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Cell-of-origin determination has emerged as an important prognostic factor for patients initially diagnosed with diffuse large B cell lymphoma (DLBCL). Specifically, the nongerminal center B cell-like (non-GCB) subtype, composed predominantly of the activated B cell-like (ABC) molecular subtype, has been shown to portend poor prognosis because of its more aggressive nature and resistance to standard cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP)-like chemotherapy compared with the GCB subtype. The recurrent MyD88 L265P mutation, present in 29% of ABC DLBCL, was reported as an independent poor prognostic factor for patients with newly diagnosed DLBCL. For patients whose disease relapses or is refractory to first-line chemotherapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT) is frequently offered as salvage therapy. However, the impact of MyD88 mutation status on post-ASCT outcome has not been reported. Here, we retrospectively analyzed, with up to 20 years of follow-up, 165 patients who underwent ASCT for relapsed/refractory DLBCL at our institution. We found that MyD88 mutation status did not correlate with overall survival (OS), post-ASCT OS, or progression-free survival (PFS). Patients with non-GCB subtype had significantly worse OS from initial diagnosis and after ASCT. Notably, high International Prognostic Index score was predictive of poor pre- and post-transplant PFS and post-transplant OS., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Collection of an adequate number of hematopoietic stem cells can be difficult in patients with relapsed or refractory Hodgkin lymphoma (HL) who are candidates for autologous stem cell transplantation (ASCT). Plerixafor (AMD3100), an inhibitor of the interaction between stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4, is an effective hematopoietic stem cell mobilization agent in patients with multiple myeloma and non-Hodgkin lymphoma (NHL). This study was undertaken to investigate the efficacy and safety of hematopoietic stem cell mobilization with plerixafor in patients with HL. Twenty-two patients with HL who were candidates for ASCT underwent hematopoietic stem cell mobilization with a combination of granulocyle-colony stimulating factor (G-CSF), 10 microg/kg daily, and plerixafor, 240 microg/kg subcutaneous, 10-11 hours prior to apheresis. The primary endpoint was the proportion of patients who collected>or=5x10(6) CD34+ cells/kg. Outcomes were compared to a historical control population of HL patients mobilized with G-CSF alone. Pharmacokinetic (PK) analysis of plerixafor was performed in a subset of patients. Fifteen patients (68%) collected>or=5x10(6) CD34+ cells/kg, and 21 patients (95%) achieved the minimum collection of >or=2x10(6) CD34+ cells/kg, in a median 2 apheresis procedures. Both the proportion of patients collecting>or=5x10(6) CD34+ cells/kg and the median CD34+ cells collected in days 1-2 of apheresis were significantly improved over historical controls. The PK of plerixafor in this patient population was similar to that previously seen in healthy volunteers. The regimen was generally safe and well tolerated.

The purpose of this article was to examine historic institutional autologous stem cell mobilization practices and evaluate factors influencing mobilization failure and kinetics. In this retrospective study we analyzed clinical records of 1834 patients who underwent stem cell mobilization for autologous transplantation from November 1995 to October 2006 at the Washington University in St. Louis. Successful mobilization was defined as collection of > or =2 x 10(6) CD34(+) cells/kg. From 1834 consecutive patients, 1040 met our inclusion criteria (502 non-Hodgkin's lymphoma [NHL], 137 Hodgkin's lymphoma, and 401 multiple myeloma [MM]). A total of 976 patients received granulocyte colony-stimulating factor (G-CSF) and 64 received G-CSF plus chemotherapy (G/C) for the initial mobilization. Although the median CD34(+) cell yield was higher in G/C group than in G-CSF alone group, the failure rates were similar: 18.8% and 18.6%, respectively. Overall, 53% of patients collected > or =2 x 10(6) CD34(+) cells/kg during the first apheresis with either mobilization regimen. Regardless of mobilization regimen used, MM patients had the highest total CD34(+) cell yield and required less aphereses to collect > or =2 x 10(6) CD34(+) cells/kg. Mobilized, preapheresis, peripheral blood CD34(+) count correlated with first day apheresis yield (r = .877, P < .001) and 20 cells/microL was the minimum threshold needed for a successful day 1 collection. For the remobilization analysis we included patients from the whole database. A total of 269 of 1834 patients underwent remobilization using G/C, G-CSF, and/or GM-CSF, and G-CSF plus plerixafor. Only 23% of remobilized patients achieved > or =2 x 10(6) CD34(+) cells/kg and 29.7% failed to pool sufficient number of stem cells from both collections. Patients receiving G-CSF plus plerixafor had lowest failure rates, P = .03. NHL patients remobilized with G-CSF who waited > or =25 days before remobilization had lower CD34(+) cell yield than those who waited < or =16 days, P = .023. Current mobilization regimens are associated with a substantial failure rate irrespective of underlying disease. Patients who fail initial mobilization are more likely to fail remobilization. These findings suggest that there is a need for more effective first-line mobilization agents.

There are many effective salvage chemotherapy regimens for the treatment of patients with Hodgkin lymphoma (HL) who relapse after or are refractory to primary therapy. All eligible patients with relapsed or refractory HL should be considered for high-dose chemotherapy with autologous stem cell transplantation. This type of therapy has become the standard of care for patients with chemosensitive disease, based on numerous phase II and two phase III clinical trials. The major considerations in the choice of salvage therapy are response rate, toxicity, and effect on subsequent stem cell collection. For patients who do not respond to salvage therapy or who relapse after autologous transplantation, available treatment options include additional salvage regimens, reduced-intensity allogeneic stem cell transplantation, and investigational agents. This review summarizes the results of various salvage chemotherapy regimens, including newer regimens that incorporate gemcitabine, in addition to novel therapies that are currently being studied in patients with relapsed or refractory HL.

Mobilized peripheral blood has become the preferred source of stem cells for both autologous and allogeneic transplantation, and granulocyte colony-stimulating factor is the most widely used cytokine for mobilization. However, the mechanisms of cytokine-induced peripheral blood stem cell mobilization are not completely understood. Several recent studies suggest a model in which proteases released into the bone-marrow microenvironment during cytokine treatment play a critical role in mobilization. However, the finding that progenitor mobilization is normal in certain protease-deficient mice suggests that this model may be too simplistic. Here we review recent studies that advance our understanding of the biology of stem cell mobilization. We then discuss cytokines in current use and in development for mobilization of autologous and allogeneic peripheral blood stem cells.

Since their initial approval as single agent therapy for multiply relapsed/refractory Hodgkin lymphoma (HL), the PD-1 inhibitors nivolumab and pembrolizumab have been incorporated into second-line salvage regimens, and they are being investigated in upfront therapy of newly diagnosed patients. As second-line therapy in combination with brentuximab vedotin or multi-agent chemotherapy, nivolumab and pembrolizumab provide high complete remission rates and durable progression-free survival after consolidative autologous stem cell transplant. Incorporation of these agents into frontline chemotherapy regimens is feasible, and early results from a Phase III trial of nivolumab-AVD compare favorably with the existing standard for advanced stage HL, brentuximab vedotin plus AVD. As nivolumab and pembrolizumab move into earlier lines of HL therapy, open research questions include the efficacy of checkpoint inhibitor regimens in patients who relapse after frontline exposure to nivolumab or pembrolizumab; the selection of patients with relapsed HL who can achieve durable remissions without autologous stem cell transplant; and the efficacy of the PD-1 inhibitors in the frontline therapy of patients with early stage Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

Summary: There have been no large studies comparing reduced‐intensity/non‐myeloablative conditioning (RIC/NMA) to myeloablative conditioning (MAC) regimens in T‐cell non‐Hodgkin lymphoma (T‐NHL) patients undergoing allogeneic transplant (allo‐HCT). A total of 803 adults with peripheral T‐cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T‐cell lymphoma (age 18–65 years), undergoing allo‐HCT between 2008–2019 and reported to the Center for International Blood and Marrow Transplant Research with either MAC (n = 258) or RIC/NMA regimens (n = 545) were evaluated. There were no significant differences between the two cohorts in terms of patient sex, race and performance scores. Significantly more patients in the RIC/NMA cohort had peripheral blood grafts, haematopoietic cell transplantation‐specific comorbidity index (HCT‐CI) of ≥3 and chemosensitive disease compared to the MAC cohort. On multivariate analysis, overall survival (OS) was not significantly different in the RIC/NMA cohort compared to the MAC cohort (hazard ratio (HR) = 1.01, 95% confidence interval (CI) = 0.79–1.29; p = 0.95). Similarly, non‐relapse mortality (NRM) (HR = 0.85, 95% CI = 0.61–1.19; p = 0.34), risk of progression/relapse (HR = 1.29; 95% CI = 0.98–1.70; p = 0.07) and therapy failure (HR = 1.14; 95% CI = 0.92–1.41, p = 0.23) were not significantly different between the two cohorts. Relative to MAC, RIC/NMA was associated with a significantly lower risk of grade 3–4 acute graft‐versus‐host disease (HR = 0.67; 95% CI = 0.46–0.99, p = 0.04). Among chemorefractory patients, there was no difference in OS, therapy failure, relapse, or NRM between RIC/NMA and MAC regimens. In conclusion, we found no association between conditioning intensity and outcomes after allo‐HCT for T‐cell NHL. [ABSTRACT FROM AUTHOR]

The lyophilized formulation of melphalan has several limitations based on its marginal solubility, limited stability after reconstitution, and the requirement to reconstitute it in propylene glycol (PG). PG-free melphalan (Evomela; Spectrum Pharmaceuticals, Irvine CA) overcomes these limitations by using the solubilizing agent Captisol (Ligand Pharmaceuticals, Inc., LaJolla CA) to improve the stability of the reconstituted melphalan and avoid the potential toxicities of PG. This phase II study investigated the safety and efficacy of high-dose PG-free melphalan when included in the carmustine, etoposide, and cytarabine (BEAM) regimen for adult patients with non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). Carmustine, etoposide, and cytarabine were given at standard doses on day –6 through day –3. PG-free melphalan, 140 mg/m 2 , was infused over 30 minutes on day –2. The primary endpoint was toxicity. Fifty patients (33 NHL/17 HL) completed BEAM with PG-free melphalan and stem cell infusion. The most common grades 3 to 4 nonhematologic toxicities were neutropenic fever (68%), infections (36%), and electrolyte abnormalities. Forty-one patients (82%) had oral mucositis, which was mostly grades 1 to 2 (6% grade 3). Moderate or severe gastrointestinal toxicities were uncommon. There were no treatment-related deaths. Forty-nine patients (98%) had neutrophil and platelet engraftment at a median of 10 and 19 days, respectively. At response assessment at 60 to 100 days after autologous stem cell transplantation, 42 patients (82%) were in complete remission, 2 in partial remission, and 6 had progressive disease. Progression-free survival at 1 year was 70%. These results demonstrate that PG-free melphalan can be used in place of the standard, lyophilized formulation of melphalan in the BEAM regimen for lymphoma patients undergoing autologous stem cell transplantation. It has a safety profile that compares favorably with standard lyophilized melphalan, and the engraftment rate and response rates were consistent with expectations. [ABSTRACT FROM AUTHOR]

Up to 30% of patients with acute myeloid leukemia (AML) and abnormal cytogenetics have persistent cytogenetic abnormalities (pCytAbnl) at morphologic complete remission (mCR). We hypothesized that the prognostic significance of pCytAbnl in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in mCR varies with cytogenetic risk group. We analyzed the data on 118 patients with AML and abnormal cytogenetics who underwent HSCT in mCR, and developed a risk stratification model based on pCytAbnl and cytogenetic risk group. The model distinguished three groups of patients ( P < 0.01) with distinct outcomes: the group with pCytAbnl and unfavorable risk cytogenetics ( n = 25) had the shortest median time to relapse (TTR; 5 months), relapse-free survival (RFS; 3 months), and overall survival (OS; 7 months). The group with favorable/intermediate risk cytogenetics and without pCytAbnl ( n = 43) had the longest median TTR (not reached), RFS (57 months), and OS (57 months). The group with pCytAbnl and favorable/intermediate risk cytogenetics, or, without pCytAbnl but with unfavorable risk cytogenetics ( n = 50) experienced intermediate TTR (18 months), RFS (9 months), and OS (18 months). In conclusion, a cytogenetic risk model identifies patients with AML in mCR with distinct rates of relapse and survival following HSCT. [ABSTRACT FROM AUTHOR]

Positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET) has emerged as the standard response assessment tool in frontline therapy for classical Hodgkin lymphoma (cHL). The ability of FDG-PET to predict outcomes in patients with relapsed cHL treated with modern standard salvage chemotherapy and autologous stem cell transplantation (ASCT) remains uncertain. Forty-six patients with relapsed/refractory cHL treated from 2001 to 2007 with standard salvage/ASCT therapy had FDG-PET available for blinded review. The results of pre-ASCT FDG-PET interpreted by the international harmonization project (IHP) criteria were compared with published prognostic models for prediction of event-free survival (EFS) and overall survival (OS). Overall, 3-year EFS was 62% and OS was 78%, with a median follow-up of 38 months. Pre-ASCT FDG-PET response significantly predicted 3-year EFS in FDG-PET-negative (82%) versus FDG-PET-positive (41%) patients (P = .02). A trend was observed for 3-year OS comparing FDG-PET-negative (91%) versus -positive (64%) patients (P = .08). Multivariate analysis demonstrated the independent prognostic significance of pre-ASCT FDG-PET for EFS with a hazard ratio (HR) of 3.2 (confidence interval [CI] 1.1-9.0, P = .03). Pre-ASCT FDG-PET scans predict EFS in patients with relapsed cHL patients treated with modern salvage/ASCT therapy and warrant prospective evaluation. [ABSTRACT FROM AUTHOR]

Summary: The majority of patients who are diagnosed with Hodgkin lymphoma (HL) will be cured with primary chemotherapy. For those who relapse, autologous stem cell transplantation (ASCT) has become the standard of care. Randomized clinical trials have demonstrated that approximately 50% of patients with chemosensitive relapsed HL can achieve long term disease free survival with ASCT. However, optimal therapy of those who have chemorefractory disease or who relapse after an ASCT has not been established. Reduced intensity allogeneic stem cell transplantation may benefit these patients, although a definite graft versus HL effect has not been demonstrated and treatment-related mortality remains relatively high. New salvage regimens that incorporate gemcitabine, vinorelbine, rituximab, and/or monoclonal antibodies against CD30 are being investigated. [Copyright &y& Elsevier]

As hematopoietic stem cells collected from peripheral blood are increasingly used for autologous and allogeneic stem cell transplantation, new approaches for the mobilization of stem cells are needed. These should have the goal of improving stem cell collection and reducing the duration and toxicity of the mobilization process. AMD3100, a specific inhibitor of CXCR4, one of the key molecules that tethers hematopoietic stem cells to the bone marrow microenvironment, is a promising new agent currently in clinical development for autologous and allogeneic stem cell mobilization. Early clinical trials have demonstrated that AMD3100 rapidly mobilizes stem cells to the peripheral blood, with minimal side effects. In Phase II trials, mobilization with the combination of AMD3100 and granulocyte colony-stimulating factor (G-CSF) results in the collection of more progenitor cells than G-CSF alone. [ABSTRACT FROM AUTHOR]

• We performed a pilot clinical trial to determine the feasibility of maintenance lenalidomide after autologous stem cell transplant in relapsed/refractory classical Hodgkin lymphoma (rel/ref cHL). • An unexpectedly high frequency of hematologic toxicities resulting in early lenalidomide discontinuation was observed. • The lenalidomide maintenance dose and schedule used in this study are not feasible in rel/ref cHL. For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD). In mice, administration of azacitidine (AzaC) on days 4, 6, 8, and 10 post DLI increases regulatory T cell (Treg) numbers and prevents GVHD without hindering Graft vs. Leukemia (GVL). Based on these findings, we conducted a phase 1 study of AzaC post DLI for AML relapse post allo-SCT. AzaC was administered on days 4, 6, 8 and 10 post-DLI. Dose escalation was done using a 3 + 3 design with three AzaC dose levels: 30 mg/m 2 (level −1), 45 mg/m 2 (level 1) and 75 mg/m 2 (level 2). Three patients were treated in the 45 mg/m 2 dose level and 5 patients were treated in the 75 mg/m 2 dose level; no DLTs or grade 3–5 treatment related toxicities were observed. After a median follow-up of 5.2 months, no patients developed grade III–IV aGVHD and no patients died of aGVHD. Six out of 8 patients in the treatment group responded to treatment including two cytogenetic complete remissions, one hematologic complete remission, and three complete remissions with incomplete count recovery. In conclusion, administration of AzaC early post DLI is well tolerated and can potentially prevent GVHD after DLI. Further studies are required to evaluate the effect of azacitidine early post DLI on GVHD and GVL. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For patients with relapsed disease after transplantation, intensive chemotherapy followed by donor lymphocyte infusion (DLI) or a second allo-SCT may result in a durable response in some patients. High-intensity chemotherapy and less aggressive therapy with hypomethylating agents (HAs) with and without DLI are often used for relapse after allo-SCT. Here we compared the treatment outcomes of intensive chemotherapy with that of HAs in relapsed AML and MDS after allo-SCT. Patients who had received a second SCT within 90 days of the relapse date were excluded. The primary endpoints were overall response rate (ORR) and overall survival (OS). Secondary endpoints were complete remission (CR) rate and progression-free survival (PFS). One hundred patients were included: 73 patients received chemotherapy and 27 patients received an HA. Fifty-six percent of patients in the chemotherapy group and 33% of patients in the HA group received at least 1 DLI after treatment. Treatment with chemotherapy resulted in a higher ORR (51% versus 19%, P = .004) and a higher CR rate (40% versus 7%, P = .002). The median OS (6 versus 3.9 months, P = .01) and PFS (4.9 versus 3.8 months, P = .02) were longer in the chemotherapy group. Similar benefit of chemotherapy over HAs was maintained in all treatment outcomes after controlling for the use of DLI. The use of chemotherapy followed by DLI offered the greatest benefit (ORR, 68%; CR, 59%, 1-year OS, 44%; and median OS, 9.8 months). In conclusion, in our hands, with limited numbers, the use of more conventional salvage chemotherapy, with DLI when possible, for the treatment of relapsed AML and MDS after allo-SCT is associated with better outcomes than nonchemotherapy (HA) options. [ABSTRACT FROM AUTHOR]

Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m 2 /day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m 2 for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m 2 , where most hematological toxicities occurred. [ABSTRACT FROM AUTHOR]

Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge, with limited effective treatment options available after stem cell transplantation. In a multicenter phase 2 study, the efficacy of lenalidomide in rel/ref cHL patients was evaluated at a dose of 25 mg/d on days 1-21 of a 28-day cycle. Patients remained on lenalidomide until disease progression or an unacceptable adverse event (AE) occurred. Thirty-eight cHL patients were enrolled with a median of 4 (range, 2-9) prior therapies; 87% had undergone prior stem cell transplantation and 55% of patients did not respond to their last prior therapy. Of 36 evaluable patients, responses were 1 complete remission (CR), 6 partial remissions (PRs), and 5 patients with stable disease (SD) for ⩾ 6 months resulting in an International Working Committee (IWC) objective overall response rate (ORR) of 19% and a cytostatic ORR of 33%. Decreased chemokine (CCL17 and CCL22) plasma levels at 2 weeks were associated with a subsequent response. The treatment was well tolerated, and the most common grade 3/4 AEs were neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Four patients discontinued lenalidomide because of rash, elevated transaminases/bilirubin, and cytopenias. We provide preliminary evidence of lenalidomide's activity in patients with rel/ref cHL, and therefore exploration of lenalidomide in combination with other active agents is warranted. [ABSTRACT FROM AUTHOR]