Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group

While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18–36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0–3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58–65% vs. MRDpos 10–19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.     

Superior survival of unmanipulated haploidentical haematopoietic stem cell transplantation compared with intensive chemotherapy as post-remission treatment for children with very high-risk philadelphia chromosome negative B-cell acute lymphoblastic leukaemia in first complete remission

We explored the prognostic factors for children with very high-risk (VHR) Philadelphia chromosome (Ph) negative B-cell acute lymphoblastic leukaemia (B-ALL) and compared the therapeutic effects of intensive chemotherapy and unmanipulated haploidentical haematopoietic stem cell transplantation (haplo-HSCT) as post-remission treatment in these patients undergoing first complete remission (CR1). A total of 104 paediatric patients with VHR B-ALL in CR1 were retrospectively enrolled in this study, including 42 receiving unmanipulated haplo-HSCT (Group A) and 62 receiving ongoing chemotherapy (Group B). Estimated 3-year overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) at 36·2 months median follow-up were 69·5 ± 4·7%, 63·5 ± 4·8% and 32·4 ± 4·7%, respectively. Maintenance of persistent positive or conversion from negative to positive of measurable residual disease (MRD) and chemotherapy were independent risk factors associated with inferior long-term survival and higher CIR. OS, DFS, and CIR differed significantly between the groups in patients with persistent positive or negative-to-positive MRD. Haplo-HSCT may be an option for children with VHR Ph-negative B-ALL in CR1, especially for patients with persistent positive or negative-to-positive MRD, and could achieve better survival than intensive chemotherapy as post-remission treatment.     

Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation

This study evaluated the prognostic value of minimal residual disease (MRD) monitoring by four-color flow cytometry (FCM) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). MRD was examined with four-color FCM at different time points in 139 patients (including pediatric and adult patients) with ALL after allo-HSCT. Real-time quantitative polymerase chain reaction (RQ-PCR) was applied to evaluate the MRD of Philadelphia chromosome-positive ALL (Ph+ ALL) patients. Patients who were FCM-positive (FCM+) after transplantation had a lower event-free survival (EFS) of 0.54 and a higher cumulative incidence of relapse (CIR) of 0.54 compared to an EFS of 0.80 and a CIR of 0.08 in FCM-negative (FCM−) patients (EFS, p < 0.001; CIR, p < 0.001). Similar results were obtained in high-risk patients and Ph+ ALL patients. Moreover, a FCM+ status after the second month post-HSCT (defined as MRD positive) proved to be a predictor of leukemia relapse. Multivariate analysis for EFS, OS and CIR showed that MRD status after transplantation was an independent prognostic factor (p < 0.001, p = 0.013, and p < 0.001, respectively). A good correlation was found between the MRD results of FCM and RQ-PCR (n = 126 pairs, Spearman r = 0.8139, p < 0.001). MRD monitoring by four-color FCM post-transplantation is an important tool for relapse prediction in ALL patients. Prompt and appropriate pre-emptive anti-leukemia treatment could be considered based on the status of MRD after HSCT.     

Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts

This study evaluated the effects of pretransplantation minimal residual disease (pre-MRD) on outcomes of patients with acute lymphoblastic leukemia (ALL) who underwent unmanipulated haploidentical stem cell transplantation (haplo-SCT). A retrospective study including 543 patients with ALL was performed. MRD was determined using multiparametric flow cytometry. Both in the entire cohort of patients and in subgroup cases with T-ALL or B-ALL, patients with positive pre-MRD had a higher incidence of relapse (CIR) than those with negative pre-MRD in MSDT settings (P < 0.01 for all). Landmark analysis at 6 months showed that MRD positivity was significantly and independently associated with inferior rates of relapse (HR, 1.908; P = 0.007), leukemia-free survival (LFS) (HR, 1.559; P = 0.038), and OS (HR, 1.545; P = 0.049). The levels of pre-MRD according to a logarithmic scale were also associated with leukemia relapse, LFS, and OS, except that cases with MRD <0.01% experienced comparable CIR and LFS to those with negative pre-MRD. A risk score for CIR was developed using the variables pre-MRD, disease status, and immunophenotype of ALL. The CIR was 14%, 26%, and 59% for subjects with scores of 0, 1, and 2-3, respectively (P < 0.001). Three-year LFS was 75%, 64%, and 42%, respectively (P < 0.001). Multivariate analysis confirmed the association of the risk score with CIR and LFS. The results indicate that positive pre-MRD, except for low level one (MRD < 0.01%), is associated with poor outcomes in patients with ALL who underwent unmanipulated haplo-SCT.     

Detection of measurable residual disease may better predict outcomes than mutations based on next-generation sequencing in acute myeloid leukaemia with biallelic mutations of CEBPA

Acute myeloid leukaemia (AML) patients with biallelic mutations of CEBPA (bi CEBPA) have a 30–50% relapse rate. This study established the value of mutations based on next-generation sequencing (NGS) and multiparameter flow cytometric measurable residual disease (MFC-MRD) detection and compared the outcomes. From 2014 to 2018, 124 newly diagnosed bi CEBPA AML patients were treated. The median age was 37·5 (16–69) years. The 3-year cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS) were 33·0%, 64·7% and 84·3%, respectively. Patients without additional mutations and with GATA2 mutations were defined as ‘NGS low risk’, which was the only favourable independent factor for CIR and RFS of pretreatment parameters. Patients with sustained positive MRD after two consolidation cycles and MRD negative losses at any time were defined as ‘MRD high risk’, which was the only poor independent factor for CIR, RFS and OS, including pretreatment and post-treatment parameters. In CR2 and non-remission patients who underwent allo-HSCT, superior OS was achieved. We conclude that NGS low risk was a favourable factor in the analysis of pretreatment parameters. MRD risk stratification was an independent prognostic factor in pretreatment and post-treatment parameters. Relapsed patients still have a favourable outcome followed by allo-HSCT.     

Tandem autologous hematopoietic stem cell transplantation for treatment of adult T-cell lymphoblastic lymphoma: a multiple center prospective study in China

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive form of lymphoma with poor clinical outcomes and no standard treatment regimen. In this study, we assessed the safety and efficacy of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) for adult T-LBL and evaluated prognostic factors affecting survival. A total of 181 newly-diagnosed adult T-LBL patients were enrolled: 89 patients were treated with chemotherapy alone, 46 were allocated to the single auto-HSCT group, 46 were treated with tandem auto-HSCT. Median follow-up time was 37 months; the 3-year progression/relapse rate of the tandem auto- HSCT group was significantly lower than that of the single auto-HSCT and chemotherapy groups (26.5% vs. 53.1% and 54.8%). The 3-year progression- free survival (PFS) and overall survival (OS) rates of the tandem auto- HSCT group (73.5% and 76.3%) were significantly higher than those of the single auto-HSCT group (46.9% and 58.3%) and the chemotherapy group (45.1% and 57.1%). In the tandem auto-HSCT group, age and disease status after the first transplant impacted OS and PFS. Multivariate analysis identified that disease status after the first transplant was the only independent prognostic factor for patients treated with tandem-HSCT. In addition, diagnostic models of the initial CD8⁺CD28⁺/CD8⁺CD28^– T-cell ratio in predicting the disease status were found to be significant. Taken together, tandem auto- HSCT can be considered an optimal strategy for adult T-LBL patients. (Study registered at: ChiCTR-ONN-16008480).     

Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children’s Oncology Group phase III study AALL0433

Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. The children’s Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between March 2007 and October 2013 AALL0433 enrolled 275 participants with late bone marrow or very early isolated central nervous system (iCNS) relapse of childhood B-ALL. Patients were randomized to receive standard versus intensive vincristine dosing; this randomization was closed due to excess peripheral neuropathy in 2010. Patients with matched sibling donors received allogeneic hematopoietic cell transplantation (HCT) after the first three blocks of therapy. The prognostic value of minimal residual disease (MRD) was also evaluated in this study. The 3-year event free and overall survival (EFS/OS) for the 271 eligible patients were 63.6±3.0% and 72.3±2.8% respectively. MRD at the end of Induction-1 was highly predictive of outcome, with 3-year EFS/OS of 84.9±4.0% and 93.8±2.7% for patients with MRD <0.1%, versus 53.7±7.8% and 60.6± 7.8% for patients with MRD ≥0.1% (P<0.0001). Patients who received HCT versus chemotherapy alone had an improved 3-year disease-free survival (77.5±6.2% vs. 66.9 + 4.5%, P=0.03) but not OS (81.5±5.8% for HCT vs. 85.8±3.4% for chemotherapy, P=0.46). Patients with early iCNS relapse fared poorly, with a 3-year EFS/OS of 41.4±9.2% and 51.7±9.3%, respectively. Infectious toxicities of the chemotherapy platform were significant. The AALL0433 chemotherapy platform is efficacious for late bone marrow relapse of B-ALL, but with significant toxicities. The MRD threshold of 0.1% at the end of Induction-1 was highly predictive of the outcome. The optimal role for HCT for this patient population remains uncertain. This trial is registered at clinicaltrials.gov (NCT# 00381680).     

Haploidentical haematopoietic stem cell transplantation for TP53-mutated acute myeloid leukaemia

Acute myeloid leukaemia (AML) patients with tumour protein p53 (TP53) mutations are often resistant to chemotherapy and have worse clinical outcomes than patients without TP53 mutations. In this study, we compared clinical outcomes of patients with AML with and without TP53 mutations who underwent haploidentical haematopoietic stem cell transplantation (haplo-HSCT). For the TP53-mutation group and TP53 wild-type group, the 2-year cumulative incidence of relapse (CIR) was (39.0% vs. 21.2% respectively, p = 0.088), the 2-year non-relapse mortality (NRM) rate was (3.2% vs. 8.4% respectively, p = 0.370), the 2-year leukaemia-free survival (LFS) was (57.7% vs. 71.3% respectively, p = 0.205), the 2-year overall survival (OS) rate was (69.9% vs. 81.3% respectively, p = 0.317), the 100-day cumulative incidence of Grade II–IV acute graft-versus-host disease (GvHD) was (6.5% vs. 20.7% respectively, p = 0.074), the 2-year cumulative incidence of chronic GvHD was (52.3% vs. 53.1% respectively, p = 0.493) and the 2-year GvHD-free/relapse-free survival (GRFS) was (57.7% vs. 69.6% respectively, p = 0.347). Our data showed that there were no significant differences in 2-year clinical outcomes between the two groups. Multivariable analysis showed TP53 mutations had no significant impact on CIR, NRM, OS, GvHD, LFS or GRFS. Our findings suggest that patients with AML with TP53 mutations may at least partially benefit from haplo-HSCT. Haplo-HSCT might be the recommended treatment for such patients.     

The early achievement of measurable residual disease negativity in the treatment of adults with Philadelphia-negative B-cell acute lymphoblastic leukemia is a strong predictor for survival

The minimal or measurable residual disease (MRD) status following induction/consolidation chemotherapy is an important prognostic endpoint in adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, the optimal time-point (TP) of MRD assessment and its impact on outcome remains unclear. We analyzed 215 patients with newly diagnosed Philadelphia negative B-cell ALL who received intensive chemotherapy, and had available MRD assessment by multicolor flow cytometry at two separate TPs. The median time to first TP (1TP) and second TP (2TP) were 24 and 110 days, respectively. At 1TP, 148 patients (68%) were MRD negative and 67 (32%) were positive. Of the 148 patients with negative MRD at 1TP, 147 (99%) maintained it through 2TP. Patients who were MRD negative at both TPs, early MRD responders, had the 3-year event-free survival (EFS), and overall survival (OS) rates of 65% and 76%, respectively. Patients with improved MRD status from positive to negative, late MRD responders, had lower 3-year EFS and OS rates, 42% and 58%, respectively (P = .001). Multivariate analysis showed that KMT2A (MLL) rearrangement and MRD positivity at 1TP were the only factors correlated with worse OS. In conclusion, the earlier achievement of MRD negative remission is a stronger prognostic factor for survival.     

Long-term outcomes of HLA-matched sibling compared with mismatched related and unrelated donor hematopoietic stem cell transplantation for chronic phase chronic myelogenous leukemia: a single institution experience in China

Allogeneic hematopoetic stem cell transplantation (allo-HSCT) remains the only curative therapy for chronic myelogenous leukemia (CML). In this study, the long-term outcomes of HLA-matched sibling donor (MSD) with mismatched related donor (MRD) and unrelated donor (URD) transplantation for CML in the first chronic phase (CML-CP1) using different graft vs. host disease (GVHD) prophylaxis regimens according to donor source and the degree of HLA matching were compared. The data of 91 patients with CML-CP1 were analyzed with respect to GVHD, overall survival (OS), and transplant-related mortality (TRM). The incidence of grade II?CIV acute GVHD was 25.5% in the MSD and 40.5% in the MRD/URD group (P?=?0.133). The 1-year cumulative incidence of chronic GVHD was not different between the MSD and the MRD/URD groups, while extensive chronic GVHD was different between the two groups (31.9% vs. 10.8%, P?=?0.023). The 5-year cumulative relapse rate was not different between the MSD and the MRD/URD groups, while TRM was different between the two groups (6.6% vs. 26.3%, P?=?0.010). The 5-year cumulative OS was 90.9%, 71.5%, and 85.4% in the MSD, the MRD/URD, and the HLA allele-matched URD transplantation, respectively (MSD vs. MRD/URD, P?=?0.013; MSD vs. HLA allele-matched URD, P?=?0.437). In conclusion, survival in HLA allele-matched URD is equivalent to MSD, but in MRD and mismatched URD is inferior to MSD in patients with CML-CP1 undergoing allo-HSCT using different GVHD prophylaxis regimens according to donor source and degree of HLA matching. Patients undergoing MRD/URD transplantation have an equal quality of life as patients undergoing MSD transplantation.     

Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: An open-label pragmatic clinical trial

Chimeric antigen receptor-modified T-cell (CAR-T) therapy is effective and safe for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), but its value has been limited in terms of long-term leukemia-free survival. New strategies that can help CAR-T therapy achieve lasting effect are urgently warranted. This non-randomized interventional pragmatic clinical trial had a particular aim. It explored whether consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) could improve the long-term prognosis of the minimal residual disease-negative complete remission (MRD⁻ CR) patients after CAR-T therapy. In the first stage, 58 r/r B-ALL patients received split doses of CAR-T cells after lymphodepleting chemotherapy, and 51 (87.9%) achieved CR. In the second stage, 21/47 MRD⁻ CR patients without previous allo-HSCT and contraindications or other restrictions, on their own accord, received consolidative allo-HSCT within three months after CAR-T therapy. There was no difference in overall survival (OS) between the MRD⁻ CR patients who received allo-HSCT and those who did not. However, event-free survival (EFS) and relapse-free survival (RFS) were significantly prolonged by allo-HSCT in the subgroups. This was with either high (≥5%) pre-infusion bone marrow MRD assessed by flow cytometry (BM-FCM-MRD) or poor prognostic markers (P < .05). However, no difference was found in EFS and RFS for patients with pre-infusion BM-FCM-MRD <5% and without poor prognostic markers (P > .05). To conclude, CAR-T therapy bridging to allo-HSCT is a safe and effective therapeutic strategy for r/r B-ALL patients, and may prolong their EFS and RFS, especially when they have high pre-infusion BM-FCM-MRD or poor prognostic markers.     

Outcome of children with newly diagnosed acute lymphoblastic leukemia treated with CCLG‐ALL 2008: The first nation‐wide prospective multicenter study in China

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. The trial Chinese Children Leukemia Group (CCLG)‐ALL 2008 was a prospective clinical trial designed to improve treatment outcome of childhood ALL through the first nation‐wide collaborative study in China. Totally 2231 patients were recruited from ten tertiary hospitals in eight cities. The patients were stratified according to clinical‐biological characteristics and early treatment response. Standard risk (SR) and intermediate risk (IR) groups were treated with a modified BFM based protocol, and there was 25%‐50% dose reduction during intensification phases in the SR group. Patients in high risk (HR) group received a more intensive maintenance treatment. Minimal residual disease (MRD) monitoring with treatment adjustment was performed in two hospitals (the MRD group). Complete remission (CR) was achieved in 2100 patients (94.1%). At five years, the estimate for overall survival (OS) and event‐free survival (EFS) of the whole group was 85.3% and 79.9%, respectively. The cumulative incidence of relapse (CIR) was 15.3% at five years. The OS, EFS and CIR for the SR group were 91.5%, 87.9%, and 9.7%, respectively. The outcome of the MRD group is better than the non‐MRD group (5y‐EFS: 82.4% vs 78.3%, P = .038; 5y‐CIR: 10.7% vs 18.0%, P < .001). Our results demonstrated that the large‐scale multicenter trial for pediatric ALL was feasible in China. Dose reduction in the SR group could achieve high EFS. MRD‐based risk stratification might improve the treatment outcome for childhood ALL.     

Impact of minimal residual negativity using next generation flow cytometry on outcomes in light chain amyloidosis

We evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥1 × 10⁻⁵; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in 2 years from start of therapy (median: 7 months). The overall MRD negative rate was 64% (n = 28). The MRD-negative rate after one-line of therapy was 71% (20/28). And, MRD negative rates were higher with stem-cell transplant as first-line therapy (86%, 18/21) vs chemotherapy alone as first-line treatment (29%, 2/7), P = .005. The MRD negative rate amongst patients in complete response was 75% (15/20), and in very good partial response, 50% (11/22). There were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs MRD positive patients, except younger age amongst MRD-negative patients. Patients with MRD negativity were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs 22% (2/7), P = .04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow-up of 14 months, the estimated 1-year progression free survival in MRD negative vs MRD positive patients was 100% (26 patients, 0 events) vs 64% (16 patients, five events), P = .006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk-adapted trials may help optimize treatment in AL amyloidosis.     

The superiority of allogeneic hematopoietic stem cell transplantation from unrelated donor over chemotherapy for adult patients with high-risk acute lymphoblastic leukemia in first remission

For adult patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched related donors (MSD) is recommended for standard and high-risk patients. The role of unrelated donor transplantation (URD) in first remission has not been fully determined. We sought to compare directly the outcome of URD allo-HSCT and chemotherapy in patients with high-risk ALL. In this single-center retrospective analysis, we included 74 consecutive adult patients with high-risk ALL in first complete remission (CR) and without a sibling donor, in which 32 patients received URD allo-HSCT in CR1 with busulfan-cyclophosphamide preparation regimen and in vivo T-cell depletion with anti-T-lymphoglobulin (ATG). The remaining 42 patients received chemotherapy consolidation and maintenance only in first remission. With median follow-up of 18 months, in the URD allo-HSCT group, the relapse rate (RR) was 30.6 ± 11.4 % which was significantly lower than that of the chemotherapy group (80.5 ± 10.1 %, p < 0.001), while non-relapse mortality (NRM) was higher (16.4 ± 6.7 % vs. 0, p = 0.028). Overall, 3-year leukemia-free survival (LFS) was superior in the URD allo-HSCT group compared to chemotherapy group (57.8 ± 10.6 vs. 19.5 ± 10.5 %, p = 0.002), as was 3-year overall survival (OS, 63.5 ± 13.3 vs. 31.6 ± 10.6 %, p = 0.016). URD HSCT was the only factor associated with improved OS, LFS and reduced RR in multivariate analysis. Based on our data, URD allo-HSCT significantly reduced the relapse in high-risk ALL and the benefit translated into improvement in both LFS and OS. Prospective studies based on availability of HLA-matched URD are warranted to evaluate the precise role of URD transplantation in adult ALL.     

The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients

STUDY OBJECTIVES: To review our experience with diagnostic bronchoscopy in the evaluation of pulmonary infiltrates in adult hematopoietic stem cell transplantation (HSCT) recipients in the era of Pneumocystis prophylaxis and cytomegalovirus antigen testing. The study focused on diagnostic yields and the influence of bronchoscopic findings on pharmacologic therapy and mortality, comparing allogeneic (allo) HSCT patients to autologous (auto) HSCT patients. DESIGN: Case series review. SETTING: Tertiary care academic urban medical centers. PATIENTS: All adult allo-HSCT and auto-HSCT patients undergoing bronchoscopy for the evaluation of pulmonary infiltrates from January 1997 to September 2001. MEASUREMENTS AND RESULTS: The review identified 169 bronchoscopies that had been performed on HSCT patients, representing 12.5% of all HSCT patients (allo-HSCT patients, 125 bronchoscopies; auto-HSCT patients, 44 bronchoscopies). Bronchoscopy was requested more often in allo-HSCT patients (18.7%) compared to auto-HSCT patients (6.6%). Findings at bronchoscopy provided a specific diagnosis more frequently in allo-HSCT patients (50%) compared to auto-HSCT patients (34%). For both allo-HSCT and auto-HSCT patients, most diagnoses were obtained by BAL alone, whereas transbronchial biopsy (TBBx) provided additional specific information in < 10% of cases. For select patients (n = 27), surgical lung biopsy following bronchoscopy provided unique diagnoses in 47 to 50% of cases. Information from bronchoscopy influenced clinical decisions more often in allo-HSCT patients (50%) than in auto-HSCT patients (36%), and allowed for the discontinuation or addition of antimicrobial, corticosteroid, or antineoplastic agents to treatment. Complications from bronchoscopy occurred in 9% of all HSCT patients (n = 15), and were associated with higher in-hospital mortality rates in allo-HSCT patients (82%; n = 9) compared to auto-HSCT patients (50%; n = 2). The overall in-hospital mortality rates for allo-HSCT and auto-HSCT patients having bronchoscopy was similar (38% vs 27%, respectively; p = 0.25), and establishing a specific diagnosis by bronchoscopy did not improve the in-hospital mortality rate for allo-HSCT or auto-HSCT patients. CONCLUSIONS: Bronchoscopy may provide clinically useful information in the evaluation of adult allo-HSCT and auto-HSCT recipients with pulmonary infiltrates. The results of testing BAL fluid samples alone suggested an etiology in most cases, whereas the findings of TBBx provided unique diagnoses infrequently. Further studies are warranted to improve the utility of diagnostic bronchoscopy in the evaluation of HSCT patients.     

A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma

Mantle cell lymphoma (MCL) is associated with high relapse rates and poor survival when treated with conventional chemotherapy, with or without rituximab. We report the long-term follow-up of a phase II clinical trial using a new intensive multiagent chemotherapeutic regimen [cyclophosphamide, teniposide, doxorubicin and prednisone (CTAP) alternating with vincristine and high-dose methotrexate and cytarabine (VMAC)] in newly diagnosed MCL. Following 4–6 cycles of CTAP/VMAC induction, patients aged ≤65 years proceeded to consolidative autologous haematopoietic stem cell transplantation (auto-HSCT), while patients ≤55 years who had a HLA-identical sibling received allogeneic-HSCT (busulfan/cyclophosphamide conditioning for both). Twenty-five untreated MCL patients enrolled on the protocol between 1997 and 2002. Among evaluable patients, overall response rate (ORR) was 74% following induction chemotherapy. Seventeen patients received HSCT (autologous-13/allogeneic-4). On intent-to-treat analysis, ORR for patients who received consolidative HSCT was 100% (complete remission 76%). Therapy was well-tolerated with 4% treatment-related mortality (including HSCT). The 5-year event-free-survival (EFS) and overall survival (OS) for all patients was 35% and 50% respectively. Furthermore, at 66-months median follow-up, the 5-year EFS and OS for patients who received consolidative auto-HSCT was 54% and 75% respectively. Patients who received auto-HSCT had improved outcomes compared to no auto-HSCT (EFS P  = 0·001; OS P  = 0·0002). CTAP/VMAC induction followed by consolidative auto-HSCT for newly diagnosed MCL is associated with high ORR and durable survival.     

ABCG2 overexpression in patients with acute myeloid leukemia: Impact on stem cell transplantation outcome

ABGG2 protein overexpression in acute myeloid leukemia (AML) has been associated with poor response to conventional chemotherapy and increased relapse risk. No data are available on the role of allogeneic stem cell transplantation (SCT) in reversing its negative prognostic role. We have reviewed the outcome of 142 patients with high risk AML who underwent allogeneic SCT in complete remission (n = 94) or with active disease (n = 48). Patients with ABCG2 overexpression at AML diagnosis have lower leukemia free survival (LFS) and increased cumulative incidence of relapse (CIR) compared with ABCG2? patients (5‐year LFS 50% vs. 65%, P = 0.01; 5‐year CIR 46% vs. 27%, P = 0.003). Five‐year overall survival was not significantly different between ABCG2+ and ABCG2? patients (39% vs. 51%, P = 0.1). However, if we consider only disease‐related deaths, ABCG2 maintains its negative role (64% vs. 78%, P = 0.018). The negative impact of ABCG2 overexpression was higher in patients undergoing SCT in CR compared with patients receiving transplant with active disease. Conditioning regimen did not abrogate the effect of ABCG2 overexpression, as CIR was higher in ABCG2+ patients receiving both myeloablative (44% vs. 22%, P = 0.018) or reduced intensity conditioning (50% vs. 32%, P = 0.03). In conclusion, ABCG2 overexpression at AML diagnosis identifies a subset of patients with poor outcome also after allogeneic SCT, mainly in terms of higher relapse rates. Prospective studies employing conditioning drugs or post‐transplant strategies able to target ABCG2 are needed to maximize the curative potential of stem cell transplantation.Am. J. Hematol. 90:784–789, 2015. © 2015 Wiley Periodicals, Inc.     

A comprehensive SEER registry analysis of elderly patients with classical Hodgkin lymphoma based on treatment era and race

We conducted a Surveillance, Epidemiology, and End Results Program (SEER-18) registry analysis of classical Hodgkin lymphoma (cHL) patients more than 60 years old and compared outcomes of those diagnosed between 2006 and 2010 (cohort 1) to those identified between 2011 and 2015 (cohort 2) based on treatment era and race. Cohort 1 had a median overall survival (OS) of 4 years and cohort 2 had a median OS of 4.75 years [hazard ratio (HR): 0.92 (0.85–1.00); p = 0.052]. Non-Hispanic blacks (NHBs) had a similar 5-year OS compared to non-Hispanic whites (NHWs) of 48.6% vs. 50.2% (HR: 0.95 [0.79–1.15]; p > 0.99); on the contrary, Hispanics had worse 5-year OS of 41.8% vs. 48.6% (HR: 1.24 [1.09–1.41]; p < 0.001). NHW was the only race that had improvement in 5-year OS in 2011–2015 compared to 2006–2010 (51% vs. 46.5%, p = 0.002). In the multivariable analysis, older age, male gender, stage III–IV, unmarried status, Hispanic race, lack of chemotherapy, and diagnosis in 2006–2010 were associated with worse OS. Lymphoma was the most common cause of death in 60% of patients. In conclusion, elderly cHL patients diagnosed after 2010 had improved OS by nine months that was most prevalent in NHWs, and disparity in OS existed between NHWs and Hispanics throughout the study period.     

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment‐related mortality of 8%. Leukaemia‐free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre‐HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre‐HSCT (LFS 41%, OS 64%, P < 0·0001) or post‐HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B‐other ALL had more relapses (CIR 50%, LFS 41%) than T‐ALL and the main precursor‐B subtypes including BCR‐ABL1, KMT2A (MLL), ETV6‐RUNX1 (TEL‐AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B‐other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post‐HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post‐HSCT therapy.     

High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL

Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n=35) or at relapse (n=38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P=0.049) and overall survival (OS) (P=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1-1% and <0.1% respectively. Among relapsed patients, 23 received blinatumomab with overt relapse and 15 were in complete response (CR) after bridging chemotherapy. At 3 years, overall CR rate was 68% and complete MRD response rate was 84%. Patients who directly received blinatumomab had shorter relapse-free survival (P=0.033) and OS (P=0.003) than patients bridged to blinatumomab. Three-year OS was 66% in the latter group compared to 16% in the former group. Our observations suggest that pre-blinatumomab tumor burden should help to design more tailored strategies including tumor load reduction in relapsed patients.