Central Nervous System Relapse in Adults with Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a 3-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post-transplantation CNS prophylaxis practice varied by institution and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n = 8; combined bone marrow and CNS relapse, n = 10). Patients with a previous history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P = .002), and pretransplantation CNS involvement was the only risk factor for post-transplantation CNS relapse found in this study. We failed to find a significant effect of post-transplantation CNS prophylaxis to prevent relapse after transplantation. Furthermore, no benefit for post-transplantation CNS prophylaxis could be detected when a subgroup analysis of patients with (P = .10) and without previous CNS involvement (P = .52) was performed. Finally, we could not find any significant effect for intensity of the transplantation conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event after HSCT for patients with ALL in CR1 or CR2, but with higher risk among patients with CNS involvement before transplantation. Furthermore, neither the use of post-HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse.     

Impact of Pretransplantation Risk Factors on Post Transplantation Outcome of Patients with Acute Myeloid Leukemia in Remission after Haploidentical Hematopoietic Stem Cell Transplantation

The impact of risk-related parameters has not been defined in transplantation settings. We wondered whether the currently recognized predictors could be used to categorize acute myeloid leukemia (AML) patients who underwent transplantation during remission into risk groups. We analyzed the data of 255 consecutive patients (median age, 26) with AML in their first or second remission (CR1 or CR2) after haploidentical hematopoietic stem cell transplantation (HSCT). Three parameters were found to be predictive of outcome: response after induction therapy, white blood cell count at diagnosis, and cytogenetics. These three factors were combined to yield two risk groups. The 2-year cumulative incidences of relapse for patients at low and high risk were 8% and 36% (P = .001), respectively. The 3-year probabilities of leukemia-free survival for these two groups were 80% and 52% (P = .001), respectively. Multivariate analysis for relapse and for leukemia-free survival showed that not achieving CR after two courses of therapy was the strongest independent prognostic factor (P = .001 and P = .028, respectively). In addition, in a subgroup of patients with quantification of minimal residual disease at the time of HSCT, positive minimal residual disease at this time point was correlated with a poor outcome. Our results suggest that the pretransplantation risk factors influence posttransplantation outcomes of patients with AML in CR after haploidentical HSCT and might be applicable to assist with risk-directed posttransplantation therapy.     

Outcomes of Adults with Acute Lymphoblastic Leukemia Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation

For patients with acute lymphoblastic leukemia (ALL) who relapse after allogeneic hematopoietic stem cell transplantation (HSCT), treatment options are limited, and the clinical course and prognostic factors affecting outcome have not been well characterized. We retrospectively analyzed outcomes of 123 adult patients with ALL who relapsed after a first HSCT performed at our center between 1993 and 2011. First-line salvage included second HSCT (n = 19), donor lymphocyte infusion with or without prior chemotherapy (n = 11), radiation therapy (n = 6), cytoreductive chemotherapy (n = 30), mild chemotherapy (n = 27), or palliative care (n = 23), with median postrelapse overall survival (OS) of 10 months, 6.5 months, 3 months, 4 months, 4 months, and 1 month, respectively. Despite a complete remission rate of 38% after first-line salvage in the treated patients, the OS rate remained limited with 1- and 2- year OS rates of 17% (95% confidence interval, 13 to 29) and 10% (95% confidence interval, 6 to 20), respectively. On univariate analysis, adverse factors for OS included active disease at the time of first HSCT and short time to progression from first HSCT (<6 months). There was no difference in the 6-month survival postrelapse in patients with isolated extramedullary relapse (44%) compared with combined extramedullary and bone marrow relapse (29%) or those with isolated bone marrow relapse (34%) (P = .8). Our data provide more insight into the disease behavior and treatment outcomes of ALL at relapse after HSCT against which future trials may be compared.     

Autologous Hematopoietic Stem Cell Transplantation in Extranodal Natural Killer/T Cell Lymphoma: A Multinational,Multicenter, Matched Controlled Study

Extranodal natural killer (NK)/T cell lymphoma, nasal type, is a recently recognized distinct entity and the most common type of non–B cell extranodal lymphoma in Asia. This retrospective analysis studied the potential survival benefits of hematopoeitic stem cell transplantation (HSCT) compared with a historical control group. A total of 47 patients from 3 previously published series of HSCT were matched according to NK/T cell lymphoma International Prognostic Index (NKIPI) risk groups and disease status at transplantation with 107 patients from a historical control group for analysis. After a median follow-up of 116.5 months, the median survival time was not determined for the HSCT group, but it was 43.5 months for the control group (95% confidence interval [CI] = 6.7 to 80.3 months; P = .127, log-rank test). In patients who were in complete remission (CR) at the time of HSCT or at surveillance after remission, disease-specific survival rates were significantly higher in the HSCT group compared with the control group (disease-specific 5-year survival rate, 87.3% for HSCT vs 67.8% for non-HSCT; P = .027). In contrast, in subgroup analysis on non-CR patients at the time of HSCT or non-HSCT treatment, disease-specific survival rates were not significantly prolonged in the HSCT group compared with the control group (1-year survival rate, 66.7% for HSCT vs 28.6% for non-HSCT; P = .141). The impact of HSCT on the survival of all patients was significantly retained at the multivariate level with a 2.1-fold (95% CI =1.2- to 3.7-fold) reduced risk of death (P = .006). HSCT seems to confer a survival benefit in patients who attained CR on postremission consolidation therapy. These findings suggest that, in particular, patients in CR with high NKIPI risk scores at diagnosis should receive full consideration for HSCT.     

Allogeneic Hemopoietic Stem Cell Transplants in Patients with Acute Myeloid Leukemia (AML) Prepared with Busulfan and Fludarabine (BUFLU) or Thiotepa,Busulfan, and Fludarabine (TBF): A Retrospective Study

This is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan, and fludarabine (TBF). Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant centers, with AML in first or second remission: 201 patients received BUFLU, whereas 253 received TBF. The 2 groups (BUFLU and TBF) were comparable for age (P = .13) and adverse AML risk factors (P = .3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA-identical siblings, unrelated donors, and family haploidentical donors. The 5-year cumulative incidence of nonrelapse mortality (NRM) was 19% for BUFLU and 22% for TBF (P = .8), and the 5-year cumulative incidence of relapse was 30% and 15%, respectively (P = .0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (P = .002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared with BUFLU (P = .03) and the risk of death (P = .03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of haploidentical grafts, TBF reduced the risk of relapse (P = .006) and there was a trend for improved survival (P = .07). Superior survival of patients receiving TBF as compared with BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.     

Cytogenetics,Donor Type,and Use of Hypomethylating Agents in Myelodysplastic Syndrome with Allogeneic Stem Cell Transplantation

We investigated the impact of patient and disease characteristics, including cytogenetics, previous therapy, and depth of response, on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome (MDS). We analyzed 256 MDS patients who underwent transplantation from a matched related (n = 133) or matched unrelated (n = 123) donor after 2001. Of the 256, 78 (30.5%) did not receive cytoreductive therapy before HSCT; 40 (15.6%) received chemotherapy, 122 (47.7%) received hypomethylating agents (HMA), and 16 (6.2%) received both (chemo+HMA). Disease status at HSCT defined by International Working Criteria was complete remission in 46 (18%) patients. There were significant differences between therapy groups: there were more therapy-related MDS and higher use of matched related donor in the untreated group. The chemotherapy group had higher serum ferritin levels at HSCT. Patients were older and had more high-risk disease by revised International Prognostic Scoring in the HMA group. Despite those differences, transplantation outcomes were similar in patients who were untreated and who received cytoreductive therapy before HSCT. Three-year event-free survival (EFS) was 44.2%, 30.6%, 34.2%, and 32.8% for untreated, chemotherapy, HMA, and chemo+HMA groups, respectively (P = .50). Multivariate analyses revealed that older age (hazard ratio [HR], 1.3; P = .001); high-risk histologic subtypes, including refractory anemia with excess blasts (HR, 1.5; P = .05) and chronic myelomonocytic leukemia (HR, 2.1; P = .03), high-risk cytogenetics with monosomal karyotype (MK) (HR, 4.0; P < .0001) and high serum ferritin level at HSCT (HR, 1.8; P = .002) were poor prognostic factors for EFS. Bone marrow blast count 5% or higher at HSCT (HR, 1.6; P = .01) and MK (HR, 4.2; P < .0001) were the only prognostic factors for increased relapse incidence after HSCT. Patients with MK represented a poor prognostic group, with 3-year EFS of 11.4% and relapse incidence of 60.9%. In this analysis, various therapy approaches before HSCT did not lead to different transplantation outcomes. Cytogenetics defined by MK was able to identify a very poor prognostic groups that innovative transplantation approaches to improve outcomes are urgently needed.     

Impact of Anti-CMV IgG Titers and CD34 Count Prior to Hematopoietic Stem Cell Transplantation from Alternative Donors on CMV reactivation

Cytomegalovirus (CMV) reactivation remains one of the main infectious complications following hematopoietic stem cell transplantation (HSCT). In this study, we explored the role of anti-CMV antibody titers in HSCT from alternative donors and to compare the risk of CMV reactivation between posttransplant cyclophosphamide-based haploidentical HSCT and antithymocyte globulin-based unrelated donor (URD) HSCT. We included 98 CMV-positive patients, 30 undergoing haploidentical HSCT and 68 undergoing URD HSCT. The majority of patients had a malignant disease (84%), received a myeloablative conditioning regimen (78%), and received a bone marrow graft (90%). The median pretransplantation anti-CMV IgG level was 109 U/mL. With median follow-up of 2.2 years, a total of 72 CMV reactivations occurred in 50 patients. There was no difference in CMV reactivation pattern between haploidentical HSCT recipients and URD HSCT recipients. In multivariable analysis until the first event, the incidence of CMV reactivation was higher in patients with anti-CMV IgG levels >100 U/mL (hazard ratio [HR], 2.38; P = .005) and in patients diagnosed with grade II-IV acute graft-versus-host disease (GVHD) (HR, 10.8; P = .003) after day +50 and lower in patients who received higher doses of CD34 cells (HR, .44; P = .006). In multivariable analysis for recurring events, the incidence of CMV reactivation was higher in patients receiving reduced-intensity conditioning (HR, 1.69: P = .04) and in patients with acute GVHD (HR, 1.88; P = .02), and lower in those who received higher doses of CD34 cells (HR, .55; P = .01). In summary, we have shown that pretransplantation anti-CMV IgG titers are correlated with CMV reactivation risk. More studies are needed to assess how this information can be incorporated in HSCT. The use of high-dose cellular grafts, a modifiable risk factor, also protects against CMV reactivation.     

Transplantation Conditioning Regimens and Outcomes after Allogeneic Hematopoietic Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia

Relapse is common after hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL). Although 1200 cGy total body irradiation (TBI) and cyclophosphamide (Cy) is the standard conditioning regimen, attempts to reduce relapse have led to the addition of a second chemotherapeutic agent and/or higher dose of TBI. We examined HSCT outcomes in patients age <18 years with ALL, in second or subsequent remission or in relapse at transplantation. Most transplantations were performed with the patient in remission. Patients received grafts from an HLA-matched sibling or unrelated donor. Four treatment groups were created: (1) Cy + TBI ≤ 1200 cGy (n = 304), (2) Cy + etoposide + TBI ≤ 1200 cGy (n = 108), (3) Cy + TBI ≥ 1300 cGy (n = 327), and (4) Cy + etoposide + TBI ≥ 1300 cGy (n = 26). Neither TBI > 1200 cGy nor the addition of etoposide resulted in fewer relapses. The 5-year probability of relapse was 30% for group 1, 28% for group 2, 35% for group 3, and 31% for group 4. However, transplantation-related mortality was higher (35% versus 25%, P = .02) and overall survival lower (36% versus 48%, P = .03) in group 4 compared with group 3. Our findings indicate that compared with the standard regimen, neither TBI > 1200 cGy nor the addition of etoposide improves survival after HSCT for ALL.     

Favorable Effect of Cytomegalovirus Reactivation on Outcomes in Cord Blood Transplant and Its Differences Among Disease Risk or Type

The effects of cytomegalovirus (CMV) reactivation on cord blood transplant (CBT) are unclear. We assessed the effect of CMV reactivation in adult single-unit CBT without in vivo T cell depletion. Of 3147 eligible cases, 2052 were acute myeloid leukemia (AML), 643 acute lymphoblastic leukemia (ALL), and 452 myelodysplastic syndrome (MDS). CMV reactivation up to 100 days after CBT was associated with better overall survival (OS) compared with no reactivation cases (57.3% versus 52.6% at 3 years after CBT), whereas nonrelapse mortality (NRM) was increased in ALL (16.2% versus 8.9%) and standard disease risk (17.1% versus 10.6%, P = .014) by CMV reactivation. On multivariate analysis, CMV reactivation had favorable effects on relapse in MDS (hazard ratio [HR], .55; P = .044) and high disease risk (HR, .77; P = .047). In NRM, only standard-risk cases showed adverse effects of CMV reactivation (HR, 1.56; P = .026). OS was significantly improved with CMV reactivation in a subgroup of patients with AML (HR, .84; P = .044), MDS (HR, .68; P = .048), and high disease risk (HR, .81; P = .013). This favorable effect of CMV reactivation on OS in AML and high disease risk cases was maintained even after considering the effect of grades II to IV acute graft-versus-host disease. Thus, CMV reactivation might have beneficial or adverse effects on relapse, NRM, and OS, depending on the disease type or disease risk.     

Extramedullary Relapse of Acute Leukemia after Haploidentical Hematopoietic Stem Cell Transplantation: Incidence,Risk Factors,Treatment, and Clinical Outcomes

We examined the incidence, risk factors, treatment, and clinical outcomes of extramedullary relapse (EMR) in 961 acute leukemia patients undergoing HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) between 2002 and 2013. Multiple control subjects were selected at random from the same cohort and matched to EMR cases for diagnosis, disease status at HSCT, age at the time of the HSCT, and year of HSCT. Forty patients exhibited EMR, with a median time to EMR of 207 days. The cumulative incidence of EMR was 4.0% at 3 years, and the incidence was higher in acute lymphoblastic leukemia patients compared with acute myeloid leukemia patients (5.6% versus 2.4%). In the multivariate analysis, non–complete remission (CR) status at HSCT (hazard ratio [HR] = 4.6; P = .018) and non–chronic graft-versus-host disease after HSCT (HR = 3.2; P < .001) were the independent risk factors for EMR after haplo-HSCT. Twenty-seven patients received combination treatments, and the proportion of patients who achieved CR was higher than those who received single treatment. Multifocal involvement at EMR (HR = 2.7; P = .024) and non-CR after EMR treatments (HR = 4.6; P < .001) were the independent risk factors for poor survival rates among EMR patients. We found that graft-versus-leukemia effect may help to prevent EMR after haplo-HSCT.     

Allogeneic Hematopoietic Cell Transplantation in First Remission Abrogates Poor Outcomes Associated with High-Risk Pediatric Acute Myeloid Leukemia

Despite remission rates of approximately 85% for children diagnosed with acute myeloid leukemia (AML), greater than 40% will die from relapsed disease. Patients with poor-risk molecular/cytogenetics and/or inadequate response to up-front therapy are typically considered high-risk (HR) and historically have poor outcomes with chemotherapy alone. We investigated whether allogeneic hematopoietic cell transplantation (allo-HCT) with best available donor in first remission (CR1) would abrogate the poor outcomes associated with HR AML in children and young adults treated with chemotherapy. We reviewed the outcomes of 50 consecutive children and young adults (ages 0 to 30 years) with AML who received a myeloablative allo-HCT between 2001 and 2010. Thirty-six patients (72%) were HR, defined as having FLT3-ITD mutations, 11q23 MLL rearrangements, chromosome 5 or 7 abnormalities, induction failure, and/or having persistent disease. The majority of patients received cyclophosphamide and total body irradiation conditioning, and graft-versus-host-disease (GVHD) prophylaxis was cyclosporine based. Transplantation outcomes for HR patients were compared to standard-risk patients, with no significant differences observed in overall survival (72% versus 78%, P = .72), leukemia-free survival (69% versus 79%, P = .62), relapse (11% versus 7%, P = .71), or treatment-related mortality (17% versus 14%, P = .89). Children and young adults with HR-AML have comparable outcomes to standard-risk patients following allo-HCT in CR1.     

Total Body Irradiation and Cyclophosphamide Plus Antithymocyte Globulin Regimen Is Well Tolerated and Promotes Stable Engraftment as a Preparative Regimen before T Cell–Replete Haploidentical Transplantation for Acute Leukemia

We compared total body irradiation (TBI, 700 cGy)/cyclophosphamide (Cy, 3.6 g/m²)/simustine (250 mg/m²) plus antithymocyte globulin (ATG) (TBI/Cy plus ATG) with cytarabine (8 g/m²)/i.v. busulfan (Bu, 9.6 mg/kg)/Cy (3.6 g/m²)/simustine (250 mg/m²) plus ATG (modified Bu/Cy plus ATG) as preparative therapy in T cell–replete haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for acute leukemia. From August 2009 to August 2013, 38 consecutive patients using TBI/Cy plus ATG regimen for T cell–replete haplo-HSCT (TBI group) at our center were eligible, which contained 28 high-risk and 10 standard-risk patients. A nested case-control study was designed. Seventy-seven patients using modified Bu/Cy plus ATG regimen (Bu group) were randomly selected in a 1 to 3:1 ratio matching for age, disease and status, year of HSCT (±2 years), and length of follow-up. Only 1 graft failure occurred in the TBI group. The incidence and time of neutrophil and platelet engraftment were comparable between the 2 groups. Severe grades III/IV graft-versus-host disease was observed in 13.4% of Bu group and only 2.6% of TBI group (P = .083). More toxicity of the liver (37.7% versus 10.5%; P = .002) and more hemorrhagic cystitis occurred in the Bu group (49.3% versus 23.7%, P = .008). Diarrhea was more common in the TBI group (44.7% versus 22.1%; P = .031). No significant differences were found in the 2-year incidences of relapse (26.5% for TBI group versus 32.3% for Bu group, P = .742), 1-year transplant-related mortality (12.6% versus 16.2%, P = .862), 2-year overall survival (60.2% versus 57.0%, P = .937), and 2-year incidence of disease-free survival (57.9% versus 56.6%, P = .845) between the 2 groups. We conclude that the TBI/Cy plus ATG regimen seems to be feasible in T cell–replete haplo-HSCT, which promotes stable engraftment and a lower incidence of liver toxicity and hemorrhagic cystitis. However, longer follow-up is necessary to determine the late relapse rate and late toxicity.     

Impact of Allogeneic Stem Cell Transplantation in First Complete Remission in Acute Myeloid Leukemia: A National Population-Based Cohort Study

To examine the outcomes of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared with chemotherapy alone in a population-based setting, we identified a cohort of patients with acute myeloid leukemia (AML) aged 15 to 70 years diagnosed between 2000 and 2014 in Denmark. Using the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival (OS) between patients with unfavorable cytogenetic features receiving postremission therapy with conventional chemotherapy only versus those undergoing HSCT in CR1. To minimize immortal time bias, we performed Cox proportional hazards regression, included date of allogeneic HSCT as a time-dependent covariate, and stratified the results by age (<60 or ≥60 years) and cytogenetic risk group. Overall, 1031 patients achieved a CR1. Of these, 196 patients (19%) underwent HSCT. HSCT was associated with a lower relapse rate (24% versus 49%) despite a similar median time to relapse (287 days versus 265 days). In all subgroups, the risk of relapse was lower and both RFS and OS were superior in recipients of HSCT (OS, adjusted mortality ratios: all patients, .54 [95% confidence interval (CI), .42-.71]; patients?age <60 years, .58 [95% CI, .42-.81]; patients?age ≥60 years, .42 [95% CI, .26-.69]; patients with intermediate-risk cytogenetics, .63 [95% CI, .43-.87]; patients with adverse-risk cytogenetics, .40 [95% CI, .24-.67]). In conclusion, in this population-based nationwide cohort study, HSCT was associated with improved survival in both younger and older patients and in patients with both intermediate and adverse cytogenetic risk.     

Mesenchymal Stem Cells versus Mesenchymal Stem Cells Combined with Cord Blood for Engraftment Failure after Autologous Hematopoietic Stem Cell Transplantation: A Pilot Prospective,Open-Label,Randomized Trial

Engraftment failure (EF) after autologous hematopoietic stem cell transplantation is a serious complication. We prospectively evaluated the effects and safeties of mesenchymal stem cells (MSCs) alone and MSCs combined with cord blood (CB) for EF. Twenty-two patients were randomized to receive MSCs (MSC group; n = 11) or MSCs plus CB (CB group; n = 11). Patients with no response (NR) to MSCs received the therapeutic schedule in the CB group, and those patients with partial response (PR) in the MSC group and patients without complete remission (CR) in the CB group received another cycle of MSC treatment. Patients who did not achieve CR after 2 cycles of treatments received other treatments, including allogeneic HSCT. After the first treatment cycle, response was seen in 7 of 11 patients in the MSC group and in 9 of 11 in the CB group (P = .635), with a significant difference in neutrophil reconstruction between the 2 groups (P = .030). After 2 treatment cycles, 16 patients achieved CR, 3 achieved PR, and 3 had NR. No patient experienced graft-versus-host disease (GVHD). With a median follow-up of 345 d (range, 129 to 784 d) post-transplantation, 18 patients remained alive and 4 had died (3 from primary disease relapse and 1 from cytomegalovirus pneumonia). The 2-year overall survival, disease-free survival, and cumulative incidence of tumor relapse post-transplantation were 75.2% ± 12.0%, 79.5% ± 9.4%, and 20.5% ± 9.4%, respectively. Our data indicate that the 2 strategies are effective for EF and do not result in GVHD or increase the risk of tumor relapse, but the MSC plus CB regimen has a superior effect on neutrophil reconstruction.     

Extramedullary Relapse of Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Different Characteristics between Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia

Extramedullary relapse (EMR) of acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a contributor to post-transplantation mortality and remains poorly understood, especially the different characteristics of EMR in patients with acute myelogenous leukemia (AML) and those with acute lymphoblastic leukemia (ALL). To investigate the incidence, risk factors, and clinical outcomes of EMR for AML and ALL, we performed a retrospective analysis of 362 patients with AL who underwent allo-HSCT at the First affiliated Hospital of Soochow University between January 2001 and March 2012. Compared with patients with AML, those with ALL had a higher incidence of EMR (12.9% versus 4.6%; P = .009). The most common site of EMR was the central nervous system, especially in the ALL group. Multivariate analyses identified the leading risk factors for EMR in the patients with AML as advanced disease status at HSCT, hyperleukocytosis at diagnosis, history of extramedullary leukemia before HSCT, and a total body irradiation–based conditioning regimen, and the top risk factors for EMR in the patients with ALL as hyperleukocytosis at diagnosis, adverse cytogenetics, and transfusion of peripheral blood stem cells. The prognosis for EMR of AL is poor, and treatment options are very limited; however, the estimated 3-year overall survival (OS) was significantly lower in patients with AML compared with those with ALL (0 versus 18.5%; P = .000). The characteristics of post–allo-HSCT EMR differed between the patients with AML and those with ALL, possibly suggesting different pathogenetic mechanisms for EMR of AML and EMR of ALL after allo-HSCT; further investigation is needed.     

Treatment of Acute Leukemia with Unmanipulated HLA-Mismatched/Haploidentical Blood and Bone Marrow Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the best therapeutic options to cure acute leukemia (AL). However, many patients have no human leukocyte antigen (HLA)-matched donor. Recently, we developed a new method for HLA-mismatched/haploidentical transplantation without in vitro T cell depletion (TCD). This method combined granulotyce-colony stimulating factor (G-CSF)-primed bone marrow and peripheral blood with intensive immunosuppression. We analyzed the outcome of 250 consecutive patients with AL who underwent HLA-mismatched/haploidentical transplantation with 1-3 mismatched loci of HLA-A, B, and DR from family donors via our new transplant protocol. Two hundred forty-nine patients achieved sustained, full donor chimerism. The incidence of grade 2-4 acute graft-versus-host disease (aGVHD) was 45.8%, and that of grades 3 and 4 was 13.4%, which was not associated with the extent of HLA disparity. The cumulative incidence of total chronic GVHD (cGVHD) was 53.9% and that of extensive cGVHD was 22.6% in 217 evaluable patients. One hundred forty-one of the 250 patients survived free of disease recurrence at a median of 1092 days (range: 442-2437 days) of follow-up. Seventeen patients received DLI as a treatment for relapse after transplantation and 7 patients achieved leukemia-free survival (LFS). The 3-year probability of LFS for acute myelogenous leukemia (AML) was 70.7% and 55.9%, and for acute lymphoblastic leukemia (ALL) it was 59.7% and 24.8% in standard-risk and high-risk groups, respectively. Lower LFS were associated with diagnosis of acute leukemia in the high-risk group (P = .001, relative risk [RR], 95% confidence interval [CI]: 2.94[1.535-5.631]) and the occurrence of aGVHD of grades 3 and 4 (P = .004). HLA-mismatched/haploidentical HSCT was feasible with unmanipulated blood and bone marrow harvest.     

Early Donor Chimerism Levels Predict Relapse and Survival after Allogeneic Stem Cell Transplantation with Reduced-Intensity Conditioning

The success of hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) is limited by a high rate of disease relapse. Early risk assessment could potentially improve outcomes by identifying appropriate patients for preemptive strategies that may ameliorate this high risk. Using a series of landmark analyses, we investigated the predictive value of early (day-30) donor chimerism measurements on disease relapse, graft-versus-host disease, and survival in a cohort of 121 patients allografted with a uniform RIC regimen. Chimerism levels were analyzed as continuous variables. In multivariate analysis, day-30 whole blood chimerism levels were significantly associated with relapse (hazard ratio [HR] = .90, P < .001), relapse-free survival (HR = .89, P < .001), and overall survival (HR = .94, P = .01). Day-30 T cell chimerism levels were also significantly associated with relapse (HR = .97, P = .002), relapse-free survival (HR = .97, P < .001), and overall survival (HR = .99, P = .05). Multivariate models that included T cell chimerism provided a better prediction for these outcomes compared with whole blood chimerism. Day-30 chimerism levels were not associated with acute or chronic graft-versus-host disease. We found that high donor chimerism levels were significantly associated with a low lymphocyte count in the recipient before transplant, highlighting the impact of pretransplant lymphopenia on the kinetics of engraftment after RIC HSCT. In summary, low donor chimerism levels are associated with relapse and mortality and can potentially be used as an early predictive and prognostic marker. These findings can be used to design novel approaches to prevent relapse and to improve survival after RIC HSCT.     

Addition of Thiotepa to Total Body Irradiation and Cyclophosphamide Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia

Total body irradiation (TBI)/cyclophosphamide (CY) is a standard-of-care conditioning regimen in allogeneic hematopoietic stem cell transplant (HSCT) for pediatric acute lymphoblastic leukemia (ALL). This study sought to identify whether the addition of thiotepa (TT) to TBI/CY improves HSCT outcomes for pediatric patients with ALL. A retrospective analysis was performed on 347 pediatric ALL patients who underwent HSCT between 1995 and 2015, with 242 receiving TBI/CY/TT and 105 patients receiving TBI/CY. There were no statistical differences in age, donor source, or complete remission status between the 2 groups. Comparison of the TBI/CY/TT versus TBI/CY groups demonstrated no difference in transplant-related mortality at 1 (11% versus 11%), 5 (13% versus 16%), or 10 years (16% versus 16%). There was lower relapse in the TBI/CY/TT group at 1 (14% versus 26%), 5 (24% versus 36%), 10 (26% versus 37%), and 15 years (26% versus 37%) (P= .02) but was not statistically significant on multivariate analysis. The TBI/CY/TT group showed a trend toward improved disease-free survival (DFS) at 5 (59% versus 47%), 10 (56% versus 46%), and 15 years (49% versus 40%) (P = .05) but was not statistically significant on multivariate analysis. Comparing overall survival at 5 (62% versus 53%), 10 (57% versus 50%), and 15 years (50% versus 44%) demonstrated no statistical difference between the 2 groups. The addition of thiotepa to TBI/CY demonstrated no increase in transplant-related mortality for pediatric ALL HSCT but was unable to demonstrate significant benefit in disease control. Minimal residual disease status remained the key risk factor impacting both relapse and DFS. More studies are warranted to better clarify the benefits of using thiotepa in conditioning for ALL HSCT.     

Allogeneic Hematopoietic Cell Transplantation in Children with Relapsed Acute Lymphoblastic Leukemia Isolated to the Central Nervous System

Allogeneic hematopoietic cell transplantation (HCT) is the standard of care for pediatric patients with early medullary relapse of acute lymphoblastic leukemia (ALL). Most patients with isolated central nervous system (CNS) relapse have good outcomes when treated with intrathecal and systemic chemotherapy followed by irradiation to the neuroaxis. However, the role of HCT remains unclear for those patients with early isolated CNS relapse (<18 months) or who had high risk disease at diagnosis. We therefore compared the HCT outcomes of 116 children treated at the University of Minnesota from 1991 to 2006 with relapsed ALL involving the CNS alone (CNS, n = 14), the bone marrow alone (BM, n = 85), or both bone marrow and CNS (BM + CNS, n = 17). There were no significant differences among groups in age at diagnosis or transplant, length of first complete remission (CR1), remission status (CR2 versus ≥CR3), graft source, or preparative regimen. The incidence of acute GVHD was similar between groups. Patients with isolated CNS relapse had the lowest cumulative incidence of mortality following transplant (CNS: 0%, BM: 19%, BM + CNS: 29%, P = .03) and relapse (CNS: 0% BM: 30%, BM + CNS: 12%, at 2 years, P = .01) and highest leukemia-free survival (CNS: 91%, BM: 35%, BM + CNS: 46%, P < .01) at 5 years. Risk factors for poor survival were: T cell leukemia or BCR-ABL gene rearrangement, history of marrow relapse, and receipt of HLA-mismatched marrow. These data support the use of allogeneic HCT in the treatment of children with poor prognosis isolated CNS relapse.     

Allogeneic Hematopoietic Stem Cell Transplantation,Especially Haploidentical,May Improve Long-Term Survival for High-Risk Pediatric Patients with Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia in the Tyrosine Kinase Inhibitor Era

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly haploidentical (haplo)-HSCT, in pediatric patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in the tyrosine kinase inhibitor (TKI) era is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of Ph+ ALL in the TKI era. We analyzed clinical data of Ph+ ALL patients aged 1 to 18 years who received imatinib added to intensive chemotherapy at the start of induction therapy. Among the 68 patients who completed at least 2 consolidation cycles, 44 underwent transplantation (transplant arm) and 24 received continuous TKI with chemotherapy (nontransplant arm). At the 3-year follow-up the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 23.5%, 73.4%, and 80.3%, respectively. Multivariate analysis showed that hematologic response (whether complete remission [CR] was achieved) at the induction end, BCR-ABL levels (whether major molecular response [MMR] was achieved) at 3 months, and transplantation were independent affecting factors for CIR, EFS, and OS. In the risk stratification analysis based on the first 2 prognostic factors mentioned above, no significant difference existed between the transplant and nontransplant arms for the probabilities of 3-year OS, EFS, and CIR in the standard-risk group (no poor prognostic factors). Meanwhile, OS, EFS, and CIR rates were significantly better in the transplant arm in the high-risk group (≥1 poor prognostic factor). Among the 44 patients in the transplant arm, 37 underwent haplo-HSCT. Achieving CR at the induction end, MMR at 3 months, and haplo-transplant were also independent favorable factors of CIR, EFS, and OS in the nontransplant and haplo-HSCT arms. Haplo-HSCT showed a significant survival advantage in the high-risk group only. Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph+ ALL patients at a high risk of relapse in the TKI era. Children with Ph+ ALL in first CR may benefit from allo-HSCT, particularly those at high risk. Haplo-HSCT could achieve good long-term survival for pediatric Ph+ ALL. Thus, haplo-HSCT can be an alternative approach for high-risk Ph+ ALL patients.