsed post-HSCT. Outcomes after HSCT2 have been reported from different groups [14,19,20], and several factors, such as the absence of GVHD, a younger age, or remission status at the time of HSCT2, have been reported to impact the outcome of HSCT2. However, the outcome of HSCT2 in patients with relapsed/refractory AL post-Chemo+m-DLI remains unknown.

Therefore, we retrospectively analyzed patients who received HSCT2 for relapsed/refractory AL post-Chemo+m-DLI in our center to examine the efficacy and safety of HSCT2 for these patients and verify whether patients could benefit from such treatment.

2 Methods

2.1 Patients

The present study was performed at Peking University People’s Hospital, Peking University Institute of Hematology, and was approved by the Ethics Committee of Peking University People’s Hospital. The individual medical records of all relapsed patients (defined as progression or relapse of disease any time after HSCT) were examined. Molecular or cytogenetic relapses were not considered relapse events.

For enrollment in this study, the following conditions had to be met: (1) diagnosis of AL, (2) relapse after HSCT1, (3) treatment with sequential Chemo+m-DLI, (4) no CR or relapse again after a short duration of CR (within 2 months), and (5) treatment with HSCT2. The study cohort included 28 patients from March 2010 to June 2016.

2.2 Transplant routine

The transplant routine, including the conditioning regimen, stem cell collection, acute GVHD (a-GVHD) prophylaxis, and supportive care, was as described in our previous studies [2,21,22]. The conditioning regimen used at our center is a busulfan (BU)-based or total body irradiation (TBI)-based regimen.

For patients who received haploidentical or unrelated HSCT, the modified BU-based conditioning regimen consisted of cytarabine (4 g/m² per day in haploidentical HSCT and 2 g/m² per day in unrelated HSCT, intravenously on days –10 to –9), BU (3.2 mg/kg per day, intravenously on days –8 to –6), cyclophosphamide (CY, 1.8 g/m² per day, intravenously on days –5 to –4), Me-CCNU (250 mg/m², orally once on day –3), and thymoglobulin (ATG, Sang Stat, Lyon, France; 2.5 mg/kg per day, intravenously for 4 consecutive days from days –5 to –2). The TBI-based conditioning regimen comprised TBI (a single dose of 770 cGy on day –6), CY (1.8 g/m² per day, intravenously on days –5 to –4), and Me-CCNU (250 mg/m², orally once on day –3); ATG was used in patients who received haplo-HSCT and unrelated HSCT, and the dosage and time were consistent with the above description [2,21,22].

In addition, patients undergoing HLA-matched sibling donor (MSD) HSCT received hydroxycarbamide (80 mg/kg, orally on day –10) and a lower dose of cytarabine (2 g/m² per day, on day –9); otherwise, the regimen was identical to that received by the haploidentical patients without ATG.

All subjects received a combination of granulocyte colony-stimulating factor (G-CSF)-mobilized bone marrow (BM) and peripheral blood cells. The conditioning regimen used for HSCT1 and HSCT2 was chosen according to the donor type as mentioned above. If patients received a BU-based conditioning regimen in HSCT1, they were given a TBI-based conditioning regimen in HSCT2, and vice versa. If it was not feasible for patients to receive TBI, a BU-based conditioning was given.

The prophylaxis for a-GVHD comprised cyclosporine, mycophenolate mofetil, and short-term methotrexate (MTX) [2,21,22], which was used in HSCT1 and HSCT2.

The protocol for the m-DLI included the following two features: (1) the use of G-CSF-mobilized peripheral blood stem cells (PBSCs) and (2) the administration of short-term immunosuppressants for the prevention of GVHD following DLI as reported in our previous studies [4, 12, 16, 23, 24].

2.3 Salvage approach for relapse post-HSCT1

For patients who relapsed post-HSCT1, we adopted the following procedure (Fig. 1):

2.3.1 Discontinuation of immune suppression

Post-transplant immunosuppression was immediately withdrawn.

2.3.2 Chemotherapy

Induction chemotherapy in persons with acute myeloid leukemia (AML) comprised homoharringtonine 2 mg/m²/day for 5 days, aclacinomycin 10 mg/m²/day for 5 days, and cytarabine 100 mg/m²/day for 5 days (HAA). Induction chemotherapy in persons with acute lymphoblastic leukemia (ALL) consisted of CY 800 mg/m²/day for 2 days, vincristine 1 mg/m²/day for 1 day, daunorubicin 40 mg/m²/day for 3 days, and prednisone 60 mg/day for 7 days (CODP). Subjects not achieving CR after the first course of induction chemotherapy and DLI received a second course of induction chemotherapy with HAA or fludarabine 30 mg/m²/day for 5 days, cytarabine 1 g every 12 h for 10 doses, and G-CSF 300 µg/day for 6 days (FLAG) in subjects with AML and CODP or MTX 1 g/m²/day for 1 day and pegaspargase 2000 U/m²/day for 1 day in subjects with ALL. Consolidation chemotherapy in persons with AML comprised AA or HAA. Consolidation chemotherapy in persons with ALL consisted of CODP or MTX 1 g/m²/day for 1 day.

2.3.3 m-DLI

If GVHD did not occur within 2 weeks after the withdrawal of immunosuppressants, the patients consented to undergo m-DLI, and the donors consented to undergo PBSC collection, then induction chemotherapy was administered, and DLI was given 48–72 h later [12,16,17].

2.3.4 HSCT2

After performing the Chemo+m-DLI protocol, if the patients met both of the following criteria, HSCT2 may have been proposed: (1) the patients did not achieve CR following 1 to 2 cycles of induction Chemo+m-DLI or relapsed again after 1 to 2 cycles of consolidation Chemo+m-DLI, and (2) the patients were willing to undergo HSCT2.

2.4 Definitions and criteria

Hematological relapse was defined as more than 5% BM blasts. CR was defined as less than 5% BM blasts.

The risk stratification was differentiated in the two groups among patients with AL. Patients in their first or second remission (CR1 or CR2) were defined as the standard-risk group, and patients beyond CR2 or non-remission (NR) were defined as the high-risk group. The response criteria, cytogenetics, and MRD were defined as previously described [4,16,17,25,26]. The date of white blood cell (WBC) engraftment was defined as the first day of three consecutive days of neutrophil count recovery to>0.5 × 10⁹/L. The date of platelet (PLT) engraftment was defined as the first day of PLT count recovery to 20 × 10⁹/L for 7 consecutive days without transfusion. GVHD (acute and chronic) was diagnosed and graded according to established criteria [27,28].

OS was defined as the interval from HSCT to death, and DFS was calculated from the day of HSCT to the day of relapse or death due to any other cause. Surviving patients were censored on the date of their last follow-up. Nonrelapse mortality (NRM) was defined as death due to any cause without a prior relapse [22,29,30].

2.5 Statistical analysis

The patients’ baseline characteristics, pre-transplantation variables, and post-transplantation variables are described. Regarding the descriptive characteristics, the continuous variables are depicted as the median (range), whereas the categorical variables are described using frequencies. The c² test and Mann–Whitney U test were used to analyze the categorical variables and continuous variables, respectively.

All times to cytomegalovirus (CMV) viremia, WBC engraftment, PLT engraftment, a-GVHD, and chronic GVHD (c-GVHD) were measured from the date of HSCT2 (day 0). The Kaplan–Meier method was used to estimate the probability of DFS and OS. The cumulative incidences of a-GVHD, c-GVHD, NRM, CMV, and relapse were estimated using the competing risk model. The cumulative incidence and multivariate analysis for variables with competing risk factors were performed using R statistical software, version 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria). The multivariate Cox proportional model and survival analysis were performed with SPSS software (SPSS 21.0, Chicago, IL, USA), and multivariate analysis for variables with competing risk factors such as relapse or NRM was performed using “Fine and Gray analysis”with R statistical software.

3 Results

3.1 HSCT1 patient characteristics

Twenty-eight patients with a median age of 22.5 (3–48) years were enrolled in this study. There were 22 male patients and 6 female patients. All patients received allogeneic HSCT, including HLA-MSDs (MSD, n = 15), haploidentical donors (n = 11), and unrelated donors (URD, n = 2). The HSCT1 patient and donor characteristics are summarized in Table 1.

3.2 Chemotherapy plus m-DLI

All 28 patients received Chemo+m-DLI for relapse after HSCT1. Five patients received one cycle of induction Chemo+m-DLI, and 14 patients received two cycles of induction Chemo+m-DLI post-HSCT1. Five patients achieved CR after one cycle of Chemo+m-DLI, but these patients relapsed again after a cycle of consolidation Chemo+m-DLI. One patient achieved a CR after the second cycle of induction Chemo+m-DLI but relapsed after the first cycle of consolidation Chemo+m-DLI (Fig. 2).

3.3 HSCT2 situations

3.3.1 HSCT2 patient characteristics

Twenty-eight patients relapsed after a median of 272.5 (60–1867) days post-HSCT1. All patients received HSCT2 after a median of 146.5 (55–1070) days after the relapse following HSCT1. The median length of time from HSCT1 to HSCT2 was 360.5 (121–1890) days. The HSCT2 patient and donor characteristics are summarized in Table 2.

3.3.2 Engraftment and complications

Twenty-seven patients received WBC engraftment, and the median time of WBC engraftment was 13 (10–26) days post-HSCT. Thirty-eight patients underwent PLT engraftment after a median of 15.5 (9–56) days post-HSCT with a cumulative incidence of 87.1%±6.6% on day 100 post-HSCT2. In total, six patients did not undergo PLT engraftment.

Seven patients developed CMV viremia at a median of 49 (35–100) days post-HSCT2, and the cumulative incidence of CMV viremia was 27.4%±8.9% on day 100 post-HSCT2. Eleven patients developed a-GVHD at a median of 43.0 (21–86) days post-HSCT2. The cumulative incidence of a-GVHD was 35.7%±9.2% on day 100 post-HSCT2. Eight patients developed grade 2–4 a-GVHD at a median of 32.0 (21–100) days, and the cumulative incidence of grade 2–4 a-GVHD was 22.4%±8.3% on day 100 post-HSCT2. Nine patients were diagnosed with c-GVHD, and the cumulative incidence of c-GVHD 1 year post-HSCT2 was 38.3%±10.9%. c-GVHD occurred at a median of 113 (100–210) days. Three patients developed mild c-GVHD, six patients developed moderate c-GVHD, and two patients developed severe c-GVHD.

3.3.3 Survival

Over a median follow-up of 918 (457–1732) days post-HSCT2, 26 patients achieved CR, and 2 patients had persistent disease; the CR rate was 92.9%. Among these 26 patients, 16 patients relapsed again after a median of 122 (35–740) days post-HSCT2. The CIRs at 1 and 2 years post-HSCT2 were 50.0%±9.8% and 53.5%±9.9%, respectively. The probabilities of OS at 1 and 2 years post-HSCT2 were 25.0% and 17.9%, respectively. The probabilities of DFS at 1 and 2 years post-HSCT2 were 21.4% and 14.3%, respectively.

Through April 2018, 23 patients died, including 16 patients who died from relapse, 3 patients who died from infection, 2 patients who died from veno-occlusive disease, 1 patient who died from thrombotic microangiopathy, and 1 patient who died from hepatitis. The cumulative incidences of NRM on day 100 and at 1 year post-HSCT2 were 7.1%±4.9% and 25.0%±8.4% (Fig. 3), respectively.

3.3.4 Donor change and outcomes

Nine patients changed donors for HSCT2. The cumulative incidences of CMV viremia and a-GVHD were comparable between patients who changed donors and those who reused the original donors. The OS and DFS were also comparable between patients who changed donors and those who reused the original donors. Among the patients who reused the original donors, nine patients developed c-GVHD with a cumulative incidence of 67.3%±14.5%; no patients developed c-GVHD among the patients who changed donors (Fig. 4).

3.3.5 Univariate and multivariate predictors of the outcome of HSCT2

In the multivariate analysis, risk stratification before HSCT1 and percentage of blasts before HSCT2 were independent risk factors for OS post-HSCT2. Relapse within 6 months post-HSCT1 was an independent risk factor for DFS post-HSCT2 (Table 3) and for relapse post-HSCT2 (Table S1). Multivariate analysis for NRM (with competing risk factors) was also performed in this study, but we did not identify any risk factors (Table S1).

4 Discussion

HSCT2 is a well-known treatment option for malignant hematological disease [13,14,31–33] and is the preferred option offered by most clinicians to patients who achieve remission following reinduction chemotherapy [4,12,16,17,34,35]. For patients who do not respond to induction Chemo+m-DLI or relapsed again after Chemo+m-DLI, HSCT2 may still be an option; however, its effects on these patients have not been investigated. In the present study, we treated 28 patients with HSCT2 after relapse post Chemo+m-DLI in our single center. Twenty-six patients achieved CR at a promising rate of 92.9%, which is greater than that reported in previous treatment with chemotherapy with/without DLI (16%–37%) [36]. However, relapse remains the main problem, as reported in other studies [37,38]. The probabilities of OS at 1 and 2 years post-HSCT2 were 25.0% and 17.9%, respectively. The probabilities of DFS at 1 and 2 years post-HSCT2 were 21.4% and 14.3%, respectively. The data were comparable with those reported in the entire cohort (ranging from approximately 10% to 30%) [14,29,32,39–42].

In the present study, only one patient (without CR) did not achieve WBC engraftment, which was due to early death. The engraftment kinetics did not substantially differ from those of HSCT1, and primary engraftment failure was rare [13,40,43]. The incidence of a-GVHD in HSCT2 ranged between 21% and 41%, and the incidence of c-GVHD in HSCT2 ranged between 37% and 52% in a larger series [13,29,37,38,43]. The cumulative incidences of a-GVHD and c-GVHD were comparable to those in previous reports [38,44]. NRM on day 100 post-HSCT2 was 7.1%±4.9%, which was comparable to previous data (5.9% to 25.9%) following HSCT1. All the data indicate that this approach is safe in this setting.

As previously reported, various factors are related to the outcome of HSCT2. First, the reported NRM was lower in younger patients and children, which may be due to their higher tolerance of the toxicity [39,40,45,46]. A short interval between the two allo-HSCTs was also an independent risk factor for NRM in HSCT2, indicating cumulative toxicity [33,37,39,40,45,46]. Unfortunately, we did not identify any new risk factors in the present study, which may be due to the limited number of patients. Second, CR before HSCT2 is known to benefit survival, which has been acknowledged in all series. According to the risk stratification before HSCT2, 50% of the patients with the best prognosis can achieve long-term survival, and 10% of patients with the worst prognosis can achieve long-term survival [37,46]. In addition, different time points of relapse post-HSCT1, especially at 6 months [37,46–48] or 1 year [37,49], were independent risk factors for DFS and OS post-HSCT2. In the present study, all patients were NR (with the worst prognosis), and we also found that relapse within 6 months post-HSCT1 was an independent risk factor for DFS and OS. However, due to the limited numbers of patients, we need to clarify these factors in a future study.

Finally, as previously reported, the response rate and survival in relapsed AML (15%–56%) [50] after therapeutic DLI were increased compared with those in patients with relapsed ALL (5%–13%) [51]. The poor response of relapsed ALL to DLI is thought to be mediated by diverse immune escape mechanisms of leukemia cells [52–54]. In the present study of HSCT2, we did not observe that the type of AL influenced the results, which may be due to the limited number of patients. This finding needs to be clarified in a future study.

Due to the poor results of HSCT2, something needs to be improved. On the one hand, should the donor be changed? Theoretically, a donor change for HSCT2 could improve the prognosis by enhancing the graft-versus-leukemia effect. Hosing et al. found that a donor change tended to improve the prognosis, and Imus et al. demonstrated that using major histocompatibility-mismatched donors could improve OS post-HSCT2 [55,56]. However, a report from IBMTR of 41 patients who received HSCT2 found that a donor change did not improve their prognosis [29]. In one report, the authors demonstrated that patients with an MSD following the first allo-HSCT achieved a better prognosis compared with those with a URD [37]. Although a donor change did not improve their prognosis, the authors concluded that a donor change was not harmful [37]. In the present study, a donor change did not influence the prognosis.

On the other hand, which conditioning regimen is better? The choice of the conditioning regimen is of vast importance in these fragile patients, as the need for powerful cytoreduction should not negate an acceptable toxicity profile of the protocol. Historically, regimens employed in this setting mainly included standard myeloablative protocols based on TBI or alkylators. The sequential fludarabine, intermediate dose Ara-C, amacrines, TBI/BU, CY (FLAMSA) regimen, designed by Kolb et al. in the early 2000s [57,58], has demonstrated promising outcomes (anti-leukemia efficacy with 88% [59] to 98% [60]) and currently represents one of the most widely employed protocols in patients with relapsed/refractory leukemia.

Consensus regarding whether the conditioning regimen influences the outcome of HSCT2 is lacking. Some studies have reported that reduced-intensity conditioning did not reduce the incidence of relapse and NRM and that the OS was comparable to that following a standard regimen [61,62]. The use of TBI in HSCT2, if it was not applied in HSCT1, may provide a slight advantage [40,63], but a second use of TBI is discouraged [45]. Recently, FLAMSA has also been used in patients with recurrent AML after allogeneic transplantation for remission induction followed by blood stem cells from the original donor. In the present study, we could not identify any difference between TBI-based and BU-based conditioning regimens due to the limited number of patients. We may focus on the efficacy of different conditioning regimens in a future study.

Within the limitations of its retrospective nature and the limited number of patients, this study showed that HSCT2 represents a potential salvage treatment option for patients with relapsed/refractory AL post Chemo+m-DLI, especially patients who relapsed more than 6 months after HSCT1 and those with a standard risk stratification pre-HSCT1. This study provides a foundation for additional prospective investigations of HSCT2 in patients with relapsed/refractory AL post-Chemo+m-DLI.

References

[1] Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354(17): 1813–1826

[2] Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X, Fan ZP, Wu DP, Huang XJ. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood 2015; 125(25): 3956–3962

[3] Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol 2016; 13(1): 10–24

[4] Yan CH, Liu DH, Liu KY, Xu LP, Liu YR, Chen H, Han W, Wang Y, Qin YZ, Huang XJ. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 2012; 119(14): 3256–3262

[5] Chang YJ, Wang Y, Huang XJ. Haploidentical stem cell transplantation for the treatment of leukemia: current status. Expert Rev Hematol 2014; 7(5): 635–647

[6] Oran B, de Lima M. Prevention and treatment of acute myeloid leukemia relapse after allogeneic stem cell transplantation. Curr Opin Hematol 2011; 18(6): 388–394

[7] Mielcarek M, Storer BE, Flowers ME, Storb R, Sandmaier BM, Martin PJ. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2007; 13(10): 1160–1168

[8] Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R, Drobyski WR, Barrett AJ, Porter DL, Giralt S, Leis J, Holmes HE, Johnson M, Horowitz M, Collins RH Jr. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 2002; 20(2): 405–412

[9] Choi SJ, Lee JH, Lee JH, Kim S, Seol M, Lee YS, Lee JS, Kim WK, Chi HS, Lee KH. Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse. Leukemia 2004; 18(11): 1789–1797

[10] Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A, Volin L, Gürman G, Maertens J, Bordigoni P, Holler E, Ehninger G, Polge E, Gorin NC, Kolb HJ, Rocha V; EBMT Acute Leukemia Working Party. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007; 25(31): 4938–4945

[11] Lübbert M, Bertz H, Wäsch R, Marks R, Rüter B, Claus R, Finke J. Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting. Bone Marrow Transplant 2010; 45(4): 627–632

[12] Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W. Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation. Haematologica 2007; 92(3): 414–417

[13] Michallet M, Tanguy ML, Socié G, Thiébaut A, Belhabri A, Milpied N, Reiffers J, Kuentz M, Cahn JY, Blaise D, Demeocq F, Jouet JP, Michallet AS, Ifrah N, Vilmer E, Molina L, Michel G, Lioure B, Cavazzana-Calvo M, Pico JL, Sadoun A, Guyotat D, Attal M, Curé H, Bordigoni P, Sutton L, Buzyn-Veil A, Tilly M, Keoirruer N, Feguex N. Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemias for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Société Française de Greffe de moelle (SFGM). Br J Haematol 2000; 108(2): 400–407

[14] Tomonari A, Iseki T, Ooi J, Nagayama H, Sato H, Takahashi T, Ito K, Nagamura F, Uchimaru K, Takahashi S, Shirafuji N, Tojo A, Tani K, Asano S. Second allogeneic hematopoietic stem cell transplantation for leukemia relapse after first allogeneic transplantation: outcome of 16 patients in a single institution. Int J Hematol 2002; 75(3): 318–323

[15] Tsirigotis P, Byrne M, Schmid C, Baron F, Ciceri F, Esteve J, Gorin NC, Giebel S, Mohty M, Savani BN, Nagler A. Relapse of AML after hematopoietic stem cell transplantation: methods of monitoring and preventive strategies. A review from the ALWP of the EBMT. Bone Marrow Transplant 2016; 51(11): 1431–1438

[16] Yan CH, Wang Y, Wang JZ, Chen YH, Chen Y, Wang FR, Sun YQ, Mo XD, Han W, Chen H, Zhang XH, Xu LP, Liu KY, Huang XJ. Minimal residual disease- and graft-vs.-host disease-guided multiple consolidation chemotherapy and donor lymphocyte infusion prevent second acute leukemia relapse after allotransplant. J Hematol Oncol 2016; 9(1): 87

[17] Yan CH, Wang JZ, Liu DH, Xu LP, Chen H, Liu KY, Huang XJ. Chemotherapy followed by modified donor lymphocyte infusion as a treatment for relapsed acute leukemia after haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion: superior outcomes compared with chemotherapy alone and an analysis of prognostic factors. Eur J Haematol 2013; 91(4): 304–314

[18] Miyamoto T, Fukuda T, Nakashima M, Henzan T, Kusakabe S, Kobayashi N, Sugita J, Mori T, Kurokawa M, Mori SI. Donor lymphocyte infusion for relapsed hematological malignancies after unrelated allogeneic bone marrow transplantation facilitated by the japan marrow donor program. Biol Blood Marrow Transplant 2017; 23(6): 938–944

[19] Ruutu T, de Wreede LC, van Biezen A, Brand R, Mohty M, Dreger P, Duarte R, Peters C, Garderet L, Schönland S, Gratwohl A, Niederwieser D, de Witte T, Kröger N; European Society for Blood and Marrow Transplantation (EBMT). Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT. Bone Marrow Transplant 2015; 50(12): 1542–1550

[20] Vrhovac R, Labopin M, Ciceri F, Finke J, Holler E, Tischer J, Lioure B, Gribben J, Kanz L, Blaise D, Dreger P, Held G, Arnold R, Nagler A, Mohty M; Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes. Bone Marrow Transplant 2016; 51(2): 186–193

[21] Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Wang JZ, Gao ZY, Zhang YC, Jiang Q, Shi HX, Lu DP. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 2006; 38(4): 291–297

[22] Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Zhang XH, Lu DP. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant 2009; 15(2): 257–265

[23] Yan CH, Liu QF, Wu DP, Zhang X, Xu LP, Zhang XH, Wang Y, Huang H, Bai H, Huang F, Ma X, Huang XJ. Prophylactic donor lymphocyte infusion (DLI) followed by minimal residual disease and graft-versus-host disease-guided multiple DLIs could improve outcomes after allogeneic hematopoietic stem cell transplantation in patients with refractory/relapsed acute leukemia. Biol Blood Marrow Transplant 2017; 23(8): 1311–1319

[24] Huang XJ, Wang Y, Liu DH, Xu LP, Chen H, Chen YH, Han W, Shi HX, Liu KY. Modified donor lymphocyte infusion (DLI) for the prophylaxis of leukemia relapse after hematopoietic stem cell transplantation in patients with advanced leukemia—feasibility and safety study. J Clin Immunol 2008; 28(4): 390–397

[25] Brüggemann M, Kotrova M. Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation. Blood Adv 2017; 1(25): 2456–2466

[26] Wang Y, Chen H, Chen J, Han M, Hu J, Jiong Hu, Huang H, Lai Y, Liu D, Liu Q, Liu T, Jiang M, Ren H, Song Y, Sun Z, Wang C, Wang J, Wu D, Xu K, Zhang X, Xu L, Liu K, Huang X. The consensus on the monitoring, treatment, and prevention of leukemia relapse after allogeneic hematopoietic stem cell transplantation in China. Cancer Lett 2018; 438: 63–75

[27] Przepiorka D, Nath R, Ippoliti C, Mehra R, Hagemeister F, Diener K, Dimopoulos M, Giralt S, Khouri I, Samuels B, . A phase I–II study of high-dose thiotepa, busulfan and cyclophosphamide as a preparative regimen for autologous transplantation for malignant lymphoma. Leuk Lymphoma 1995; 17(5–6): 427–433

[28] Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18(4): 295–304

[29] Eapen M, Giralt SA, Horowitz MM, Klein JP, Wagner JE, Zhang MJ, Tallman MS, Marks DI, Camitta BM, Champlin RE, Ringdén O, Bredeson CN, Martino R, Gale RP, Cairo MS, Litzow MR, deLima M. Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant 2004; 34(8): 721–727

[30] Duncan CN, Majhail NS, Brazauskas R, Wang Z, Cahn JY, Frangoul HA, Hayashi RJ, Hsu JW, Kamble RT, Kasow KA, Khera N, Lazarus HM, Loren AW, Marks DI, Maziarz RT, Mehta P, Myers KC, Norkin M, Pidala JA, Porter DL, Reddy V, Saber W, Savani BN, Schouten HC, Steinberg A, Wall DA, Warwick AB, Wood WA, Yu LC, Jacobsohn DA, Sorror ML. Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant 2015; 21(1): 151–158

[31] Al-Qurashi F, Ayas M, Al Sharif F, Ibrahim E, Sahovic E, Al Mahr M, Chaudhri N, Al Mohareb F, Al Zahrani H, Al Jefri A, Al Omar H, Al Shanqeeti A, Seth P, Aslam M, El Solh H, Aljurf M. Second allogeneic bone marrow transplantation after myeloablative conditioning analysis of 43 cases from single institution. Hematology 2004; 9(2): 123–129

[32] Pawson R, Potter MN, Theocharous P, Lawler M, Garg M, Yin JA, Rezvani K, Craddock C, Rassam S, Prentice HG. Treatment of relapse after allogeneic bone marrow transplantation with reduced intensity conditioning (FLAG± Ida) and second allogeneic stem cell transplant. Br J Haematol 2001; 115(3): 622–629

[33] Shaw BE, Mufti GJ, Mackinnon S, Cavenagh JD, Pearce RM, Towlson KE, Apperley JF, Chakraverty R, Craddock CF, Kazmi MA, Littlewood TJ, Milligan DW, Pagliuca A, Thomson KJ, Marks DI, Russell NH. Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant 2008; 42(12): 783–789

[34] Zeidan AM, Forde PM, Symons H, Chen A, Smith BD, Pratz K, Carraway H, Gladstone DE, Fuchs EJ, Luznik L, Jones RJ, Bolaños-Meade J. HLA-haploidentical donor lymphocyte infusions for patients with relapsed hematologic malignancies after related HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 2014; 20(3): 314–318

[35] Goldsmith SR, Slade M, DiPersio JF, Westervelt P, Schroeder MA, Gao F, Romee R. Donor-lymphocyte infusion following haploidentical hematopoietic cell transplantation with peripheral blood stem cell grafts and PTCy. Bone Marrow Transplant 2017; 52(12): 1623–1628

[36] Bejanyan N, Weisdorf DJ, Logan BR, Wang HL, Devine SM, de Lima M, Bunjes DW, Zhang MJ. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant 2015; 21(3): 454–459

[37] Christopeit M, Kuss O, Finke J, Bacher U, Beelen DW, Bornhäuser M, Schwerdtfeger R, Bethge WA, Basara N, Gramatzki M, Tischer J, Kolb HJ, Uharek L, Meyer RG, Bunjes D, Scheid C, Martin H, Niederwieser D, Kröger N, Bertz H, Schrezenmeier H, Schmid C. Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change. J Clin Oncol 2013; 31(26): 3259–3271

[38] Horstmann K, Boumendil A, Finke J, Finel H, Kanfer E, Milone G, Russell N, Bacigalupo A, Chalandon Y, Diez-Martin JL, Ifrah N, Chacon MJ, Dreger P. Second allo-SCT in patients with lymphoma relapse after a first allogeneic transplantation. A retrospective study of the EBMT Lymphoma Working Party. Bone Marrow Transplant 2015; 50(6): 790–794

[39] Meshinchi S, Leisenring WM, Carpenter PA, Woolfrey AE, Sievers EL, Radich JP, Sanders JE. Survival after second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia. Biol Blood Marrow Transplant 2003; 9(11): 706–713

[40] Bosi A, Laszlo D, Labopin M, Reffeirs J, Michallet M, Gluckman E, Alessandrino PE, Locatelli F, Vernant JP, Sierra J, Jouet JP, Frassoni F; Acute Leukemia Working Party of the European Blood and Marrow Transplant Group. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 2001; 19(16): 3675–3684

[41] Keil F, Prinz E, Kalhs P, Lechner K, Moser K, Schwarzinger I, Jäger U, Fonatsch C, Worel N, Mannhalter C, Rabitsch W, Loidolt H, Schulenburg A, Mitterbauer M, Höcker P, Greinix HT. Treatment of leukemic relapse after allogeneic stem cell transplantation with cytotoreductive chemotherapy and/or immunotherapy or second transplants. Leukemia 2001; 15(3): 355–361

[42] Blau IW, Basara N, Bischoff M, Günzelmann S, Römer E, Kirsten D, Schmetzer B, Kiehl MG, Fauser AA. Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant. Bone Marrow Transplant 2000; 25(1): 41–45

[43] Radich JP, Sanders JE, Buckner CD, Martin PJ, Petersen FB, Bensinger W, McDonald GB, Mori M, Schoch G, Hansen JA. Second allogeneic marrow transplantation for patients with recurrent leukemia after initial transplant with total-body irradiation-containing regimens. J Clin Oncol 1993; 11(2): 304–313

[44] Arellano ML, Langston A, Winton E, Flowers CR, Waller EK. Treatment of relapsed acute leukemia after allogeneic transplantation: a single center experience. Biol Blood Marrow Transplant 2007; 13(1): 116–123

[45] Muñoz A, Badell I, Olivé T, Verdeguer A, Gómez P, Bureo E;Spanish Working Party for Bone Marrow Transplantation in Children (GETMON). Second allogeneic hematopoietic stem cell transplantation in hematologic malignancies in children: long-term results of a multicenter study of the Spanish Working Party for Bone Marrow Transplantation in Children (GETMON). Haematologica 2002; 87(3): 331–332

[46] Kato M, Horikoshi Y, Okamoto Y, Takahashi Y, Hasegawa D, Koh K, Takita J, Inoue M, Kigasawa H, Ogawa A, Sasahara Y, Kawa K, Yabe H, Sakamaki H, Suzuki R, Kato K. Second allogeneic hematopoietic SCT for relapsed ALL in children. Bone Marrow Transplant 2012; 47(10): 1307–1311

[47] McIver ZA, Yin F, Hughes T, Battiwalla M, Ito S, Koklanaris E, Haggerty J, Hensel NF, Barrett AJ. Second hematopoietic SCT for leukemia relapsing after myeloablative T cell-depleted transplants does not prolong survival. Bone Marrow Transplant 2013; 48(9): 1192–1197

[48] Naik S, Martinez C, Leung K, Sasa G, Nguyen NY, Wu MF, Gottschalk S, Brenner M, Heslop H, Krance R. Outcomes after second hematopoietic stem cell transplantations in pediatric patients with relapsed hematological malignancies. Biol Blood Marrow Transplant 2015; 21(7): 1266–1272

[49] Chueh HW, Lee SH, Sung KW, Yoo KH, Koo HH. Second allogeneic stem cell transplantation in hematologic malignancies: a single-center experience. J Pediatr Hematol Oncol 2013; 35(6): 424–429

[50] Castagna L, Sarina B, Bramanti S, Perseghin P, Mariotti J, Morabito L. Donor lymphocyte infusion after allogeneic stem cell transplantation. Transfus Apheresis Sci 2016; 54(3): 345–355

[51] Spyridonidis A, Labopin M, Schmid C, Volin L, Yakoub-Agha I, Stadler M, Milpied N, Socie G, Browne P, Lenhoff S, Sanz MA, Aljurf M, Mohty M, Rocha V; Immunotherapy Subcommittee of Acute Leukemia Working Party. Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT. Leukemia 2012; 26(6): 1211–1217

[52] Brouwer RE, van der Heiden P, Schreuder GM, Mulder A, Datema G, Anholts JD, Willemze R, Claas FH, Falkenburg JH. Loss or downregulation of HLA class I expression at the allelic level in acute leukemia is infrequent but functionally relevant, and can be restored by interferon. Hum Immunol 2002; 63(3): 200–210

[53] Choi SJ, Lee JH, Lee JH, Kim S, Lee YS, Seol M, Ryu SG, Lee JS, Kim WK, Jang S, Park CJ, Chi HS, Lee KH. Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study. Bone Marrow Transplant 2005; 36(2): 163–169

[54] Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat Rev 2010; 36(7): 528–538

[55] Hosing C, Saliba RM, Shahjahan M, Estey EH, Couriel D, Giralt S, Andersson B, Champlin RE, De Lima M. Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia. Bone Marrow Transplant 2005; 36(2): 157–162

[56] Imus PH, Blackford AL, Bettinotti M, Iglehart B, Dietrich A, Tucker N, Symons H, Cooke KR, Luznik L, Fuchs EJ, Brodsky RA, Matsui WH, Huff CA, Gladstone D, Ambinder RF, Borrello IM, Swinnen LJ, Jones RJ, Bolaños-Meade J. Major histocompatibility mismatch and donor choice for second allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 2017; 23(11): 1887–1894

[57] Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23(24): 5675–5687

[58] Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D, Harsdorf SV, Scheid C, Holtick U, Greinix H, Keil F, Schneider B, Sandherr M, Bug G, Tischer J, Ledderose G, Hallek M, Hiddemann W, Kolb HJ. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 2006; 108(3): 1092–1099

[59] Saraceni F, Labopin M, Brecht A, Kröger N, Eder M, Tischer J, Labussière-Wallet H, Einsele H, Beelen D, Bunjes D, Niederwieser D, Bochtler T, Savani BN, Mohty M, Nagler A. Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). J Hematol Oncol 2019; 12(1): 44

[60] Ram R, Scheid C, Amit O, Chemnitz JM, Moshe Y, Hallek M, Wolf D, Avivi I, Holtick U. Sequential therapy for patients with primary refractory acute myeloid leukemia: a historical prospective analysis of the German and Israeli experience. Haematologica 2019; 104(9): 1798–1803

[61] Kono N, Ohashi K, Sasaki E, Okoshi Y, Mizuchi D, Mori S, Akiyama H, Karasawa K, Kaku H, Okamoto R, Maeda Y, Sasaki T, Okuyama Y, Hiruma K, Sakamaki H. Second allogeneic peripheral blood stem cell transplantation with fludarabine-based low-intensity conditioning regimen for relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation. Int J Hematol 2001; 73(1): 122–125

[62] Grüllich C, Bertz H, Spyridonidis A, Müller CI, Finke J. A fludarabine, thiotepa reduced toxicity conditioning regimen designed specifically for allogeneic second haematopoietic cell transplantation after failure of previous autologous or allogeneic transplantation. Bone Marrow Transplant 2008; 41(10): 845–850

[63] Kishi K, Takahashi S, Gondo H, Shiobara S, Kanamaru A, Kato S, Hirabayashi N, Moriyama Y, Harada M, Asano S, Hara H, Shibata A. Second allogeneic bone marrow transplantation for post-transplant leukemia relapse: results of a survey of 66 cases in 24 Japanese institutes. Bone Marrow Transplant 1997; 19(5): 461–466

RIGHTS & PERMISSIONS

Higher Education Press