Outpatient autologous hematopoietic stem cell transplantation for patients with relapsed follicular lymphoma

Autologous stem cell transplantation (ASCT) has emerged as a viable option for the treatment of relapsed follicular non-Hodgkin’s lymphoma. We report on the outpatient experience of 60 patients who underwent ASCT for this condition. The median age was 51 years (30–65). Pre-transplantation conditioning regimens consisted of either etoposide/melphalan/TBI, CBV or BEAM. Patients participated in this transplant program for a median of 20.5 days (14–78), and 58.4% of the total program days were spent in the outpatient setting. Six patients were well enough to be treated solely as outpatients. Ninety percent of patients required at least one inpatient admission (median 7 days), and 70% of first inpatient transfers occurred within the first week following transplant and always before day +12. There were no predictors for prolonged inpatient stays. Febrile neutropenia and gastrointestinal toxicity were the main reasons for inpatient transfers. No outpatient required an urgent admission to the ICU or died in the outpatient setting. The treatment-related mortality at days 30 and 100 was 0 and 1.7%, respectively. The overall and progression-free survivals at 5 years were 65.7 and 56.1%, respectively. Outpatient ASCT with total body irradiation is feasible, safe, and effective for patients with relapsed follicular lymphoma.     

Rituximab as in vivo purging agent in autologous stem cell transplantation for relapsed B-NHL

In vivo purging may avoid relapse after high dose therapy (HDT) for relapsed lymphoma. Therefore, we have evaluated feasibility and efficacy of Rituximab as in vivo purging agent included into a sequential salvage protocol for CD20+ B-NHL in chemosensitive relapse or induction failure. Thirty seven patients were treated within this protocol and in 36/37 a stem cell product could be acquired with rare NHL contamination. Overall, due to the intensity of treatment there has been a substantial morbidity, including high rates of viral reactivation. However, only one patient died during treatment due to sepsis. Response rates were favourable with an overall response rate of 97% (with 30/35CR). With a maximum follow up of 3.5 years, 15 patients relapsed. Overall, the treatment protocol has proven feasible with high purging efficiency and encouraging remission rates in this unfavourable patient group.     

Long-term follow-up demonstrates curative potential of autologous stem cell transplantation for relapsed follicular lymphoma

Although autologous stem cell transplantation (ASCT) can achieve durable responses in eligible patients with follicular lymphoma (FL), long-term follow-up is needed to determine if it has curative potential. This retrospective, multicenter study included 162 patients who received ASCT for relapsed FL in Alberta, Canada. With a median (range) follow-up time of 12.5 years (0.1–27.9), the 12-year time-to-progression (TTP) was 57% (95% confidence interval [CI] 49%–65%), time-to-next-treatment was 61% (95% CI 52%–69%), progression-free survival was 51% (95% CI 42%–59%) and overall survival was 69% (95% CI 60%–76%). A plateau emerged on the TTP curve at 57% starting 9 years after ASCT with no relapses occurring beyond this timepoint. Ten patients remained in remission 20 years or more after ASCT. Patients undergoing ASCT at first or second relapse had superior outcomes compared to third or later relapse (12-year TTP 61% vs. 34%), as did patients without progression of disease within 24 months (POD24) of frontline treatment versus those with POD24 (12-year TTP 67% vs. 50%). ASCT achieves high rates of durable remission in relapsed FL, with long-term follow-up revealing that more than 50% of transplanted patients may be functionally cured of their lymphoma. The optimal timing to consider ASCT is at first or second relapse, regardless of POD24 status.     

Influenza-induced rhabdomyolysis after autologous peripheral blood stem cell transplantation for malignant lymphoma

We report influenza-induced rhabodmyolysis and congestive heart failure after high-dose therapy and hematopoietic stem cell transplantation for malignant lymphoma. Four months after autologous peripheral blood stem cell transplantation for the treatment of malignant lymphoma, a 65-year-old Japanese man developed acute congestive heart failure requiring artificial ventilation and rahbdomyolysis. Since influenza A virus was documented from his nasal cavity, he was diagnosed as rhabdomyolysis and congestive heart failure induced by influenza A infection. Neuraminidase inhibitor (oseltamivir 150 mg/ day for 5 days) was administrated, and heart failure and respiratory status were improved. Our experience suggests that early treatment with neuraminidase inhibitor may improve the clinical outcome of influenza-induced rhabdomyolysis and congestive heart failure.     

In vitro megakaryocyte expansion in patients with delayed platelet engraftment after autologous stem cell transplantation

Increasing the number of megakaryocytic cells in stem cell transplants by ex vivo expansion culture may provide an approach to accelerate platelet engraftment after high-dose chemotherapy. However, it is unknown if a relationship exists between the expansion potential of progenitor cells and the time to platelet engraftment in vivo. Therefore, we questioned if those patients who potentially would benefit most from expanded cell supplements are able to generate megakaryocytic cells efficiently in vitro. The in vitro megakaryocyte proliferation was analyzed from 19 leukapheresis samples from a group of multiple myeloma patients who all showed rapid neutrophil engraftment, but varied from 7 to 115 days post-transplant to achieve platelet levels >20x10(9)/l. CD34+ cells were isolated and analyzed for their potential to form megakaryocytic colonies (CFU-Mk) in colony assays and megakaryocytic (CD61+) cells in suspension cultures. The frequency and size of CFU-Mk and the expansion potential of CD61+ cells varied eightfold between individual patients. A similar range was found with CD34+ cells isolated from normal bone marrow (n=9). Rapid platelet engraftment occurred in patients receiving both high or low CFU-Mk doses and with high and low expansion of CD61+ cells. Four patients who experienced prolonged (>3 weeks) thrombocytopenia received low CFU-Mk doses, but the expansion potential was around median values or higher. Therefore, we conclude that the megakaryocyte proliferation is not impaired and that in vitro expansion could increase the number of megakaryocytic cells, although other factors could be more relevant in platelet engraftment in this group of patients.     

Ex vivo expansion of human hematopoietic stem cells

There has been great interest in the ex vivo expansion of human long-term repopulating hematopoietic stem cells (LTR-HSCs) for a variety of clinical applications such as umbilical cord blood transplantation. The glucoprotein130 signal, activated by a complex of interleukin 6 (IL-6) and soluble IL-6 receptor (IL-6/sIL-6R), acts dramatically in synergy with the c-Kit or Flk2/Flt3 signal to expand immature human HSCs. We demonstrate a significant ex vivo expansion of human LTR-HSCs capable of repopulating in newly discovered nonobese diabetes/Shi-severe combined immunodeficient (NOD/Shi-SCID) mice. The proportion of human CD45+ cells in recipient marrow was 10 times higher in animals receiving the cultured cells with stem cell factor, Flk2/Flt3 ligand, thrombopoietin, and IL-6/sIL-6R than in those receiving comparable numbers of fresh cord blood CD34+ cells. The expansion rate provided by this combination was estimated to be 4.2-fold by a limiting dilution method. Addition of IL-3 to the culture with the cytokine combination abrogated the repopulating ability of the expanded cells. The culture method with the IL-6/sIL-6R complex and other cytokines may pave the way for ex vivo expansion of human transplantable HSCs suitable for clinical applications.     

High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma

Relapsed mantle cell lymphoma is a radiation-sensitive malignancy that is unlikely to be cured by treatment with conventional high-dose therapy and autologous stem cell transplantation. We tested the safety and efficacy of using a CD20-specific monoclonal antibody conjugated with (131)I to deliver high-dose radiation selectively to all lymphoma sites. Patients with relapsed or refractory mantle cell lymphoma received infusions of (131)I-labeled CD20-specific monoclonal antibody (Tositumomab). The antibody dose was 1.7 mg/kg body weight, and the amount of (131)I was calibrated to deliver 20 to 25 Gy to vital normal organs. This treatment was followed 10 days later by administration of high-dose etoposide (30-60 mg/kg), cyclophosphamide (60-100 mg/kg), and infusion of cryopreserved autologous stem cells. The 16 patients in this study had received a median of 3 prior treatments, and 7 had chemotherapy-resistant disease. The median dose of (131)I was 510 mCi (18.87 GBq). There were no therapy-related deaths. Among the 11 patients with conventionally measurable disease at the time of treatment, the respective complete and overall response rates were 91% and 100%. Fifteen patients remain alive, and 12 have had no progression of lymphoma at 6 to 57 months from transplantation and 16 to 97 months from diagnosis. Overall survival at 3 years from transplantation is estimated at 93%, and progression-free survival is estimated at 61%. High-dose treatment with (131)I-Tositumomab, etoposide, and cyclophosphamide results in a high remission rate and may provide long-term disease-free survival for patients with relapsed or refractory mantle cell lymphoma.     

Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: A GITMO study

Patients who relapse after an autologous hematopoietic stem cell transplantation (SCT) have a very poor prognosis. We have retrospectively analyzed diffuse large B cell lymphoma patients who underwent an allo-SCT after an auto-SCT relapse reported in the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) database. From 1995 to 2008, 3449 autologous transplants were reported in the GITMO database. Eight hundred eighty-four patients relapsed or progressed after transplant; 165 patients, 19% of the relapsed patients, were treated with allo-transplant. The stem cell donor was related to the patient in 108 cases. A reduced intensity conditioning regimen was used in 116. After allo-SCT, 72 patients (43%) obtained a complete response and 9 obtained a partial response with an overall response rate of 49%; 84 patients (51%) experienced rapid progression of disease. Ninety-one patients died, 45 due to disease and 46 due to treatment-related mortality. Acute graft-versus-host disease was recorded in 57 patients and a chronic GvHD in 38 patients. With a median follow-up of 24 months (2-144) after allo, overall survival (OS) was 39%, and after a median of 21 months (2-138) after allo, progression-free survival (PFS) was 32%. Multivariate analysis indicated that the only factors affecting OS were status at allo-SCT, and those affecting PFS were status at allo-SCT and stem cell donor. This retrospective analysis shows that about one-fifth of patients with diffuse large B cell lymphoma who experience relapse after autologous transplantation may be treated with allogeneic transplantation. Moreover, the only parameter affecting either OS or PFS was the response status at the time of allo-SCT.     

Prothrombotic hemostatic abnormalities in patients with refractory malignant lymphoma presenting for autologous stem cell transplantation

Forty-six patients with refractory malignant lymphoma (Hodgkin's and non-Hodgkin's) admitted for autologous marrow or peripheral blood stem cell transplantation (ASCT) were evaluated for the presence of hemostatic abnormalities known to be associated with a hypercoagulable state in other patient populations. All patients had received numerous chemotherapeutic agents in the past and often radiation therapy as well. Hemostatic abnormalities were found to be common in these patients. The most frequent finding was hyperfibrinogenemia, present in 35% of patients. Decreased protein C activity was present in 32% of patients. Protein C antigen was low in only one individual and protein S was normal or increased in all patients. Low levels of antithrombin III were present in 16%. Plasminogen activator inhibitor was elevated in 20%. Anticardiolipin antibodies were present in 29% of patients; other evidence of a lupus anticoagulant was present in only eight patients. The frequency of each hemostatic abnormality was similar for patients with Hodgkin's disease (HD) and those with non-Hodgkin's lymphoma (NHL) despite the fact that significantly more patients with HD had received irradiation and/or previous splenectomy than patients with NHL. We conclude that multiple prothrombotic abnormalities of hemostasis are present in patients with refractory lymphoma referred for ASCT. Whether these are the result of lymphoma or the result of therapy cannot be determined from this study.     

Frontline autologous stem cell transplantation for peripheral T-cell lymphoma

Peripheral T-cell lymphoma constitutes a heterogeneous group, with a low incidence and no standard frontline therapy. The current study evaluates the use of frontline autologous stem cell transplantation in 83 peripheral T-cell lymphomas included in the first and largest prospective trial. Results indicate that the procedure is feasible, with a low treatment-related mortality, and is associated with a better outcome than obtained with conventional chemotherapy. A general problem in this and other prospective trials is that approximately 30% of cases do not receive transplantation owing to disease progression. Thus, new approaches aimed at increasing the number of chemosensitive patients should be found, some of which are discussed in this article. For chemoresistant or relapsing patients, promising results have been reported using allogeneic stem cell transplantation or adding new agents.     

Monoclonal antibodies and autologous stem cell transplantation for lymphoma

The introduction of monoclonal antibodies into the clinic has paved the way for new approaches to stem cell transplantation for patients with lymphoma. These approaches include the development of new high-dose regimens with radiolabeled antibodies, in vivo purging techniques with the unlabeled antibodies, and post-transplant adjuvant immunotherapy. Numerous trials have demonstrated the feasibility of these approaches. However, questions remain regarding the application of these antibodies including the ultimate efficacy. The recent results of the incorporation of monoclonal antibodies into stem cell transplantation and current research directions are reviewed.     

Successful autologous peripheral blood stem cell transplantation for relapsed intravascular lymphomatosis

We describe a case of relapsed intravascular lymphomatosis (IVL) successfully treated with autologous PBSCT. A 59-year-old Japanese female patient with IVL who had achieved CR after six courses of biweekly CHOP therapy developed lymphoma. She achieved a second CR after six courses of modified biweekly CHOP therapy, followed by autologous PBSCH and high-dose chemotherapy (CBDCA, VP-16, MCNU, CY) with PBSCT. There has not been any evidence of recurrence 48 months after PBSCT. Our case suggests that PBSC is acceptable as a source for stem cell rescue in IVL.     

Ex vivo expansion of mobilized peripheral blood stem cells.

The scarcity of donors for allogeneic bone marrow transplantation, the limited number of haematopoietic stem cell (HSC)/progenitors in cord blood samples and the sometimes insufficient number of mobilized peripheral blood cells collected from heavily treated cancer patients may benefit from ex vivo expansion of these cells for clinical transplantation. Depending on the clinical application, expansion of different haematopoietic cell subsets is required. HSC transplantation requires expansion of all cellular subsets including precursors, progenitors and HSCs for the short and long-term engraftment of patients. Quiescent HSCs may also be required for gene therapy by retrovirus. Finally, amplification of cells such as dendritic cells (DC) and different subsets of T and natural killer (NK) cells is required for immunotherapy. The different haematopoietic lineages are produced under different experimental conditions and the starting population is a critical parameter for the proposed clinical application. So it is essential to define the aims of haematopoietic cell expansion and to adapt the experimental conditions to obtain the required cell population. Mobilized peripheral blood cells are increasingly used as a source of haematopoietic cells. We review the biological characteristics of mobilized peripheral blood and the expansion of the different components according to the aims of their clinical use in the context of the progress currently achieved.     

Ex vivo expansion of human hematopoietic stem and progenitor cells

Despite progress in our understanding of the growth factors that support the progressive maturation of the various cell lineages of the hematopoietic system, less is known about factors that govern the self-renewal of hematopoietic stem and progenitor cells (HSPCs), and our ability to expand human HSPC numbers ex vivo remains limited. Interest in stem cell expansion has been heightened by the increasing importance of HSCs in the treatment of both malignant and nonmalignant diseases, as well as their use in gene therapy. To date, most attempts to ex vivo expand HSPCs have used hematopoietic growth factors but have not achieved clinically relevant effects. More recent approaches, including our studies in which activation of the Notch signaling pathway has enabled a clinically relevant ex vivo expansion of HSPCs, have led to renewed interest in this arena. Here we briefly review early attempts at ex vivo expansion by cytokine stimulation followed by an examination of our studies investigating the role of Notch signaling in HSPC self-renewal. We will also review other recently developed approaches for ex vivo expansion, primarily focused on the more extensively studied cord blood-derived stem cell. Finally, we discuss some of the challenges still facing this field.     

Brentuximab vedotin for the treatment of patients with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplantation

Brentuximab vedotin (BV) is the first approved novel agent for salvage treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT). In this study, a literature-based analysis was undertaken to assess, via an indirect treatment comparison, the comparative efficacy of BV to salvage chemotherapy as treatment for R/R cHL patients following ASCT. This comparative effectiveness research was undertaken to support a reimbursement submission for BV to the Australian Pharmaceutical Benefits Advisory Committee. Retrospective analysis of individual patient data from four data sources demonstrated that the use of BV as first salvage treatment in cHL patients relapsing or progressing post-ASCT achieved improvements in both clinical response and overall survival. More specifically, BV was associated with an incremental improvement of 22% in overall response rate compared to salvage chemotherapy. Five-year overall survival and progression-free survival rates were 92·2% [95% confidence interval (CI): 85·5–99·3%] and 32·2% (95% CI: 19·1–54·6%) respectively for BV, compared to 30·5% (95% CI: 22·2–42·0%) and 3·2% (95% CI: 1·1–8·9%) respectively for salvage chemotherapy. The encouraging results from this conservative analysis have the potential to support informed clinical management and funding decisions for the first salvage of cHL patients demonstrating recurrence after ASCT.