A Comparison of Long-Term Outcomes of Donor Lymphocyte Infusions and Tyrosine Kinase Inhibitors in Patients With Relapsed CML After Allogeneic Hematopoietic Cell Transplantation

BackgroundDonor lymphocyte infusion (DLI) and tyrosine kinase inhibitors (TKIs) are the 2 standard treatment options in chronic myeloid leukemia (CML) that relapses after hematopoietic cell transplantation (HCT), but reports comparing long-term outcomes of these modalities are rare.Patients and MethodsA total of 46 patients were treated with either DLI (n = 28) or TKIs (n = 18) during a first relapse of CML after HCT between 1993 and 2012. The stage of relapse was the chronic phase in 37 patients and the advanced phase in 9 patients. All patients had myeloablative conditioning without T-cell depletion during HCT. The median interval between HCT and treatment for relapse was 34 (range, 2-197) months.ResultsAt a median follow-up of 146 and 70 months, respectively, 32% of the DLI group and 33% of the TKI group had died. Six (21%) patients initially treated with DLI received TKIs during a second relapse. In multivariable analyses, DLI was associated with inferior overall survival (OS) (hazard ratio [HR], 37.4; 95% confidence interval [CI], 2.2-625.4; P = .01), shorter failure-free survival (FFS) (HR, 21.15; 95% CI, 1.8-251; P = .02), higher cumulative incidence of failure (CIF) (HR, 19.5; 95% CI, 1.6-236.5; P = .02), and increased incidence of treatment-induced graft vs. host disease (GVHD) (68% vs. 6%; P = .001).ConclusionTKIs appear better than DLI in chronic-phase relapses after myeloablative non–T-cell-depleted HCT. Outcomes were poor in advanced-phase relapses irrespective of treatment modality.     

Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research

There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23-46%) in the autologous group and 20% (95% CI, 10-34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48-72%) in the autologous group and 38% (95% CI, 25-53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52-75%) in the autologous group and 39% (95% CI, 26-54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1-11%) in the autologous group and 41% (95% CI, 28-56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit.     

Comparison of Outcomes After Second Allogeneic Hematopoietic Cell Transplantation Versus Donor Lymphocyte Infusion in Allogeneic Hematopoietic Cell Transplant Patients

BackgroundAllogeneic hematopoietic cell transplantation (HCT) is potentially curative for hematological disease however can be complicated by relapse or graft failure (GF), for which second-HCT and donor lymphocyte infusions (DLI) are performed. This study aimed to compare outcomes following the two interventions.MethodsWe retrospectively investigated 89 patients with relapse or GF after first-HCT, 50 (56%) underwent second HCT and 39 (44%) received (DLI), from June 2011 to September 2020.ResultsMedian age at intervention was 55 years (19-72). Second-HCT was performed for relapse in 19 patients and for GF in 31 patients (primary GF in 11 and secondary in 20 patients), same donor was used in 25 (50%) patients. DLI was performed for relapse in 20 and for secondary GF in 19 patients. Median number of DLI administered was 2 (range 1-11). Univariate analysis demonstrated 2 year overall survival (OS) for second-HCT was superior when performed for relapse (65%) compared to GF (44%) (P = .03). For DLI patients, 2 year OS was 49% for GF and 45% for relapse patients (P = .49). For relapse as an indication, second-HCT demonstrated borderline superiority compared to DLI (P = .07). Multivariable analysis demonstrated for OS for the entire cohort demonstrated donor mismatch (HR 0.50, 95% CI 0.26%-0.94%, P = .03), KPS at time of intervention (HR 2.10, 95% CI 1.14%-3.85%, P = .02) and time from first-HCT to intervention (HR 0.51, 95% CI 0.28%-0.93%, P = .03) as significant variables.ConclusionSecond-HCT may improve outcomes when performed for relapse post-transplant if patients achieve remission again, while DLI may be reserved for patients with active disease.     

Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Waldenström Macroglobulinemia: A Systematic Review and Meta-analysis

IntroductionWaldenström macroglobulinemia (WM) is an IgM-producing lymphoproliferative disorder that remains incurable. Patients with high-risk disease have an overall survival (OS) of less than 3 years. Both autologous (AHCT) and allogeneic (allo-HCT) hematopoietic cell transplantation (HCT) are prescribed for treatment of WM despite a lack of randomized controlled studies.Materials and MethodsWe performed a comprehensive literature search using PubMed/Medline and EMBASE on September 10, 2019. Data on clinical outcomes related to benefits and harms was extracted independently by 3 authors. Fifteen studies (8 AHCT [n = 278 patients], 7 allo-HCT [n = 311 patients]) were included in this systematic review/meta-analysis.ResultsPooled OS, progression-free survival (PFS), and nonrelapse mortality (NRM) rates post AHCT were 76% (95% confidence interval [CI], 65%-86%), 55% (95% CI, 42%-68%), and 4% (95% CI, 1%-7%), respectively. Pooled OS, PFS, and NRM rates post allografting were 57% (95% CI, 50%-65%), 49% (95% CI, 42%-56%), and 29% (95% CI, 23%-34%), respectively. OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies. Pooled ORR (at day 100) post AHCT and allo-HCT were 85% (95% CI, 72%-94%) and 81% (95% CI, 69%-91%), respectively. Pooled complete response rates post AHCT and allo-HCT were 22% (95% CI, 17%-28%) and 26% (95% CI, 7%-50%), respectively. Relapse rates post AHCT and allo-HCT were 42% (95% CI, 30%-55%) and 23% (95% CI, 18%-28%), respectively.ConclusionsOur results show that both AHCT and allo-HCT are effective in the treatment of WM. A 2-fold lower relapse rate but a 7-fold higher NRM was noted for allo-HCT compared with AHCT. The role of transplant in WM needs to be addressed in the era of novel agents.     

Day +100 Platelet Count Predicts Survival After Allogeneic Hematopoietic Stem-Cell Transplantation in Children With Hematologic Malignancies

IntroductionRecovery of platelet count by day 100 after hematopoietic stem-cell transplantation (HSCT) is affected by many factors and has been reported to be a predictor of overall survival (OS) in a variety of diseases and donor types. We investigated the correlation between day +100 platelet count and OS after allogeneic HSCT in a relatively homogeneous cohort of pediatric patients with hematologic malignancies.Patients and MethodsWe conducted a retrospective study of 152 consecutive patients who underwent allogeneic HSCT at the Children’s Cancer Hospital Egypt between 2009 and 2015 with a minimum follow-up duration of 1 year after transplantation. All eligible patients received myeloablative conditioning, and all had matched related donors. Patients who survived without relapse until day 100 after HSCT were divided into 2 groups: early platelet recovery (EPR; platelet count ≥ 100 × 10⁹/L at day +100 after transplantation) and delayed platelet recovery (DPR; platelet count < 100 × 10⁹/L at day +100 after transplantation).ResultsAt day +100, 113 patients (74%) had EPR and 39 patients (26%) had DPR. With a median follow-up of 41 months (range, 12-93 months), 41 patients (27.2%) died, 35 of relapsed disease. The 3-year disease-free survival (DFS) and OS were 68 ± 7.84% and 71.9 ± 7.84%, respectively. The 3-year OS was 77.9% in the EPR group and 57.1% in the DPR group (P = .006). Three-year DFS of the EPR and DPR groups were 73.2 ± 9% and 54.8 ± 16.3%, respectively (P = .02). Incidence of disease relapse for EPR and DPR patients was 22.6% and 39.5%, respectively (P = .04). Multivariate analysis for survival identified DPR as a predictor of decreased survival (P = .002).ConclusionPatients with a robust platelet count at day 100 are likely to do well. However, patients who do not experience a platelet count of ≥ 100 × 10⁹/L have inferior long-term OS and DFS and may require further evaluation at the day 100 time point.     

A Portrait of SARS-CoV-2 Infection in Patients Undergoing Hematopoietic Cell Transplantation: A Systematic Review of the Literature

The management of COVID-19 in hematopoietic cell transplant (HCT) recipients represents a special challenge given the variable states of immune dysregulation and altered vaccine efficacy in this population. A systematic search (Ovid Medline and Embase on 1 June 2021) was needed to better understand the presenting features, prognostic factors, and treatment options. Of 897 records, 29 studies were identified in our search. Most studies reporting on adults and pediatric recipients described signs and symptoms that were typical of COVID-19. Overall, the mortality rates were high, with 21% of adults and 6% of pediatric HCT recipients succumbing to COVID-19. The factors reported to be associated with increased mortality included age (HR = 1.21, 95% CI 1.03–1.43, p = 0.02), ICU admission (HR = 4.42, 95% CI 2.25–8.65, p < 0.001 and HR = 2.26, 95% CI 1.22–4.20, p = 0.01 for allogeneic and autologous HCT recipients), and low platelet count (OR = 21.37, 95% CI 1.71–267.11, p = 0.01). Performance status was associated with decreased mortality (HR = 0.83, 95% CI 0.74–0.93, p = 0.001). A broad range of treatments was described, although no controlled studies were identified. The risk of bias, using the Newcastle–Ottawa scale, was low. Patients undergoing HCT are at a high risk of severe morbidity and mortality associated with COVID-19. Controlled studies investigating potential treatments are required to determine the efficacy and safety in this population.     

Results of a Phase II Trial of Allogeneic Hematopoietic Stem Cell Transplantation Using 90Y-Ibritumomab Tiuxetan (Zevalin) in Combination With Fludarabine and Melphalan in Patients With High-Risk B-Cell Non-Hodgkin's Lymphoma

BackgroundAllogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (B-cell NHL). However, relapse remains a major cause of treatment failure, especially in patients with either positron emission tomography (PET)-positive and/or chemoresistant disease prior to alloHCT. ⁹⁰Y-ibritumomab tiuxetan (Zevalin) is a radiolabeled anti-CD20 antibody which is a safe and effective therapy in multiple histologic subtypes of B-cell NHL and has also been incorporated in both autologous HCT (autoHCT) and alloHCT conditioning regimens.ObjectivesThe purpose of this study was to evaluate the efficacy and confirm the safety of the radiolabeled anti-CD20 antibody ibritumomab tiuxetan (Zevalin) combined with the reduced intensity conditioning (RIC) regimen of fludarabine and melphalan (Flu/Mel) in patients with high-risk B-cell NHL.Study DesignWe conducted a phase II trial (NCT00577278) of Zevalin with Flu/Mel in patients with high-risk B-cell NHL. We enrolled 41 patients from October 2007 to April 2014, all of whom had either a fully matched sibling or 8/8 or 7/8 matched unrelated donor (MUD). Patients received ¹¹¹In-Zevalin (5.0 mCi) on day −21 pre-HCT, followed by ⁹⁰Y-Zevalin (0.4 mCi/kg) on day −14. Fludarabine (25 mg/m² daily) was given from days −9 to −5 and melphalan (140 mg/m²) was administered on day −4. All patients received rituximab 250 mg/m2 on day +8 and an additional dose on either day +1 or −21 depending on the baseline rituximab level. Patients with a low rituximab level were given rituximab on days −21 and −15. All patients received tacrolimus/sirolimus (T/S) with or without methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis starting on day −3, and stem cells were infused on day 0.ResultsThe 2-year overall survival (OS) and progression-free survival (PFS) for all patients were 63% and 61%, respectively. The incidence of relapse at 2 years was 20%. Nonrelapse mortality (NRM) at day +100 and 1 year were 5% and 12%, respectively. The overall cumulative incidence of grade II-IV and III-IV acute GVHD (aGVHD) were 44% and 15%, respectively. Extensive chronic GVHD (cGVHD) occurred in 44% of patients. On univariate analysis, histology (diffuse large B cell lymphoma (DLBCL) vs. others) was negatively predictive for OS (P = .0013) and PFS (P = .0004), while histology (DLBCL vs. others, P = .0128) predicted for relapse. PET positivity pre-HCT did not correlate with any of the efficacy endpoints.ConclusionAddition of Zevalin to Flu/Mel is safe and effective in high-risk NHL and met the prespecific endpoint. Results were suboptimal in patients with DLBCL.     

Patterns of Relapse After Salvage Autologous Stem Cell Transplant for Hodgkin's Lymphoma: Should Sites of Relapse Relative to Initially Involved Sites Be Used to Guide Indications for Peri-Transplant Radiation Therapy

PurposeWe aimed to assess patterns of relapse in patients undergoing salvage autologous stem cell transplant (ASCT) for relapsed Hodgkin lymphoma in the modern era with the hypothesis that patients who suffer a relapse at initially involved sites are at increased risks of relapse post-ASCT that may help guide the application of peri-transplant radiation therapy.Methods and MaterialsA retrospective review was conducted of 38 patients undergoing ASCT between 2002 and 2017 for relapsed or refractory Hodgkin lymphoma. The site of relapse at the time of ASCT and subsequent relapses were compared with sites of the initial involvement at the time of diagnosis using follow-up imaging (most commonly positron emission computed tomography). Relapse and overall survival rates were calculated from the date of ASCT using the Kaplan-Meier method with a multivariate analysis, completed using a Cox multivariate analysis.ResultsThe median follow-up time was 38 months (interquartile range, 18-66 months). Twenty-two patients (58%) suffered a relapse after ASCT at a median time to relapse of 9.1 months (interquartile range, 2.9-12.3 months) with a 5-year risk of relapse of 58% (95% confidence interval [CI], 41%-75%). On univariate analysis, relapse at an initially involved site was significant for higher rates of relapse at 71% at 5-years (95% CI, 52%-90%) compared with relapse at initially uninvolved sites at 30% (95% CI, 2%-58%; P = .05). The relapse rate was also significantly higher in patients age <30 years at the time of diagnosis at 80% (95% CI, 59%-100%) compared with 40% (95% CI, 18%-62%) at 5 years in patients aged >30 years (P < .01). On multivariate analysis, relapse at initially involved sites was significant for higher rates of relapse (hazard ratio: 8.3; 95% CI, 1.2-57.4; P = .03).ConclusionsRelapses at initially involved sites may potentially increase the risk of relapse after ASCT. Additional studies are needed to clarify whether this should be used as an additional factor to guide recommendations for peri-transplant radiation therapy.     

Favorable Outcomes With Tumor Burden Reduction Following Administration of Hypomethylating Agents Before Allogeneic Hematopoietic Cell Transplantation in Patients With Higher Risk Myelodysplastic Syndrome

IntroductionThe clinical significance of tumor burden reduction following administration of hypomethylating agents (HMAs) for transplant-eligible patients with higher risk myelodysplastic syndrome (MDS) was evaluated.Patients and MethodsData of 79 transplant-eligible patients (< 65 years) diagnosed with higher-risk MDS between July 2002 and March 2013 were retrospectively analyzed. Among 79 patients, 30 (38%) underwent allogeneic hematopoietic cell transplantation (HCT group), and 49 (62%) were treated with HMA alone (non-HCT group).ResultsThe median follow-up duration was 732 days (range, 28-1952 days), and the 3-year overall survival (OS) rate of all patients was 30.6%. In the HCT group, early HCT showed a better 3-year OS rate than late HCT (67.1% vs. 25.7%; P = .035). In multivariate analysis, time/performance of allogenic transplant (no HCT vs. early HCT, hazard ratio, 0.18; 95% confidence interval, 0.04-0.81; P = .026) and follow-up higher risk International Prognostic Scoring System (hazard ratio, 6.22; 95% confidence interval, 2.09-18.51; P = .001) were significantly correlated with OS.ConclusionTo predict the clinical outcomes of patients with higher risk MDS, the optimal time for tumor burden evaluation is prior to follow-up rather than at the time of initial diagnosis. Patients with lower International Prognostic Scoring System risk groups after HMA treatment or early HCT had favorable OS.     

High-dose Therapy and Autologous Hematopoietic Cell Transplantation as Consolidation Treatment for Primary Effusion Lymphoma

BackgroundPrimary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma. The limited disease-free survival after chemotherapy has resulted in a poor prognosis. The outcomes data for high-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) for PEL are limited owing to the rarity of the disease.Patients and MethodsThe present study included 9 patients with PEL from 2 major academic centers. Of these patients, 4 had received auto-HCT after high-dose therapy. Of the 9 patients, 8 (89%) had immunodeficiency (7 with human immunodeficiency virus seropositivity; 1, a solid organ transplant recipient) at the diagnosis. Human herpesvirus-8 by immunohistochemistry was positive in 8 patients. Anthracycline-based combination chemotherapy was used as first-line treatment in 7 patients; 4 underwent auto-HCT after attaining first complete remission.ResultsThe median follow-up of the surviving patients was 25 months (95% confidence interval [CI], 8%-29%). The 2-year progression-free and overall survival for the 8 patients who had received treatment was 58% (95% CI, 22%-95%) and 73% (95% CI, 41%-100%), respectively. The 2-year progression-free and overall survival for the patients who had received auto-HCT was 50% (95% CI, 1%-99%) and 75% (95% CI, 33%-100%), respectively. Of the 4 auto-HCT recipients, all had been in first complete remission at the time of autografting. The cumulative incidence of relapse was 50% (95% CI, 19%-100%). No deaths were attributable to auto-HCT at 2 years after autografting.ConclusionDespite the small sample size, our data have shown that consolidative auto-HCT is safe and effective and should be considered for eligible patients with PEL after demonstration of an objective response to induction chemotherapy. However, the high relapse rate remains a concern and warrants the development of new strategies to mitigate post-transplantation relapse.     

Role of Allogeneic HCT as Postremission Therapy for Transplant-Eligible Adult Lymphoblastic Leukemia/Lymphoma After Frontline Hyper-CVAD

BackgroundHyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with cytarabine and methotrexate (hyper-CVAD) is a commonly used regimen in adults with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Adult patients fit for pediatric-inspired protocols have an excellent outcome with chemotherapy alone. However, it is unclear whether patients receiving hyper-CVAD should undergo allogeneic hematopoietic cell transplantation (HCT) as postremission therapy. Our aim was to examine the role of HCT at first complete remission (CR1) in adult ALL/LBL after hyper-CVAD.Patients and MethodsAdult patients with newly diagnosed ALL/LBL receiving frontline hyper-CVAD from 2008 to 2018 were identified and records retrospectively extracted.ResultsA total of 85 patients were identified and included for further analysis. The median (range) age was 23 (14-68) years, and 56 (66%) were male. A total of 24 (28%) had adverse cytogenetics, and 48 (56%) had at least one risk factor. All patients received hyper-CVAD as induction; induction failure was seen in 10 (12%). A total of 38 patients continued the hyper-CVAD course, while the remaining 47 received HCT in CR1. Three-year event-free survival (EFS) and overall survival for the entire cohort were 51.4% and 61.6%, respectively. Median follow-up of alive patients was 39.9 (3.8-123.8) months. At multivariable analysis for EFS, induction failure was associated with worse outcome (hazard ratio [HR], 4.8; 95% confidence interval [CI] 1.7-13.7; P = .003), whereas HCT in CR1 improved outcome (HR, 0.42; 95% CI 0.18-0.97; P = .044). Furthermore, HCT in CR1 was the only prognostic factor for overall survival (HR, 0.3; 95% CI 0.11-0.85; P = .023).ConclusionHCT at CR1 resulted in a favorable EFS and overall survival in ALL/LBL patients after hyper-CVAD frontline therapy. Given that hyper-CVAD is a widely used protocol for adult patients, further examination of this observation is warranted.     

Allogeneic Hematopoietic Cell Transplantation Outcomes in Patients Carrying Isocitrate Dehydrogenase Mutations

BackgroundMutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown.Patients and MethodsWe report on the clinical outcome of a cohort of AML patients, who were tested for IDH mutations and underwent alloHCT at City of Hope (2015-2017). Of a total of 317 screened patients, 99 (31%) underwent alloHCT, of whom 23 carried and 76 did not carry IDH mutations (control).ResultsNo statistical significance was detected in patient’s overall survival (P = .84). With a median follow-up of 7.8 months, 1-year relapse rate of 29% and 13% was seen in the IDH-mutated and control group, respectively (P = .033). IDH1/2 mutation status remained significantly associated with relapse (hazard ratio, 2.8; P = .046) after inclusion of pre-HCT disease status in a multivariable model.ConclusionOur results, despite low patient numbers, indicate that IDH mutations are associated with higher relapse rate after alloHCT. Further prospective studies on post transplantation IDH inhibition is required to improve outcomes in AML patients who carry IDH mutations.     

Interim Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography for Early Metabolic Assessment of Therapeutic Response to Chemotherapy for Metastatic Transitional Cell Carcinoma

BackgroundThe prognostic impact of early metabolic response by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) after 2 cycles of first-line chemotherapy is still unrecognized in metastatic transitional cell carcinoma (TCC).Patients and MethodsPatients with metastatic TCC receiving the modified combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), according to institutional protocol, underwent computed tomography (CT) and FDG-PET imaging at baseline, a restaging with PET imaging after 2 cycles only (PET2), and a CT (± FDG-PET) scan at the end of treatment and during follow-up. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan–Meier method; univariate (UVA) and multivariate (MVA) Cox models were fitted. Prespecified variables were the presence of visceral metastases, nodal or soft tissue disease, and early PET response.ResultsIn the period from May 2010 to October 2012, 31 patients with Eastern Cooperative Oncology Group performance status 0 received the modified MVAC regimen every 3 weeks. In all, 6 patients (19.3%) had a complete response (CR) and 17 (54.8%) a partial metabolic response (PR), 4 had stable disease (SD), and 4 progressed. PET2 responders had a median PFS of 8 months (95 % CI, 7-11 mo) compared with 3 months (95 % CI, 2-5 mo) of patients without response (P = .024). They also had a significant benefit in 8-month PFS (P < .001 via Klein test) and 15-month OS (P = .016). PET2 response was significant for PFS in both UVA and MVA Cox models (P = .027 and P = .023, respectively).ConclusionPET response after 2 cycles of first-line chemotherapy, compared with detection by early CT, was associated with longer PFS and OS in advanced TCC and warrants further investigation in the field.     

Predictors of avascular necrosis of bone in long‐term survivors of hematopoietic cell transplantation

BACKGROUND:

Avascular necrosis (AVN) is a debilitating condition reported after chronic steroid use. The purpose of this study was to describe the magnitude of risk in individuals who survived ≥1 years after hematopoietic cell transplantation (HCT), and to investigate the role of immunosuppressive agents such as prednisone, tacrolimus (FK506), mycophenolate mofetil (MMF), and cyclosporine (CSA) in the development of AVN after HCT.

METHODS:

Using a retrospective study design, the authors followed 1346 eligible patients for the development of AVN. Cumulative incidence was calculated taking into consideration competing risk from death and disease recurrence. Cox proportional regression techniques were used to identify associated risk factors.

RESULTS:

The median age at HCT was 34 years (range, 7 months‐69 years), and median length of follow‐up for those surviving was 8.2 years. Seventy‐five patients developed AVN of 160 joints. The cumulative incidence of AVN at 10 years was 2.9% after autologous HCT, 5.4% after allogeneic matched related donor HCT, and 15% after unrelated donor HCT (P < .001 compared with autologous HCT recipients). For allogeneic transplant recipients, male sex (relative risk [RR], 2.1; 95% confidence interval [95% CI], 1.1‐4.0); presence of chronic graft‐versus‐host disease (RR, 2.2); and exposure to CSA, FK506, prednisone, and MMF rendered patients at increased risk, especially in patients with a history of exposure to ≥3 drugs (RR, 9.2; 95% CI, 2.42‐35.24).

CONCLUSIONS:

Future studies examining the pathogenetic mechanism underlying AVN should help develop targeted interventions to prevent this chronic debilitating condition. Cancer 2009. © 2009 American Cancer Society.     

Outcome and prognostic factors in patients with mantle-cell lymphoma relapsing after autologous stem-cell transplantation: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT)

BackgroundAutologous stem-cell transplantation (autoSCT) is considered a standard treatment of non-frail patients with mantle cell lymphoma (MCL), but little is known about outcome of MCL patients relapsing after autoSCT. We therefore sought to analyse the outcome after autoSCT failure and the efficacy of a rescue stem-cell transplantation (SCT) in this setting.Patients and methodsPatients with MCL were eligible if they had relapsed after autoSCT performed between 2000 and 2009. A total of 1054 patients could be identified in the EBMT registry. By contacting the transplant centres, a full dataset could be retrieved for 360 patients.ResultsMedian overall survival (OS) after relapse of the whole study group was 19 months. A long (>12 months) interval between autoSCT and relapse [P < 0.001, hazard ratio (HR) 0.62], primary refractory disease (P < 0.02, HR 1.92), prior high-dose ARA-C treatment (P = 0.04, HR 1.43), and the year of relapse (P = 0.02, HR 0.92) significantly influenced OS from relapse in multivariate analysis.Eighty patients (22%) received a rescue allogeneic SCT (alloSCT). Relapse incidence, non-relapse mortality, and OS 2 years after alloSCT was 33% [confidence interval (95% CI 21% to 45%)], 30% (95% CI 19% to 42%), and 46% (95% CI 33% to 59%), respectively. Remission duration after autoSCT was the only variable significantly affecting the outcome of salvage alloSCT. In contrast, rescue autoSCT was not associated with long-term disease control. However, individual patients survived long term even without salvage transplantation.ConclusionsMCL recurrence within 1 year after autoSCT has an extremely dismal outcome, while the prognosis of patients with longer remission durations after autoSCT is significantly better. AlloSCT may offer the possibility of durable survival when performed for patients with a remission duration of more than 12 months after first autoSCT, but the favourable effect of a salvage alloSCT in this setting needs further validation.     

Tracing Leukemia Stem Cells and Their Influence on Clinical Course of Adult Acute Myeloid Leukemia

BackgroundAcute myeloid leukemia (AML) evolves from neoplastic transformation of stem cell disease termed “leukemia stem cells” (LSCs). An unsatisfactory response to AML therapy is determined by the presence of minimal residual disease (MRD). The predominance of LSCs might anticipate sustained MRD results. The present study aimed to demonstrate the effect of LSCs on MRD at induction days 14 and 28 on overall survival (OS) and disease-free survival (DFS) and to compare LSC expression with MRD status.Patients and MethodsA total of 84 patients with de novo adult AML underwent testing using LSC panels for CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33 and different regular MRD panels.ResultsAt day 14 after induction, the high expression of CD123 and CD133 had adverse effects on both OS and DFS (P = .004 and P ≤ .001 and P ≤ .001 and P ≤ .001, respectively). Greater expression of CD34⁺/CD38⁻/CD123⁺ resulted in unfavorable OS and DFS (P ≤ .001 for both). Both CD34⁺/CD38⁻/CD123⁺ and CD34⁻/CD38⁺/CD123⁺ expression at day 14 after induction had an adverse effect on DFS only (P < .001 and P = .029, respectively). On multivariate analysis, CD133 expression and MRD status were independent prognostic parameters (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.2-4.4; P = .015; and HR, 2.9; 95% CI, 1.0-7.9; P = .041). At day 28 after induction, MRD and increased CD123⁺/CD34⁻, CD34⁺/CD38⁻/CD123⁺, CD133⁺/CD33⁻ expression were associated with inferior OS (P = .016, P = .0035, P = .0.002, and P = .002, respectively). MRD and high expression of CD34⁺CD123⁺, CD133⁺/CD33⁻, CD34⁺/CD38⁻/CD123⁺ were associated with inferior DFS (P < .001, P = .002, P < .001, P < .001, respectively). On multivariate analysis, only CD133⁺/CD33⁻ expression was the independent prognostic factor (HR, 3.1; 95% CI, 1.5-6.7; P = .003).ConclusionsEstimation of LSC expression is a sensitive indicator of the response to therapy in adult patients with AML and might be a better prognosticator than the findings from regular MRD panels.     

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL)

High Ki-67 is strongly associated with the risk of CNS relapse in patients with mantle cell lymphoma. Two-year incidence of CNS relapse in patients with Ki-67 ≥ 30 exceeds 25%. The incidence was not decreased by rituximab, high-dose cytarabine, high-dose methotrexate or consolidative ASCT. Development of new prophylactic strategies for CNS involvement is mandatory in patients with high Ki-67.BackgroundCentral nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach.Patients and methodsA total of 608 patients (median age, 67 years; range 22–92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis.ResultsNone of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2–141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9–19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5–39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4–4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.     

Allogeneic Hematopoietic Stem-Cell Transplantation Improves Disease-Free Survival Compared to Pediatric-Inspired Berlin-Frankfurt-Münster Chemotherapy in Adult Acute Lymphoblastic Leukemia

IntroductionAcute lymphoblastic leukemia (ALL) is a malign disease with poor prognosis in adults. After remission is achieved by induction therapy, administration of allogeneic hematopoietic stem-cell transplantation (AHSCT) is one of the standard treatment in adult ALL patients. Pediatric-inspired chemotherapy has been demonstrated to improve outcomes of adult ALL. The aim of this study was to compare the Berlin-Frankfurt-Münster-95 chemotherapy (BFM-95) regimen and AHSCT results in ALL patients with first complete remission.Patients and MethodsForty-seven patients who received the BFM-95 regimen and 83 patients who underwent AHSCT were compared. Primary endpoints were comparison of overall survival (OS) and disease-free survival (DFS) between groups.ResultsThere was no significant difference between the groups in terms of age, gender, or performance status. In BFM-95 and AHSCT, relapsed disease occurred in 11 (23.4%) and 24 (28.9%), respectively; the respective values for treatment-related mortality were 6 (12.7%) and 10 (12%) (P = .32 and .91). Five-year DFS was 38% with BFM-95 and 57% with AHSCT (P = .014). There was no 5-year OS difference in both groups (64% vs 60%, P = .13). While leukocyte count < 30 × 10⁹/L at the time of diagnosis (hazard ratio, 2.7; P = .021) and prophylaxis of central nervous system (hazard ratio, 2; P = .036) were prognostic for OS, the only factor that had a prognostic effect on DFS was AHSCT (hazard ratio, 1.6; P = .041).ConclusionAHSCT currently offers no special OS advantage but increases DFS compared to the BFM-95 regimen. AHSCT may be considered at first complete remission in patients at low risk of transplant-related mortality.     

Two stage hepatectomy (TSH) versus ALPPS for initially unresectable colorectal liver metastases: A systematic review and meta-analysis

BackgroundAlthough numerous comparisons between conventional Two Stage Hepatectomy (TSH) and Associating Liver Partition and Portal Vein Ligation for staged hepatectomy (ALPPS) have been reported, the heterogeneity of malignancies previously compared represents an important source of selection bias. This systematic review and meta-analysis aimed to compare perioperative and oncological outcomes between TSH and ALPPS to treat patients with initially unresectable colorectal liver metastases (CRLM).MethodsMain electronic databases were searched using medical subject headings for CRLM surgically treated with TSH or ALPPS. Patients treated for primary or secondary liver malignancies other than CRLM were excluded.ResultsA total of 335 patients from 5 studies were included. Postoperative major complications were higher in the ALPPS group (relative risk [RR] 1.46, 95% confidence interval [CI] 1.04–2.06, I² = 0%), while no differences were observed in terms of perioperative mortality (RR 1.53, 95% CI 0.64–3.62, I² = 0%). ALPPS was associated with higher completion of hepatectomy rates (RR 1.32, 95% CI 1.09–1.61, I² = 85%), as well as R0 resection rates (RR 1.61, 95% CI 1.13–2.30, I² = 40%). Nevertheless, no significant differences were achieved between groups in terms of overall survival (OS) (RR 0.93, 95% CI 0.68–1.27, I² = 52%) and disease-free survival (DFS) (RR 1.08, 95% CI 0.47–2.49, I² = 54%), respectively.ConclusionALPPS and TSH to treat CRLM seem to have comparable operative risks in terms of mortality rates. No definitive conclusions regarding OS and DFS can be drawn from the results.     

Evaluation and impact of residual disease in locally advanced cervical cancer after concurrent chemoradiation therapy: Results of a multicenter study

Background

The aim of this study was to evaluate the diagnosis and impact of residual disease (RD) after concurrent chemoradiation therapy (CRT) in locally advanced cervical cancer (FIGO IB2-IVA).

Methods

This retrospective multicenter study included 159 patients who were treated with completion surgery after CRT between 2006 and 2012. Magnetic resonance imaging (MRI) was performed 4–6 weeks after CRT and compared to pathological evidence of residual disease. Kaplan–Meier survival curves were plotted and univariate/multivariate analyses were performed to assess the association between RD and the outcome.

Results

Residual disease was present in 45.3% of the patients and detected by MRI in 57.1%. The MRI had a 29.2% false positive rate and an 11.1% false negative rate. The overall survival (OS) rates at 3 and 5 years were 78.6% (CI 95% [71%–86.9%]) and 76.5% (CI 95% [68.2%–85.7%]), respectively. The disease free survival (DFS) rates at 3 and 5 years were 73.4% (CI 95% [65.6%–82%]) and 71.1% (CI 95% [62.7%–80.1%]), respectively. RD greater than 10 mm decreased DFS (HR = 4.84, p = 0.03), whereas RD between 1 and 10 mm (HR = 0.31, p = 0.58) and less than 1 mm (HR = 0.37, p = 0.54) had no impact on DFS. The OS was not changed by RD.

Discussion

The MRI accuracy value is not sufficient to select patients who might benefit from completion surgery. Residual disease over 10 mm decreased DFS but did not impact OS.