Search

Background: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population., Methods: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m 2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 10 6 CD34 + cells per kg), before conditioning (fludarabine 125 mg/m 2 , cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440., Findings: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure., Interpretation: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease., Funding: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership., Competing Interests: Declaration of interests JOL reports grants for investigator-initiated research from the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation research grant for the current project, AbbVie, Gilead Sciences, Takeda UK, and Shire; honoraria for consulting or advisory boards from AbbVie, Allergan, Atlantic Healthcare, Bristol Meyers Squibb, Celgene, Celltrion, Lilly, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, MSD, Napp Pharmaceuticals, Norgine BV, Pfizer, Shire, Takeda UK, and Vifor Pharma Management; honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Ferring Pharmaceuticals, Galapagos NV, Janssen, Norgine BV, Pfizer, Shire, Takeda UK, and Cornerstone Healthcare Group; and support for attending meetings, travel, or both from AbbVie, Takeda UK, MSD, Ferring Pharmaceuticals, and Janssen, outside the submitted work. DH reports part funding for salary through the NIHR Efficacy and Mechanism Evaluation research grant for this project. RE reports participation in the NIHR Clinical Trials Unit Standing Advisory Committee (2020 to present), and the Health Technology Assessment Clinical Evaluation and Trials Committee (2017–21). LD reports various NIHR grants, none of which relate to Crohn's disease or investigate treatments similar to those in ASTIClite. SD reports salary funding from NHS Research Scotland via NHS Lothian to support clinical trial work; grants from the Edinburgh & Lothian Health Foundations Award, the Pathological Society of Great Britain & Northern Ireland, Helmsley Charitable Trust–Gut Cell Atlas Normal and Crohn's Disease, and Helmsley Charitable Trust CDTREAT and BIOPIC studies; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Jannsen, Ferring, Takeda, and AbbVie; and support for attending meetings, travel, or both from Janssen, Dr Falk Symposium, and AbbVie. SD also reports participation on a data safety monitoring board or advisory board for AbbVie and MHRA; and leadership or fiduciary role on other board, society, committee, or advocacy groups for the British Society of Gastroenterology, the Royal College of Physicians of Edinburgh, and the Scottish Government. JG reports consulting fees from AbbVie, AstraZeneca, Bristol Meyers Squibb, Gilead Sciences, Janssen, MorphoSys AG, and Novartis AG; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Gilead Sciences, and Janssen; and participation on a data safety monitoring board or advisory board for AstraZeneca, outside the submitted work. PI reports grants or contracts from MSD, Takeda UK, Celltrion, and Pfizer; consulting fees from Bristol Meyers Squibb, AbbVie, Arena, Boehringer-Ingelheim, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Celgene, Celltrion, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, MSD, Janssen, Pfizer, Takeda UK, Tillotts Pharma AG, Sapphire Medical, Sandoz, Shire, and Warner Chilcott UK, outside the submitted work. EL reports various other NIHR grants, none of which relate to Crohn's disease or investigate treatments similar to those in ASTIClite; and participation in two data monitoring and ethics committees and two trial steering committees for NIHR trials outside the submitted work, none of which relate to Crohn's disease. MP reports grants or contracts from Pfizer, Gilead Sciences, and Crohn's & Colitis UK, outside the submitted work; and a leadership role as Director of Cambridge Biomedical Research Centre, outside the submitted work (2020 to present). AL reports consulting fees from Takeda UK, Vifor Pharma Management, Janssen, and PredictImmune; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda UK, Janssen, and Celltrion; support for attending meetings, travel, or both from Janssen, Tillotts Pharma AG, Takeda UK, and Vifor Pharma Management; and is Director of the non-executive IBD Registry Board. AGP reports being the Chief Executive Officer of multimmune GmbH, Chief Scientific Officer of Alphageneron Pharmaceuticals, and a member of the scientific advisory board of Cytomos, none of which relate to Crohn's disease and all are outside the submitted work. SS reports grants or contracts from Crohn's & Colitis UK and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda UK, Janssen, AbbVie, Celltrion, Boehringer Ingelheim International GmbH, and Bristol Meyers Squibb, outside the submitted work; and participation on a data safety monitoring board or advisory board for Takeda UK, Janssen, AbbVie, Celltrion, Boehringer Ingelheim International GmbH, Bristol Meyers Squibb, and Vifor Pharma Management, outside the submitted work. JS reports grant funding for IBD research from the European Crohn's & Colitis Organization (ECCO), The Leona M and Harry B Helmsley Charitable Trust, Crohn's & Colitis UK, Crohn's & Colitis Foundation, Action Medical Research, the NIHR Efficacy and Mechanism Evaluation, European Commission FP-7, and Horizon 2020 programmes, outside the submitted work; and payment or honoraria for a lecture for the Falk Foundation, and a leadership role on the UK IBD Registry Management Board. ST reports grants or contracts from ECCO, the Leona M and Harry B Helmsley Charitable Trust, Ferring Pharmaceuticals, Janssen, Lilly, Pfizer, Takeda UK, and the Norman Collisson Charitable Trust; and consulting fees from ai4gi Joint Venture, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim International GmbH, Bristol Meyers Squibb, Bühlmann Laboratories AG, Celgene, ChemoCentryx, Cosmo Pharmaceuticals NV, Enterome, Equillium, Ferring Pharmaceuticals, Genentech–Roche, Gilead Sciences, Glenmark Pharmaceuticals, Grünenthal, GlaxoSmithKline, Immunometabolism, Indigo Diabetes, Janssen, Lilly, Merck KGaA, Mestag Therapeutics, Novartis AG, Pfizer, PharmaVentures, Phesi, Satisfai Health, Sensyne Health, Sorriso, SynDermix, Synthon, Takeda UK, Topivert, UCB SA, Vertex Pharmaceuticals, VHsquared, and Vifor Pharma Management, outside the submitted work. ST also reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Amgen, Biogen, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Janssen, Pfizer, Shire, Takeda UK, and UCB SA; payment for expert testimony from Cosmo; support for attending meetings, travel, or both from AbbVie, Amgen, Biogen, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Janssen, Pfizer, Shire, Takeda UK, and UCB SA; and participation on a data safety monitoring board or advisory board for Amgen, outside the submitted work. SR reports research funding from MacroGenics and Kura Oncology, outside the submitted work. BU reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Gilead and Novartis; and support for attending meetings, travel, or both from Takeda and Gilead. JS reports support for the current work through a NIHR Efficacy and Mechanism Evaluation grant; consulting fees from Medac (not directly related to Crohn's disease); and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Jazz Pharmaceuticals, Mallinckrodt Pharmaceuticals, Janssen, Gilead Sciences, Vertex, and Actelion, none of which directly relate to Crohn's disease, outside the submitted work. JS also reports participation on the Kiadis Pharma trial Independent Data Monitoring Committee, which does not directly relate to Crohn's disease, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Allogeneic transplantation (allo-HCT) is a curative treatment in CLL whose efficacy including the most severe forms had led to the 2006 EBMT recommendations. The advent after 2014 of targeted therapies has revolutionized CLL management, allowing prolonged control to patients who have failed immunochemotherapy and/or have TP53 alterations. We analysed the pre COVID pandemic 2009-2019 EBMT registry. The yearly number of allo-HCT raised to 458 in 2011 yet dropped from 2013 onwards to an apparent plateau above 100. Within the 10 countries who were under the EMA for drug approval and performed 83.5% of those procedures, large initial differences were found but the annual number converged to 2-3 per 10 million inhabitants during the 3 most recent years suggesting that allo-HCT remains applied in selected patients. Long-term follow-up on targeted therapies shows that most patients relapse, some early, with risk factors and resistance mechanisms being described. The treatment of patients exposed to both BCL2 and BTK inhibitors and especially those with double refractory disease will become a challenge in which allo-HCT remains a solid option in competition with emerging therapies that have yet to demonstrate their long-term effectiveness., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the US and Europe. Objective response rate (ORR), complete response (CR), progression-free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoT. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved CR in later LoT, and duration of response and survival diminished with each subsequent line.

Multiple myeloma (MM) accounts for 10% of haematological malignancies. Overall survival (OS) has improved in recent years due to increased use of autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed MM and the advent of novel agents, including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. To assess trends in ASCT including patient selection, choice of induction regimen, depth of response and survival, we performed a retrospective analysis of all patients undergoing first ASCT for MM in European Society for Blood and Marrow Transplantation centres between 1995 and 2019. A total of 117 711 patients across 575 centres were included. The number of transplants performed increased sevenfold across the study period. The median age increased from 55 to 61 years, and the percentage of patients aged >65 years rose from 7% to 30%. Use of chemotherapy-based induction fell significantly, being largely replaced by bortezomib-based regimens. The two-year complete response rate increased from 22% to 42%. The five-year progression-free survival and OS rates increased from 28% to 31% and from 52% to 69%, respectively. Transplant mortality fell from 5.9% to 1.5%. Ongoing advances in MM treatment may challenge the future role of ASCT. However, at the current time, ASCT remains central to the MM treatment paradigm., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Intestinal inflammation in Crohn's disease (CD) is caused by mucosal immune system reactivity to luminal antigen and results in debilitating symptoms, reduced quality of life, impaired work productivity and significant health care costs. Not all patients respond to conventional and biologic therapies, with chronic inflammation ensuing. Although surgical resection may be required, disease frequently returns and surgery may not be an option, or may be declined. Case reports suggest potential benefit after haematopoietic stem cell transplant (HSCT) for patients with refractory CD. The ASTIC trial asked whether HSCT could cure CD. Few patients achieved the primary endpoint of clinical remission for 3 months, off all medication with no evidence of active disease, and there were a high number of adverse events (AEs) and serious adverse events (SAEs), including one patient death. However, beneficial effects were observed in some aspects of disease activity. The ASTIClite trial will investigate these potential benefits and safety using a lower intensity regimen than ASTIC., Methods: Ninety-nine participants will be recruited from secondary care IBD centres in the UK into a multicentre, randomised controlled trial (RCT, ASTIClite) and an observational follow-up, and randomised to autologous HSCT versus standard care (ratio 2:1). The primary endpoint is treatment success at week 48, defined as mucosal healing without surgery or death. Secondary endpoints relating to efficacy, safety and mechanistic analyses will be evaluated at week 8, 14, 24, 32, 40 and 48. Long-term safety of the low intensity HSCT regimen forms the primary endpoint for the EBMT follow-up study and will be assessed annually for 4-7 years., Discussion: ASTIClite will compare HSCTlite with standard care with respect to safety, efficacy and quality of life, and capture outcomes allowing findings to be generalised to current clinical practice in the UK. It will also provide significant mechanistic insights into the immunological consequences of HSCTlite and its impact on treatment outcomes. The observational follow-up will provide information, which is currently unavailable for this population., Trial Registration: The ASTIClite RCT was registered on 31st October 2017 ( ISRCTN17160440 ) and the EBMT follow-up study on 19th January 2018 ( ISRCTN31981313 ).

Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.

We sought to establish clinical practice recommendations to redefine the role of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with chronic lymphocytic leukemia (CLL) in an era of highly active targeted therapies. We performed a systematic review to identify prospective randomized controlled trials comparing allo-HCT against novel therapies for treatment of CLL at various disease stages. In the absence of such data, we invited physicians with expertise in allo-HCT and/or CLL to participate in developing these recommendations. We followed the Grading of Recommendations Assessment, Development and Evaluation methodology. For standard-risk CLL we recommend allo-HCT in the absence of response or if there is evidence of disease progression after B cell receptor (BCR) inhibitors. For high-risk CLL an allo-HCT is recommended after failing 2 lines of therapy and showing an objective response to BCR inhibitors or to a clinical trial. It is also recommended for patients who fail to show an objective response or progress after BCR inhibitors and receive BCL-2 inhibitors, regardless of whether an objective response is achieved. For Richter transformation, we recommend allo-HCT upon demonstration of an objective response to anthracycline-based chemotherapy. A reduced-intensity conditioning regimen is recommended whenever indicated. These recommendations highlight the rapidly changing treatment landscape of CLL. Newer therapies have disrupted prior paradigms, and allo-HCT is now relegated to later stages of relapsed or refractory CLL., (Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.

Importance: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease., Objective: To evaluate the effect of autologous HSCT on refractory Crohn disease., Design, Setting, and Participants: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids., Interventions: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed., Main Outcomes and Measures: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) <150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging., Results: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died., Conclusions and Relevance: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease., Trial Registration: clinicaltrials.gov Identifier: NCT00297193.

A considerable body of evidence demonstrates that allogeneic hematopoietic stem cell transplantation (HSCT) offers the only potentially curative treatment option for patients with chronic lymphocytic leukemia (CLL). However, this approach is suitable for only a minority of CLL patients, owing to its significant treatment-related mortality and morbidity. Until recently, internationally accepted guidelines suggested that HSCT should be considered in physically fit CLL patients who carry poor-risk features, such as TP53 abnormalities, or who had a short response to previous immunochemotherapy. However, several new agents and alternative treatment strategies are available that demonstrate impressive and durable responses, even in CLL patients who previously might have been candidates for transplant. The decision about which patients merit HSCT therefore remains important, and HSCT must now be considered in light of other less toxic therapies. Until data on the long-term efficacy of novel treatment approaches mature, the choice of HSCT vs alternative strategies must be assessed on a patient-by-patient basis, and treatment in the setting of randomized clinical trials should be pursued whenever possible.

Allogeneic stem cell transplantation (HSCT) offers the only potentially curative approach in chronic lymphocytic leukemia (CLL). However, this applies only to a minority of patients, and is associated with significant treatment-related mortality and morbidity. HSCT must therefore always be considered in view of other, potentially less toxic therapies. Several new agents demonstrate impressive and durable responses in high-risk patients who might be candidates for HSCT. Therefore the choice of HSCT versus a novel agent is one that must be gauged on a patient-by-patient basis; this will change as data mature on the use of these novel agents in CLL., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chronic lymphocytic leukemia (CLL) remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced-intensity (RIC) and 32 with myeloablative conditioning (MAC) between 1998 and 2009 at Dana-Farber Cancer Institute. With median follow-up of 5.9 years in surviving patients, the 5-year overall survival (OS) for the entire cohort is 63% for RIC regimens and 49% for MAC regimens (P=0.18). The risk of death declined significantly starting in 2004, and we found that 5-year OS for HSCT between 2004 and 2009 was 83% for RIC regimens compared with 47% for MAC regimens (P=0.003). For RIC transplantation, we developed a prognostic model based on predictors of progression-free survival (PFS), specifically remission status, lactate dehydrogenase, comorbidity score and lymphocyte count, and found 5-year PFS to be 83% for Score 0, 63% for Score 1, 24% for Score 2 and 6% for Score ≥3 (P<0.0001). We conclude that RIC HSCT for CLL in the current era is associated with excellent long-term PFS and OS, and, as potentially curative therapy, should be considered early in the disease course of relapsed high-risk CLL patients.

Nonmyeloablative stem cell transplantation (NST) is increasingly used in older patients. The impact of the shift from myeloablative transplantation to NST on relapse, transplant complications, and outcome has yet to be fully examined. We performed a retrospective analysis of 152 patients older than 50 years undergoing NST or myeloablative transplantation. Seventy-one patients received nonmyeloablative conditioning, fludarabine (30 mg/m(2)/d x 4) and intravenous busulfan (0.8 mg/kg/d x 4); 81 patients received myeloablative conditioning, primarily cyclophosphamide and total body irradiation. NST patients were more likely to have unrelated donors (58% versus 36%; P = .009), a prior transplant (25% versus 4%; P = < .0001), and active disease at transplantation (85% versus 59%; P = < .001). Despite the adverse characteristics, overall survival was improved in the NST group at 1 year (51% versus 39%) and 2 years (39% versus 29%; P = .056). There was no difference in progression-free survival (2 years, 27% versus 25%; P = .24). The incidence of grade 2 to 4 graft-versus-host disease was similar (28% versus 27%). The nonrelapse mortality rate was lower for NST patients (32% versus 50%; P = .01), but the relapse rate was higher (46% versus 30%; P = .052). Our experience suggests that, in patients over age 50, NST with fludarabine and low-dose busulfan leads to an overall outcome at least as good as that following myeloablative therapy.

Background: Autologous stem cell transplantation (SCT) has become the treatment of choice for patients with relapsed chemo-sensitive intermediate grade lymphoma, but its role in the treatment of low-grade lymphomas and in selected patients in first remission remains controversial., Methods: A large number of clinical trials have evaluated the role autologous SCT in both low grade and intermediate grade non-Hodgkin's lymphomas (NHL). These studies have attempted to evaluate the role of high dose therapy with stem cell support in comparison to more conventional chemotherapy approaches. Studies have also focused on methods to assess whether contaminating tumor cells are contained with the stem cell collection and whether this has impact on outcome. With an increased number of patients now long term survivors, additional studies are focusing on long term complications and in particular the emergence of secondary malignancies., Results: Virtually all patients now receive peripheral blood stem cells rather than bone marrow as a source of stem cells. The role of purging of residual tumor cells remains controversial and no randomized trial has been published to date that could evaluate the clinical utility of cell manipulation to attempt to remove contaminating lymphoma cells. Secondary leukemia is emerging as a major source of long-term morbidity and mortality after autologous stem cell transplantation., Conclusion: Autologous SCT is associated with improved outcome in patients with relapsed intermediate grade lymphoma and most likely prolongs disease free survival in patients with low grade NHL. Morbidity and mortality of the procedure is low and major efforts are being made to attempt to decrease the major causes of failure, which remain disease relapse and occurrence of secondary malignancies.

Background: The suitability of CD34 selection for purging peripheral blood progenitor cells (PBPC) collected from patients with neuroblastoma (NB) has been called into question, largely because of reports of detection of low levels of CD34 on the surface of some NB cell lines and tumors., Procedure: We used three approaches to address the issue of purging of NB from stem cell specimens and possible labeling of NB: 1) Flow cytometric detection of CD34 on NB cell lines. We assessed CD34 expression using a panel of anti-CD34 monoclonal antibodies (MoAbs) including 9C5, 12.8, and QBend10 and showed no increase in labeling over secondary-only control. 2) Spiking experiments with the Isolex 50 system. NB cell lines were used to contaminate aliquots of PBPC collections, after which the products were purified using the Isolex 50. Purging of NB was assessed by quantitative multiplex RT-PCR (TaqMan system) using a tumor-specific transcript, GAGE. We demonstrated >2 logs of tumor cell depletion from these specimens. 3) Analysis of clinical specimens. PBPC pre- and post-CD34 selection were analyzed from patients treated on the CHP-594 transplant trial., Results: In nine specimens selected using the Ceprate LC CD34 selection system where tumor was detectable by immunocytochemistry preselection, we observed >2.4 to >4.6 logs of NB purging after selection. We then analyzed 23 aliquots of PBPC infused into patients post-CD34 selection and compared them to the product preselection; 20/23 specimens showed depletion of NB, although some level of GAGE message was observed in most post-CD34 selection specimens., Conclusion: These data show that purging of NB from PBPC specimens using CD34 selection is feasible, yielding infused products that are negative at the level of ICC but often positive at the level of RT-PCR., (Copyright 2000 Wiley-Liss, Inc.)

Most patients with advanced-stage follicular non-Hodgkin's lymphoma (NHL) are not cured with conventional therapy. The use of high-dose therapy and autologous stem-cell transplantation in patients with relapsed follicular NHL has received increasing attention. Several large studies suggest a disease-free survival rate of approximately 40% among patients transplanted during sensitive relapse, although the role of autologous transplantation in first remission remains controversial. Patients with histologic transformation from low-grade to diffuse large B-cell lymphoma whose disease remains sensitive to conventional therapy have a similar disease-free survival rate. Allogeneic transplantation has achieved relapse, overall survival, and treatment-related death rates of approximately 15%, 50%, and 40%, respectively, in patients with follicular NHL. Studies of minimal residual disease suggest that the presence of lymphoma cells in the autologous graft and within the patient before clinically apparent relapse is predictive of later recurrence. Therefore, treatment of minimal residual disease may improve the outcome of high-dose therapy. Use of a tumor-free stem-cell product through improved purging or allogeneic stem cells is one approach, although the morbidity and mortality of allogeneic transplantation remain high. Immunomodulatory strategies with monoclonal antibodies, vaccines, or adoptive immunotherapy may be particularly well suited to patients at high risk for relapse following high-dose therapy.

Stem cell transplantation (SCT) has become the treatment of choice for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). The role of SCT in the management of patients with low-grade NHL remains more controversial, although increasing numbers of patients with advanced-stage follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia are now undergoing SCT. To date, most patients with NHL have been treated with autologous SCT, currently using peripheral blood stem cells (PBSC) mobilized by chemotherapy and recombinant growth factors. There is increasing concern regarding toxicity of autologous SCT, especially the higher than expected long-term risk of development of myelodysplastic syndrome. This, among other factors, has led to renewed interest in the role of allogeneic SCT for patients with NHL. A major advantage of allogeneic SCT is the potential to exploit a graft-versus-lymphoma effect, and many studies are underway exploring the possibility of manipulating donor cells to maximize T cell responsiveness against lymphoma.

Stem-cell transplantation (SCT) has become the treatment of choice for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). The role of SCT in the management of patients with low-grade NHL remains controversial, although increasing numbers of patients with advanced-stage follicular lymphoma, mantle-cell lymphoma, and chronic lymphocytic leukemia (CLL) are now undergoing SCT. There is increasing concern regarding toxicity of autologous SCT, especially the long-term risk of development of myelodysplastic syndrome, which is higher than was expected. This has led to renewed interest in the role of allogeneic SCT for patients with NHL. A major advantage of allogeneic SCT is the potential for exploiting a graft-versus-lymphoma effect, and many studies under way are exploring the possibility of manipulating donor cells and the host to maximize T-cell responsiveness against lymphoma.

Detection of clonal tumor cells in leukemias and lymphomas by PCR in minimal residual disease (MRD) has been shown to be a valuable parameter for identifying patients who may require further treatment. Here we introduce the studies underway in our own and other institutions addressing the value of PCR technology in detecting residual CLL cells either in the autologous stem cell product or after induction of MRD in patients after autologous or allogeneic stem cell transplant. The PCR technology used for these questions and the results are discussed.

Purpose: To assess the role of bone marrow transplantation in indolent lymphomas., Patients and Methods: Autologous and allogeneic stem cell transplantations (SCTs) are performed routinely for a number of hematologic malignancies; however, few patients with indolent lymphoma have been treated with SCT. The high incidence of bone marrow infiltration in the indolent lymphomas has made it difficult to perform autologous SCT. In addition, although indolent lymphomas are initially responsive to chemotherapy, many patients have been heavily pretreated, have become chemotherapy resistant, and have a decreased marrow reserve by the time they are considered for high-dose myeloablative therapy. An advantage of studying the indolent lymphomas is that they are characterized by nonrandom chromosomal translocations and/or clonal rearrangements of the immunoglobulin heavy-chain locus. These translocations and unique immunoglobulin rearrangements provide clonal markers of disease that can be amplified with the polymerase chain reaction (PCR), allowing detection and assessment of the clinical significance of minimal residual disease (MRD) after SCT., Results: Studies demonstrate that SCT can be performed safely in patients with indolent lymphomas. Although standard-dose therapy rarely eradicates MRD, high-dose therapy and SCT result in eradication of PCR-detectable MRD in a significant number of patients. Furthermore, eradication of MRD is associated with greatly prolonged disease-free survival., Conclusion: These results suggest that our therapeutic goal should be attainment of a "molecular complete remission" for cure in these malignancies.

Recent studies have documented an increased risk of therapy-related myelodysplastic syndrome or acute myelogenous leukemia (t-MDS/AML) after autologous bone marrow transplant (ABMT) for non-Hodgkin's lymphoma (NHL). To develop methods to identify patients at risk for this complication, we have investigated the predictive value of clonal bone marrow (BM) hematopoiesis for the development of t-MDS/AML, as defined by an X-inactivation based clonality assay at the human androgen receptor locus (HUMARA), in a group of patients undergoing ABMT for NHL from a single institution (Dana-Farber Cancer Institute, Boston, MA). One hundred four female patients were analyzed. At the time of ABMT, the prevalence of polyclonal hematopoiesis was 77% (80/104), of skewed X-inactivation pattern (XIP) was 20% (21/104), and of clonal hematopoiesis was 3% (3/104). To determine the predictive value of clonality for the development of t-MDS/AML, a subgroup of 78 patients with at least 18 months follow-up was analyzed. As defined by the HUMARA assay, 53 of 78 patients had persistent polyclonal hematopoiesis, 15 of 78 had skewed XIP, and 10 of 78 (13.5%) either had clonal hematopoiesis at the time of ABMT or developed clonal hematopoiesis after ABMT. t-MDS/AML developed in 2 of 53 patients with polyclonal hematopoiesis and in 4 of 10 with clonal hematopoiesis. We conclude that a significant proportion of patients have clonal hematopoiesis at the time of ABMT and that clonal hematopoiesis, as detected by the HUMARA assay, is predictive of the development of t-MDS/AML (P = .004).

Indolent follicular lymphomas are diseases which are generally incurable with conventional therapy. Although patients can survive for prolonged periods, the median duration of first remissions is about 2.5 years, and subsequent remissions progressively shorten with time. High dose therapy with hematopoietic stem cell support leads to prolonged disease-free and overall survival in a subset of patients with aggressive non-Hodgkin's lymphoma. Mounting evidence suggests similar findings for selected patients with indolent follicular non-Hodgkin's lymphoma. Presently it remains unclear as to when this approach should be used, however inferior results have been seen in heavily pretreated patients. In contrast, encouraging results are being reported in patients undergoing such treatment early in the course of their disease. Despite these data, many patients continue to relapse and future investigations now focus on eradication of minimal residual disease.