Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study

We assessed late mortality in 854 individuals who had survived 2 or more years after autologous hematopoietic cell transplantation (HCT) for hematologic malignancies. Median age at HCT was 36.5 years, and median length of follow-up was 7.6 years. Overall survival was 68.8% +/- 1.8% at 10 years, and the cohort was at a 13-fold increased risk for late death (standardized mortality ratio [SMR] = 13.0) when compared with the general population. Mortality rates approached those of the general population after 10 years among patients at standard risk for relapse at HCT (SMR = 1.1) and in patients undergoing transplantation for acute myeloid leukemia (AML; SMR = 0.9). Relapse of primary disease (56%) and subsequent malignancies (25%) were leading causes of late death. Relapse-related mortality was increased among patients with Hodgkin disease (HD; relative risk [RR] = 3.6), non-Hodgkin lymphoma (NHL; RR = 2.1), and acute lymphoblastic leukemia (ALL; RR = 6.5). Total body irradiation (RR = 0.6) provided a protective effect. Nonrelapse-related mortality was increased after carmustine (RR = 2.3) and with use of peripheral blood stem cells (RR = 2.4). Survivors were more likely to report difficulty in holding jobs (RR = 9.4) and in obtaining health (RR = 7.7) or life insurance (RR = 8.4) when compared with siblings. Although mortality rates approach that of the general population after 10 years in certain subgroups, long-term survivors of autologous HCT continue to face challenges affecting their health and well-being.     

A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma

We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The median times to reach an absolute neutrophil count greater than 500/microL and platelet count more than 20,000/microL were 10 days and 12 days, respectively. There were 2 deaths and 5 relapses. At a median follow-up of 22 months, the 2-year estimated overall survival and relapse-free survival rates are 92% and 78%, respectively. We conclude that high-dose 90Y-ibritumomab tiuxetan can be combined safely with high-dose etoposide and cyclophosphamide without an increase in transplant-related toxicity or delayed engraftment.     

Approach to Hodgkin's lymphoma in the new millennium

Approximately 75% of patients with Hodgkin's lymphoma can be cured with modern chemotherapy and radiation. Most patients are treated according to clinical stage and the associated prognostic factors. For patients with limited stage Hodgkin's lymphoma, combined modality treatment has replaced subtotal nodal irradiation as the preferred treatment option. This approach eliminates laparotomy and potentially decreases the long-term toxicity secondary to extended field irradiation and splenectomy. Furthermore, recent studies suggest that it may improve disease control and possibly survival. Multiple novel regimens have been tested in the past 20 years in patients with advanced Hodgkin's lymphoma including dose-intense regimens, but current evidence suggests that ABVD remains the treatment of choice outside clinical trials. Over the past decade, the treatment-related morbidity and mortality associated with autologous stem cell transplantation have reduced significantly and stem cell transplant is becoming the treatment of choice for most patients with primary refractory or recurrent Hodgkin's lymphoma. With longer follow-up, long-term complications, in particular secondary malignancy have become the leading cause of late treatment failure for patients with Hodgkin's lymphoma. To improve the overall outcome of patients with Hodgkin's lymphoma, future studies need to focus on reducing the therapy-related toxicity for patients with good risk disease as well as improving disease control for patients with poor risk disease through a risk-adapted approach.     

Incorporation of camptothecin into N-phthaloyl chitosan-g-mPEG self-assembly micellar system.

The capability of N-phthaloylchitosan-grafted poly (ethylene glycol) methyl ether (mPEG)(PLC-g-mPEG) to enhance the aqueous solubility and stability of the lactone form of camptothecin (CPT) was investigated. PLC-g-mPEG formed a core-shell micellar structure after dialysis of the polymer solutions in dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) against water, with a critical micelle concentration (CMC) of 28 microg/ml. CPT was loaded into the inner core of the micelles by dialysis method. The results showed an increase in the CPT-loading amount with an increasing concentration of CPT. The stability of drug-loaded micelles was studied by gel-permeation chromatography (GPC), and their in vitro release behaviors were analyzed. Release of CPT from the micelles was sustained. When compared to the unprotected CPT, CPT-loaded PLC-g-mPEG micelles were able to prevent the hydrolysis of the lactone group of the drug. The kinetics of the CPT hydrolysis in human serum albumin (HSA) and fetal bovine serum (FBS) were pseudo-first order. The hydrolysis rate constants for CPT and CPT-loaded PLC-g-mPEG micelles in phosphate-buffered saline (PBS) pH 7.4, were 7.4 x 10(-3) min(-1) and 9.1 x 10(-3) h(-1), parallel to an increase in half-life of CPT from 94 min to 76.15 h, respectively.     

Effect of salt forms and molecular weight of chitosans on in vitro permeability enhancement in intestinal epithelial cells (Caco-2)

The purpose of this study was to investigate the effect of molecular weight (MW) and salt forms of chitosans (aspartate; CS A, glutamate; CS G, lactate; CS L and hydrochloride, CS HCl) on the transepithelial electrical resistance (TEER) and permeability of Caco-2 cells monolayer, using fluorescein isothiocyanate dextran 4000 (FD-4) as the model compound for paracellular tight junction transport. Chitosan salts were prepared by spray-drying method. FTIR and solid-state (13)C NMR spectra showed the functional groups of salts in their molecular structures. Salt form, MW of chitosan, and amount of chitosan influenced the permeation-enhancing effects. These studies showed that chitosan salts appeared to increase cell permeability in a dose-dependent manner and caused relatively reversible effects only at the lower doses of 0.001-0.01% w/v. As the MW of chitosan increased from 20 to 460 kDa, the reduction in TEER significantly decreased in the following order: 20 < 45 < 200 < 460 kDa, observed in CS L and CS HCl. In CS A and CS G, the decrease in TEER was not significantly different in all MW because both chitosan salts showed rapid reduction in TEER within 20 min after the start of the experiment. Among chitosan salts, CS A was the most potent absorption enhancer in acidic (pH 6.2) environment. Cytotoxicity of chitosan salts was concentration dependent and varied slightly among the salt forms of chitosan used. CS HCl (MW 45 kDa) was the most toxic having an IC50 of 0.22 +/- 0.06 mg/mL. The ranking of chitosan salts cytotoxicity was CS HCl > CS L> CS G > CS A.     

Role of hematopoietic stem cell transplantation for advanced-stage diffuse large cell B-cell lymphoma-B

The prognosis of patients with relapsed or refractory diffuse large cell B-cell lymphoma-B (DLCL-B) is poor with conventional salvage chemotherapy; therefore, high-dose therapy (HDT) combined with autologous stem cell transplant (ASCT) has become the treatment of choice for these patients. The outcomes of transplant are better in patients with chemosensitive relapse: those with a longer duration of first remission (>12 month) and those with an age-adjusted low-risk International Prognostic Index (IPI) at relapse. Several high-dose regimens with or without total body irradiation (TBI) have been used with similar outcomes. Relapse remains the most common cause of treatment failure, and thus the use of radioimmunotherapy (RIT) in the high-dose regimens and incorporation of rituximab in the transplant setting have been explored. Several studies have shown that RIT both at conventional dose and at high dose can be given in combination with high-dose chemotherapy regimens without additional toxicity or delay in hematopoietic recovery after ASCT. Additional studies using RIT in combination with high-dose chemotherapy and ASCT are ongoing, and preliminary results suggest that these approaches may be superior to conventional high-dose regimens. Since rituximab is an effective therapy for B-cell non-Hodgkin's lymphoma and given its limited toxicity, rituximab has been incorporated into HDT and ASCT for DLCL-B as in vivo purging, as part of high-dose regimens, and as maintenance therapy to prevent relapse. Preliminary results suggested that rituximab during ASCT and as maintenance therapy post-transplant reduces the risk of relapse and improves survival; however, these results need to be confirmed in phase III randomized trials. The role of ASCT during first remission as consolidative therapy in patients with DLCL-B remains controversial and should not be performed outside of the clinical trial setting. Allogeneic stem cell transplant (allo-SCT) for patients with relapsed DLCL-B is associated with significant toxicity and should be reserved for patients who relapse after ASCT or those with persistent marrow involvement. Innovative approaches are needed for primary refractory and chemoresistant relapsed DLCL-B since these patients have very poor outcomes after ASCT.     

Outcomes of Patients with Recurrent and Refractory Lymphoma Undergoing Allogeneic Hematopoietic Cell Transplantation with BEAM Conditioning and Sirolimus- and Tacrolimus-Based GVHD Prophylaxis

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n?=?12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.