Role Of Stem Cell Transplantation Research Articles

Outcomes in Relapsed/Refractory Patients with FLT3-ITD Mutated AML Are Poor When Treated with Non-Targeted Therapy with a Potential Role for Stem Cell Transplantation: Results from the NCRI AML Trials

Introduction: Patients with Acute Myeloid Leukaemia (AML) who harbour a FLT3-ITD mutation have a worse prognosis characterised by increased early relapse. Outcomes following relapse in such patients are typically poor, not only because of earlier relapse, but also because of worse performance post-relapse than those who have the same remission duration but are FLT3-ITD WT. In a single centre retrospective study among relapsed patients, Ravandi et al [1] found a remission rate of 24% and median survival of only 13 weeks. There are therefore twin challenges in this population: first to reduce the early relapse rate, and also to develop more effective treatments post relapse. In the recent QUANTUM-R trial [2] for patients with relapsed or refractory disease, single agent quizartinib (AC220) was found to significantly improve median survival from 20.4 weeks to 27 weeks when compared to “doctor's choice” treatment (low-dose ara-C, MEC or FLAG-Ida). There is however, no directly comparable data for the population in the QUANTUM-R trial. To contextualise these results, especially given the potentially different outcomes by control treatment, we looked at outcomes in the UK NCRI AML15,16,17 trials in patients satisfying the eligibility criteria of QUANTUM-R.Methods: Patients aged 18+ in the UK NCRI AML15,16,17 trials were identified who harboured a FLT3 ITD mutation, were treated with intensive chemotherapy, and were either refractory to two courses of induction therapy, or relapsed within six months of transplant, or did not receive a prior transplant and had a remission duration of 6 months or less. Patients were grouped hierarchically as refractory, relapsed post transplant, or relapsed without prior transplant. Eligibility was established at the point a patient first became eligible for analysis. The primary outcome was overall survival (OS), measured from point of eligibility, with subsequent remission with or without count recovery as secondary outcome. A sensitivity analysis was performed excluding those who died within 21 days of eligibility to eliminate patients who might be thought of as too unwell to enter a post-relapse trial. Cox regression was used to identify prognostic factors for survival.Results: A total of 264 patients were identified (refractory n=58, relapsed post SCT n=49, relapsed without SCT n=157). The median age was 51 (range 18-84); 25% of patients were aged 60 or older; 44% were male, 95% had intermediate cytogenetics; 11% had secondary disease. Split by age, among those under 60 45 were refractory, 44 relapsed post SCT and 110 relapsed without SCT; for ages 60+ the figures were 13 vs 5 vs 47. Overall 17% of patients experienced a subsequent remission; with median survival of 86 days and 1 year OS of 13%. If deaths within 21 days were excluded, the remission rate improved to 21%; with a median survival of 133 days and 1 year OS of 16%.In multivariable Cox regression, age group HR for age>60 1.81 (1.33-2.47) p=0.0002) and route to eligibility (HR refractory vs relapsed no SCT 0.77 (0.55-1.07); relapsed post SCT vs no SCT 1.58 (1.11-2.25) p=0.003) were the only factors affecting survival - in particular sex, secondary disease, and ITD allelic burden were not significant. In the sensitivity analyses, only age was significant (HR 1.77 (1.24-2.53) p=0.001); with route to eligibility not significant (p=0.14).Among patients with post-relapse treatment information, 65% were treated intensively, 8% non-intensively, and 20% with palliation - other patients received experimental therapies. When restricting attention to those treated intensively, median survival was 130 days with 17% 1 year OS. Figures were not materially changed if early death was excluded.Of 215 patients who had not relapsed post transplant, 53 (25%) received a transplant post-eligibility. In these 56 patients, median survival was 301 days with 42% alive at one year.Conclusions: In relapsed/refractory AML, outcomes for FLT3-ITD mutated patients are generally poor and worse for older patients. Applying the eligibility criteria of QUANTUM-R and excluding early deaths gives outcomes comparable to the control group of the QUANTUM-R study. In the 25% of patients who proceeded to transplant survival was extended indicating that a treatment which can deliver patients to transplant has the potential to improve patient outcomes.

An Analysis of Real Life Data Obtained from 30 Years Follow-up of Primary Myelodysplastic Syndromes (MDS) Patients Confirms a Leading Role of Stem Cell Transplantation (SCT) for Achievement of Prolonged Survival

AIM OF THE STUDY, PATIENTS AND METHODS : The data obtained from a long-term follow-up for a period of 30 years (1988-2017) were analyzed in a group of 529 patients with primary MDS and factors affecting prolonged survival were detected using different statistical methods including Kaplan Maier test and multivariate analysis. RESULTSThe results confirmed usefulness of both IPSS and IPSS-R (median survival in months for risk groups : very low - 73.7, low - 40.0, intermediate - 27.0, high - 9.0, very high - 3.5). In a subgroup of 249 patients with less advanced disease without excess of blasts, allogeneic SCT represented the most favouring treatment approach leading to estimated 10 years survival in 49.1% of patients. However, when compared to patients treated by supportive care only, a benefit in overall survival for SCT did not become significant before 5 years of follow-up (estimated 5 years survival /e5yS/: 43.3% for supportive care vs. 54.7 % for SCT). Only 2 (3.8%) out of 53 transplanted patients died later than after 5 years follow-up in comparison to 31 (20.8%) out of 149 patients on supportive care; 22 of them died on complications not directly related to MDS and a late disease progression (between 6 and 26 years after diagnosis of MDS) was observed in 9 patients. Transplantation related mortality was 30.2%, SCT at the time of disease progression (>5% of bone marrow /BM/ blasts) and prolonged (>3 months) administration of corticosteroids prior to SCT were independent adverse prognostic factors for SCT outcome (P<0.001). Special treatment approaches were effective in selected subgroups of patients : rHuEPO in patients with sEPO < 100 IU/l and ≤ 2 TU of RBC/month, lenalidomide in patients with isolated del(5q) and ATG in hypoplastic MDS with e5yS of 63.6%,75.0% and 83.3%, respectively. In 169 patients with advanced MDS ( ≥ 10% BM blasts), allogeneic SCT was the only treatment option leading to prolonged survival ( e5yS: 48,9%). The difference between efficiency of SCT and treatment with hypomethylating agents (HMA) became significant after 2 years of follow-up, estimated 3years survival was 53,2% for SCT and 26.9% for HMA, e5yS for HMA was only 3.8%. The differences were similar in a subset of patients older than 50 years of age (e5yS for SCT: 31.3%, for HMA: 3.2%). Reduction of BM blasts below 10% prior to SCT was an important factor affecting outcome of patients (median survival 62.3 months for those transplanted with < 10% BM blasts vs. 17.0 months for those with ≥ 10% BM blasts /P<0.001/). The type and intensity of conditioning did not affect outcome of SCT. Seven (14.9%) out of 47 transplanted patients relapsed, all of them within 3 years after SCT, 6 of them entered SCT with ≥ 10% BM blasts. Only 3 (6.4%) SCT patients died later than 5 years after SCT. Introduction of HMA improved short term outcome of patients not indicated for SCT ( estimated 1 year survival for HMA was 80.8% vs. 41.3% for combination chemotherapy and 52.9% for low dose ARA-C) but only minimum (4.1%) of non-transplanted patients survived 5 years. CONCLUSIONSThe analysis of long-term follow-up showed that younger patients with less advanced MDS without excess of blasts and adverse prognostic factors should be transplanted as soon as possible after diagnosis before disease progression. An advantage of more conservative approach to patients with early disease who are not indicated for SCT was confirmed by presence of a relatively high number of patients surviving 5 years with supportive care only. SCT represented the treatment of choice for advanced MDS and reduction of BM blasts prior to SCT siginficantly affected outcome of SCT. Administration of HMA significantly improved short term survival but did not affect long term outcome of patients. DisclosuresNo relevant conflicts of interest to declare.

Stem Cell Transplantation for Pediatric Patients with Non-Anaplastic Peripheral T-Cell Lymphoma on Behalf of the EBMT-Pediatric Diseases Working Party

Peripheral T-cell lymphomas (PTCL) other than anaplastic large cell lymphoma are rare in children, and data about outcome and treatment results especially regarding the role of stem cell transplantation (SCT) are scarce. Here we present the results of a retrospective study of SCT for pediatric patients with PTCL within the European Group of Bone marrow transplantation (EBMT). Out of 125 patients aged <18 years with PTCL diagnosed between 1995 and 2015 who were registered to the EBMT database, reports about the primary therapy and data about the course of SCT were sufficient for analysis in 55 patients. 37 (69%) had PTCL not otherwise specified (NOS), 7 (13%) hepato-splenic T-cell lymphoma, 4 (7%) angioimmunoblastic T-cell lymphoma, 3 (6%) NK/T-cell lymphoma, 2 (4%) subcutaneous panniculitis-like T-cell lymphoma, and 1 systemic EBV-lymphoproliferative syndrome. Median age at PTCL-diagnosis was 13.0 years (range: 0.7-17.6), and was 13.9 years (range: 2.5-17.9) at SCT, respectively. 35 (65%) of the patients were male. 43 (81%) of the patients had received T-NHL/ lymphoblastic lymphoma-type therapy; radiotherapy (RT) was given to 7 patients (16%) prior to SCT. 45 (83%) patients underwent allogeneic SCT (16 from related and 29 from unrelated donor), and 9 (17%) patients received autologous SCT (ASCT). Myeloablative conditioning (MAC) was used in 44 (88%) patients, 6 (12%) patients received reduced-intensity conditioning (RIC). Total body irradiation (TBI) was part of the conditioning regimen in 26 patients (48%).After SCT the 5-year overall survival (OS) and lymphoma-free survival (LFS) probability was 57% (95% CI 44.5-72.5) and 56% (95% CI 43.4-71.2), respectively. Relapse incidence was 25% (95% CI 14.1-37.9), whereas the non-relapse mortality (NRM) rate was 18% (95% CI 9.4-29.7).Patients with younger age (0-9 years, vs. 10-18 years) at diagnosis of PTCL had a tendency for better outcome (OS 80% vs. 50%, respectively p=0.069), whereas age at SCT and gender had no influence on outcome (p=0.2 and p=0.6, respectively). Year of SCT (1995-2007 vs. 2008-2015) was of no significance for the outcome (p=0.31).A tendency for better outcome (OS/LFS) was observed in patients who received RT in the pre-transplant treatment, and for patients who achieved first/second complete remission (CR1/CR2) before SCT, as compared to those with later/ without CR prior to SCT (OS 72% vs 46%, p=0.1). Patients receiving MAC conditioning had a better OS compared to patients receiving RIC (66% vs. 33%, p=0.07). LFS was inferior after ASCT compared to allogeneic SCT, resulting in non-significant difference in OS .Acute Graft-versus host disease (aGvHD) grade III/IV was seen in 6 (14.6%) patients. 6 patients suffered from chronic GvHD, 2 of them from the extensive form.In conclusion, SCT for pediatric patients with PTCL in CR1/CR2 is a valid option of treatment. MAC may currently be chosen for conditioning in order to possibly prevent relapses. DisclosuresBader:Neovii: Research Funding; Cellgene: Consultancy; Riemser: Research Funding; Novartis: Consultancy, Speakers Bureau; Medac: Patents & Royalties, Research Funding.

The role of stem cell transplantation in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia.

The concurrent administration of tyrosine kinase inhibitors (TKIs) with standard chemotherapy together with allogeneic hematopoietic stem cell transplantation (alloHSCT) has improved the outcome of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Although to date, no study has shown alloHSCT to be inferior to chemotherapy plus TKIs in any subgroup of adult Ph+ ALL, there is some evidence suggesting no additional benefit of alloHSCT in patients with deep molecular responses to intensive chemotherapy with a second-generation, and especially, third-generation TKI. As none of these positive and negative studies are controlled, randomized trials are needed to fully define the role of alloHSCT in Ph+ ALL, especially in those with deep molecular response. However, if studies combining TKIs with new approaches such as immunotherapy lead to durable responses, alloHSCT in the first complete remission could be avoided in the near future in the majority of patients with Ph+ ALL.

The role of stem cell transplantation in the management of relapsed follicular lymphoma in the era of targeted therapies

Patients with relapsed follicular lymphoma (FL) following first-line therapy have an increasing number of management strategies ranging from observation through to stem cell transplantation. There has been an exciting expansion in novel agents to treat FL, but at present there is not a universally accepted standard of care in the relapse setting. Decision-making can be difficult for the clinician as there is a paucity of data to compare the various relapse therapies available. This review will discuss conventional therapy for relapsed FL, consider the use of novel agents and explore the role and timing of autologous and allogeneic stem cell transplantation.

331 - A Systematic Review of Conventional Therapy and Role of Stem Cell Transplantation for Primary Plasma Cell Leukemia

331 - A Systematic Review of Conventional Therapy and Role of Stem Cell Transplantation for Primary Plasma Cell Leukemia

Current management of Philadelphia chromosome positive ALL and the role of stem cell transplantation.

Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia exemplifies how the addition of potent targeted agents, directed at the molecular aberrations responsible for leukemic transformation, can overcome resistance mechanisms to traditional regimens and lead to improved outcomes. The introduction of BCR-ABL1 targeted tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes not only by allowing more patients to undergo allogeneic hematopoietic cell transplantation (alloHCT) but also by decreasing our reliance on this potentially toxic strategy, particularly in the less fit population. Long-term data using chemotherapy and TKI combinations demonstrate that a proportion of patients treated can achieve durable relapse-free survival without undergoing alloHCT. Furthermore, the availability of sensitive minimal residual disease monitoring assays may allow early detection of the patients who are more likely to relapse and who are likely candidates for early alloHCT. The emergence of more potent TKIs with significant activity against resistant mutations has allowed deintensification of chemotherapy regimens. Available data indicate that complete reliance on TKIs, alone or with minimal additional therapy, and elimination of more intensive chemotherapy or alloHCT is unlikely to achieve long term cure in most patients. However, introduction of other highly effective agents that can be combined with TKIs may allow further minimization of chemotherapy and alloHCT in the future, as we have witnessed in acute promyelocytic leukemia.

Role of stem cell transplant in lymphoma in the era of new drugs.

Better understanding of the lymphoma pathogenesis and molecular biology has introduced a new era in the lymphoma therapy with the advent of targeted drugs. In this new era, the role of hematopoietic stem cell transplantation (HSCT) is evolving, and the purpose of this review is to demonstrate how the introduction of novel agents has affected the current treatment strategy of different subtypes of lymphoma. Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed Hodgkin Lymphoma and high-grade non-Hodgkin lymphoma (NHL). In the group of the indolent lymphomas, ASCT maintains its role in the relapsed setting. Novel targeted agents like idelalisib and ibrutinib have shown to induce prolonged remissions with a very good safety profile. However, the follow-up is still relatively short and none of these drugs have demonstrated a curative potential, as opposed to HSCT. For many authors, the advent of new targeted drugs is challenging the role of HSCT in different subsets of lymphoma. The actual challenge is how to make the best use of these drugs, in certain circumstances in combination with HSCT, to further improve the outcome of patients with lymphoma.

Adult Acute Lymphoblastic Leukemia and the Role of Stem Cell Transplantation: Real-World Data from an Urban Hospital

Adult Acute Lymphoblastic Leukemia and the Role of Stem Cell Transplantation: Real-World Data from an Urban Hospital

Clinical applications and safety evaluation of the new CD19 specific T-cell engager antibody construct blinatumomab

ABSTRACTIntroduction: Blinatumomab is a T-cell engager antibody construct with dual specificity for CD19 and CD3, inducing serial lysis of CD19 positive B cells by redirecting cytotoxic T cells. It has been approved for the indication of Ph chromosome negative relapsed or refractory B-acute lymphoblastic leukemia (ALL), but has also been tested in ALL with minimal residual disease, relapsed Ph/BCR-ABL positive ALL, relapsed ALL in pediatric patients and relapsed or refractory non-Hodgkin’s lymphoma (NHL). Adverse events have been mainly related to infection and hematological toxicities, as well as cytokine release syndrome and neurotoxicity.Areas covered: The review will discuss mechanisms of action, published literature on efficacy in ALL and NHL, specific aspects of administration, frequent adverse events and practical management.Expert opinion: Blinatumomab represents an effective new treatment for highly resistant relapsed/refractory B-precursor ALL. Practical handling bears challenges due to application as four week continous infusion and specific adverse effects which can be well handled by experienced centers. Most promising outcomes are reported for patients with resistant disease but lower tumor load such as MRD positive ALL patients. Future studies will focus on the use of blinatumomab during first-line therapy and the role of stem cell transplantation after blinatumomab treatment.

Management of Patients With Histologic Transformation.

The incidence of histological transformation is up to 30% over a period of 10 years. This risk persists even beyond the initial decade of diagnosis of an indent lymphoma. In this era of emerging novel therapies, one could hope for an improved survival. There are currently no randomized trials guiding therapy for transformed lymphoma. Treatment recommendations are based on observational studies or non-randomized single arm clinical trials. To that extent, although routinely recommended and performed at transplant centers, voluminous evidence to suggest the timing or type (autologous or allogeneic) of transplant is lacking. In this article, we discuss the clinical features, treatment approach and role of stem cell transplant in transformed lymphoma.

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Role of stem cell transplant and maintenance therapy in plasma cell disorders.

Autologous stem cell transplant (ASCT) has been an important component of therapy for myeloma patients eligible for high-dose chemotherapy. Recent studies comparing early transplant to low-dose chemotherapy support the continued use of ASCT as consolidation following induction therapy, even in the era of immunomodulatory drugs, proteasome inhibitors, and other novel agents. Despite the marked improvements in outcomes with this approach, most patients will eventually experience disease progression. Thus, inclusion of post-ASCT consolidation/maintenance strategies is used to improve long-term disease control. Multiple randomized studies support the use of lenalidomide maintenance therapy following ASCT. The next generation of clinical trials will incorporate novel agents such as monoclonal antibodies, proteasome inhibitors, and other novel pathway modulatory agents into post-ASCT treatment strategies with the goal of achieving even deeper responses and longer durations of disease control.

Role of stem cell transplant and maintenance therapy in plasma cell disorders

AbstractAutologous stem cell transplant (ASCT) has been an important component of therapy for myeloma patients eligible for high-dose chemotherapy. Recent studies comparing early transplant to low-dose chemotherapy support the continued use of ASCT as consolidation following induction therapy, even in the era of immunomodulatory drugs, proteasome inhibitors, and other novel agents. Despite the marked improvements in outcomes with this approach, most patients will eventually experience disease progression. Thus, inclusion of post-ASCT consolidation/maintenance strategies is used to improve long-term disease control. Multiple randomized studies support the use of lenalidomide maintenance therapy following ASCT. The next generation of clinical trials will incorporate novel agents such as monoclonal antibodies, proteasome inhibitors, and other novel pathway modulatory agents into post-ASCT treatment strategies with the goal of achieving even deeper responses and longer durations of disease control.

P076 KIR allele level typing by a novel neXtype algorithm

KIR genes are recognized to play an important role for stem cell transplantation. The high polymorphism of these genes makes it difficult to achieve high resolution typing results.Based on paired-end short amplicon next generation sequencing (NGS) data from the Ilumina Miseq and HiSeq systems, neXtype was adapted to type KIR on allelic level. neXtype reports KIR allele typing results in the genotype list (GL) string format and implicitly provides gene copy numbers.neXtype copes with KIR typing challenges in several consecutive steps:In a first step based on the IPD-KIR library, each read is assigned the best matching known exon sequence using the tree-concept of neXtype. In a second step, the copy numbers of the identified allelic variants per exon are determined for a given primer batch. This estimated exon copy number is subsequently required for the scoring system. As a third step, combination of exon-specific results determines KIR alleles present in the sample. The number of valid exon combinations per gene yields the gene copy number. Currently, neXtype uses exons 3, 4, 5, 7, 8, and 9. The assignment of reads to a specific gene is a priori not possible as some alleles of different genes share identical exon DNA sequences. Therefore, valid combinations for those gene-bridging exons must be analyzed simultaneously. neXtype uses a scoring system based on the difference between the copy number as given by valid exon combinations from step three and the estimated exon copy number from step two. The exon combination with the lowest score is taken as the typing result and presented as a GL string.With this algorithm, samples with pre-known typing results were confirmed. In summary, we show that cost efficient high-throughput NGS data can be used for allele level KIR typing. As a consequence, allele level KIR typing could be included into the standard typing profile of newly registered stem cell donors, thus allowing for refined donor selection algorithms.

Therapeutic options in peripheral T cell lymphoma.

Peripheral T cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphomas with a very poor prognosis. The standard first-line treatments have resulted in unsatisfactory patient outcomes. With the exception of low-risk anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), the majority of patients relapse rapidly; the current 5-year overall survival rates are only 10–30 %. Novel targeted therapies and combination chemotherapies are required for the treatment of patients with PTCL. In recent years, some retrospective and prospective studies have been performed concerning PTCL. Consequently, a number of novel agents and their relevant combination therapies have been identified, including histone deacetylase inhibitors, immunoconjugates, antifolates, monoclonal antibodies, immunomodulatory agents, nucleoside analogs, proteasome inhibitors, kinase inhibitors, bendamustine, l-asparaginase, and other targeted agents. It is hoped that these innovative approaches will finally improve outcomes in patients with PTCL. This review summarizes the currently available approaches for the treatment of PTCL with an emphasis on potential new agents, including the role of stem cell transplantation.

Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma previously considered to have a poor prognosis. Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients. In particular, greater depth of understanding of the molecular pathophysiology of MCL has resulted in an explosion of specifically targeted new efficacious agents. In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib. We review recent advances in the understanding of MCL biology and outline our recommended approach to therapy, including choice of chemoimmunotherapy, the role of stem-cell transplantation, and mechanism-based targeted therapies, on the basis of a synthesis of the data from published clinical trials.

Stem cell transplantation in adults with acute myelogenous leukemia, normal cytogenetics, and the FLT3-ITD mutation

Following chemotherapy, patients with acute myelogenous leukemia (AML), normal cytogenetics, and the FLT3-ITD mutation have shorter survival compared to wild type (WT) patients. To determine the role of stem cell transplantation (SCT), we performed a retrospective review of adult patients with AML who underwent SCT at our center between January 1, 2007 and December 31, 2011. Of the 200 patients transplanted, 79 patients (40%) had normal cytogenetics; of these, 17 (22%) had the FLT3-ITD mutation, 35 were WT (44%), and 27 (34%) did not have FLT3 testing performed. Clinical characteristics were similar in each group. At four years, overall survival (OS) between FLT3 positive and WT groups was similar: 0.54 (95% CI 0.29–0.75) versus 0.73 (95% CI 0.53–0.99), p=0.18. Relapse rates were also similar, 0.09 (95% CI 0.02–0.21) versus 0.12 (95% CI: 0.02–0.32); p=0.67. We conclude that SCT can abrogate the poor prognosis in FLT3-ITD positive patients.

The Evolving Role of Stem Cell Transplant in Multiple Myeloma: A Single Institution Study

The Evolving Role of Stem Cell Transplant in Multiple Myeloma: A Single Institution Study

Role of stem cell transplant in SLE

Role of stem cell transplant in SLE