A single center's experience using four different front line mobilization strategies in lymphoma patients planned to undergo autologous hematopoietic cell transplantation.

In an otherwise eligible patient with relapsed lymphoma, inadequate mobilization of hematopoietic stem cells (HSCs) is a limiting factor to proceeding with an autologous hematopoietic cell transplantation (auto-HCT). Multiple strategies have been used to mobilize an adequate number of HSCs with no obvious front-line strategy. We report a single institutional experience mobilizing HSCs using four different approaches in lymphoma patients. We prospectively collected mobilization outcomes on patients planned to undergo auto-HCT at Ohio State University. We report results of first mobilization attempts for all relapsed or refractory lymphoma patients between 2008 and 2014. We identified 255 lymphoma patients who underwent mobilization for planned auto-HCT. The 255 lymphoma patients underwent the following front line mobilization strategies: 95 (37%) G-CSF alone, 38 (15%) chemomobilization (G-CSF+chemotherapy), 97 (38%) preemptive day 4 plerixafor, and 25 (10%) rescue day 5 plerixafor. As expected, there were significant differences between cohorts including age, comorbidity indices, histology, and amount of prior chemotherapy. After controlling for differences between groups, the odds of collecting 2 × 106/kg HSCs on the first day of collection and 5 × 106/kg HSCs in total was the highest in the cohort undergoing chemomobilization. In conclusion, our experience highlights the effectiveness of chemomobilization.

Mobilization of peripheral-blood progenitor cells with high-dose etoposide and granulocyte colony-stimulating factor in patients with breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease.

PURPOSE: We analyzed the safety and effectiveness of high-dose etoposide (2 g/m2) followed by granulocyte colony-stimulating factor (G-CSF) as a peripheral-blood progenitor cell (PBPC) mobilization regimen and assessed extent of tumor reduction in patients with breast cancer, non-Hodgkin's lymphoma (NHL), and Hodgkin's disease (HD). PATIENTS AND METHODS: One hundred sixty-nine consecutive patients who eventually underwent PBPC transplantation received treatment with high-dose etoposide (2 g/m2) followed by daily G-CSF (5 microg/kg). RESULTS: This mobilization method was effective in nearly all patients. No patients died of mobilization-related complications. A 50% reduction in tumor size was seen in 19% of assessable patients with breast cancer, 44% of those with NHL, and 38% of those with HD. Hematopoietic recovery (HR) following transplantation occurred in all patients. Patients with > or = 4 x 10(6) CD34+ cells/kg engrafted with neutrophils at a median of 9 days after transplant and patients with at least 1.2 x 10(6) CD34+/CD33- cells/kg achieved platelet recovery at a median of 15 days. CONCLUSION: Etoposide plus G-CSF is an effective and safe method for mobilization of PBPCs. Etoposide is an effective agent in tumor reduction in NHL and HD and is less effective in breast cancer. The substantially lower incidence of prior exposure to this agent compared with cyclophosphamide favors its use.

High-dose busulfan, cyclophosphamide, and etoposide does not improve outcome of allogeneic stem cell transplantation compared to BuCy2 in patients with acute myeloid leukemia.

SUMMARY: To reduce relapse following allogeneic transplantation for AML, intensification of high-dose busulfan/cyclophosphamide using additional agents has been investigated but with few reported comparisons. We compared an intensified regimen of etoposide (60 mg/kg), busulphan (14 mg/kg), and cyclophosphamide (120 mg/kg) (BuCyVP) with BuCy2 in 237 AML patients. No significant difference in overall outcome was observed following BuCyVP (n=127) or BuCy2 (n=110). The 5-year survival was 27.3 and 30.1% following BuCyVP and BuCy2, respectively (P=0.48). Similarly, the 5-year cumulative incidence of relapse (CIR) was 28.3 and 34.8% with BuCyVP and BuCy2 (P=0.45), respectively. On multivariable analysis, patients transplanted in CR1 (P=0.002) and from related donors (P=0.013) had longer survival, while disease status at transplant was the only factor predicting CIR (P=0.002). In a separate analysis of CR1 patients (n=56), there was no significant difference in survival (P=0.37) or CIR (P=0.87) between the two regimens. However, for more advanced disease, there was a trend towards less relapse with BuCyVP (P=0.08), which was balanced by a higher cumulative incidence of transplant-related deaths (P=0.03) compared to BuCy2, resulting in similar survival. Overall, our results do not support the use of the more intensive BuCyVP regimen over BuCy2 in either early or more advanced disease AML patients.

Second autologous stem cell transplant for multiply relapsed Hodgkin's disease.

Therapeutic options for patients with Hodgkin's disease who relapse after high-dose chemotherapy with autologous stem cell support are limited. Salvage chemotherapy is not curative, and allogeneic stem cell transplantation in this setting is associated with mortality rates of 40-65%. We report our institution's experience with second autologous transplants in this patient population. Five patients (median age 36) with relapsed Hodgkin's disease underwent a second autologous stem cell transplant at a median of 66 months after first transplant. Four patients received CBV, and one patient received BuCy as conditioning. Neutrophil and platelet engraftment occurred by days +10 and +16, respectively. All patients achieved a complete response, and no relapses have occurred after a median follow-up of 42 months. All four patients who received CBV developed interstitial pneumonitis, and two patients died of pulmonary complications 37 and 48 months following second transplant. Three patients remain alive and disease-free 41, 42 and 155 months after second transplant. These data indicate that second autologous transplantation should be considered for selected patients who relapse after a prolonged response to first autologous transplant. However, BCNU pneumonitis is the major toxicity in patients who have undergone previous mantle radiation and received busulfan with first transplant.

Analysis of prognostic factors for allogeneic marrow transplantation following busulfan and cyclophosphamide in myelodysplastic syndrome and after leukemic transformation.

Prognostic factors in 42 patients aged 11 to 62 (median 46) years, with myelodysplastic syndrome (MDS) or after leukemic transformation, who underwent allogeneic marrow transplantation between 1984 and 1999 were analyzed. Thirty-six had advanced disease morphology; 19 had leukemic transformation. Twenty-nine received a preparative regimen of BuCy2 and 13 busulfan 14 mg/kg, etoposide 50 mg/kg and cyclophosphamide 120 mg/kg. Severe hepatic veno-occlusive disease (VOD) occurred in three patients all of whom received anti-leukemic chemotherapy prior to transplantation. Fifteen patients (36%) died from early transplant-related complications; nine patients relapsed. The estimated 4 year disease-free survival (DFS) was 35% (95% CI 26-44%). Older age was the most significant adverse prognostic factor. Patients with leukemic transformation who underwent early transplantation had significantly better DFS than those treated first with chemotherapy (P = 0.002). Delayed toxicity was rare in these patients; no late relapses occurred. Bone Marrow Transplantation (2000) 25, 1219-1222.

Busulfan levels are influenced by prior treatment and are associated with hepatic veno-occlusive disease and early mortality but not with delayed complications following marrow transplantation.

Long-term outcome was analyzed in 28 patients transplanted between 1989 and 1992 following busulfan and cyclophosphamide and who had busulfan levels studied. While there was no significant correlation of busulfan levels with diagnosis, patients who had received extensive prior chemotherapy had a significantly higher area under the curve (AUC; P = 0.02) and maximum busulfan levels (Cmax; P = 0.03). High AUC was associated with the development of hepatic veno-occlusive disease (P = 0.03) and with early transplant-related mortality (P = 0.06). No significant correlation of busulfan levels with relapse, late non-relapse death, late complications, nor event-free survival was detected.

Radiation-free regimens result in similar outcomes of allogeneic hematopoietic progenitor cell transplantation in patients aged >or=50 years compared to younger adults with low-risk disease.

Age >or=50 years has been reported to be an adverse risk factor for allogeneic BMT, and consequently many of these patients are either not transplanted or treated on nonmyeloablative protocols. To study if older patients perform poorly relative to younger adults following myeloablative allogeneic transplants, we compared the outcomes of consecutive adults aged >or=50 years (n=51) to those <50 years (n=262) who received BU, CY+/-etoposide and allogeneic transplantation for AML, CML, MDS and NHL from 1984 to 2000. Median ages were 53 (range 50-66) and 35 (range 18-49) years for older and younger patients, respectively. Patients were low-risk if they had AML in CR1, CML in first chronic phase, refractory anemia, or NHL in remission or sensitive relapse at the time of transplantation. All others were high-risk. In patients with low-risk disease, there was no significant difference in overall survival (OS) between older and younger adults (P=0.64), while older patients tended to have a shorter OS among high-risk patients (P=0.06). The 3-year OS was 53% (95% CI, 29-77%) compared to 60% (95% CI, 50-69%) for older and younger patients with low-risk disease, respectively. The corresponding 3-year OS were 27% (95% CI, 11-43%) and 37% (95% CI, 25-45%) for high-risk patients. In low-risk patients, the incidence of acute and chronic graft-versus-host disease, and treatment-related mortality were similar in older and younger patients, while older patients experienced more treatment-related deaths by day 100. On multivariable analysis, age >or=50 years was a significant adverse factor only when high-risk patients were considered. We conclude that when radiation-free conditioning is used, age >or=50 years is not a significant adverse risk factor for allogeneic BMT in patients with low-risk disease, and that such patients should not be excluded from conventional myeloablative approaches until the efficacy of nonmyeloablative transplantation is better established.

Hepatic dysfunction following busulfan and cyclophosphamide myeloablation: a retrospective, multicenter analysis.

Veno-occlusive disease continues to be a significant cause of morbidity and early mortality following bone marrow transplantation. This study retrospectively analyzes the incidence and risk factors for severe VOD in 350 patients treated with 4 days of busulfan (total 16 mg/kg) and 2 days of cyclophosphamide (120 mg/kg) at four marrow transplant centers. Using the criteria defined by McDonald et al (Hepatology 1984; 4: 116-122), 93/350 (27%) developed VOD (11% mild, 5% moderate and 11% severe). Multivariate analysis revealed the following risk factors to be significantly associated with severe VOD: pretransplant transaminase and alkaline phosphatase elevation, ciprofloxacin antibiotic prophylaxis, use of estrogen/progestins or vancomycin during the peritransplant period and methotrexate for GVHD prophylaxis. Mild to moderate grades of VOD were not associated with significantly increased mortality but mortality was higher in patients with severe VOD (31%, P = 0.0013). These data suggest that risk factors for VOD may depend on the preparative regimen used and suggest that use of these risk factors may identify a subgroup of patients that can be targetted for studies of prevention of VOD.

Influence of graft-versus-host disease on outcome following allogeneic transplantation with radiation-free preparative therapy in patients with advanced leukemia.

Between March 1984 and March 1995, 76 patients with advanced acute myelogenous, acute lymphoblastic, or chronic myelogenous leukemia underwent allogeneic marrow transplantation from HLA-identical or one-antigen mismatched sibling or unrelated donors. Patients received a preparative regimen consisting of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg or busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and etoposide (VP-16) 50 mg/kg. For GVHD prevention, patients received cyclosporine with either methotrexate or steroids or FK506 with methotrexate. Fourteen patients were leukemia-free survivors at a median of 6.5 years (range 1-11 years) following transplantation. For the group as a whole, the estimated leukemia-free survival (LFS) at 5 years is 20% (95% confidence interval 10-30%). Ten of the 14 leukemia-free survivors developed acute GVHD greater than grade II and chronic GVHD and two developed only chronic GVHD. Significantly better relapse rates and disease-free survival were associated with the development of acute and/or chronic GVHD. In the absence of acute GVHD and/or chronic GVHD, patients who underwent transplantation for advanced leukemia, after preparation with Bu/CY or Bu/CY/VP-16, were very likely to experience disease recurrence. Novel strategies designed to promote development of GVHD present a promising area for investigation to improve outcome in patients with leukemia at high risk for relapse.

The influence of early transplantation, age, GVHD prevention regimen, and other factors on outcome of allogeneic transplantation for CML following BuCy.

Results in 164 patients who underwent allogeneic marrow transplantation following busulfan and cyclophosphamide over a 15 year period were analyzed. Age (median 37, range 14-66 years) did not significantly affect the incidence of graft-versus-host disease (GVHD), but patients who received methotrexate with cyclosporine had a significantly lower incidence (P = 0.002) of chronic GVHD compared to those who received methylprednisolone with cyclosporine. Hepatic veno-occlusive disease (VOD) occurred less frequently in chronic phase patients (P = 0.002) and in those transplanted shortly after diagnosis (P = 0.001). Five year leukemia-free survival (LFS) for the entire group was 49% (95% CI 41-57%). For 102 patients who underwent transplantation in chronic phase, results were significantly improved by transplantation at a short interval following diagnosis, particularly within 3 months (P = 0.01), by the use of methotrexate and not corticosteroids for GVHD prevention (P = 0.03), and by use of HLA-identical sibling donors (P = 0.01). Age was not a significant adverse prognostic factor and transplantation was successfully performed in individuals up to age 66. Allogeneic transplantation in CML, including older patients and those with unrelated donors, can be most safely and effectively performed shortly after diagnosis.

Therapy-related myelodysplasia and leukemia occur infrequently following VP-16 priming and autotransplantation without total body irradiation.

The use of VP-16 for stem cell mobilization has been cited as a significant risk factor for the development of therapy-related myelodysplasia/leukemia (tMDS/tAML) following autologous transplantation. The present study analyzed a large cohort of patients who underwent autotransplantation following stem cell mobilization with VP-16 and radiation-free preparation in order to determine the risk of tMDS/tAML. The estimated incidence of 9.9% at 7 years suggests that in the absence of TBI, VP-16 priming is not associated with an increased incidence of tMDS/tAML.

Autotransplantation following busulfan, etoposide and cyclophosphamide in patients with non-Hodgkin's lymphoma.

The purpose of the study was to determine the toxicities and effectiveness of a novel preparative regimen of busulfan (Bu) 14 mg/kg, etoposide 50 or 60 mg/kg, and cyclophosphamide (Cy) 120 mg/kg in non-Hodgkin's lymphoma (NHL) and to analyze results using doses based on different body weight parameters and the two different etoposide doses. Three hundred and eighty-two patients aged 16 to 72 underwent first autologous transplantation with mobilized peripheral blood progenitor cells between August 1992 and December 1998 at either of two transplant centers. Mucositis was the most common toxicity. Hepatic toxicity was the most common life-threatening toxicity; severe hepatic VOD occurred in 11 patients (2.9%). Ten patients (2.6%) died from treatment-related toxicity. The 3-year progression-free survival (PFS) for the entire group was 46.9% (95% CI, 40.5-53.3%). Elevated LDH, resistance to chemotherapy, and intermediate/aggressive histology were significant adverse prognostic factors. For patients in sensitive first relapse PFS was 47.0% (95% CI, 37-57%). Neither etoposide dose nor body weight parameter utilized significantly affected outcome. In conclusion, the novel preparative regimen of Bu, etoposide and Cy results in a low incidence of treatment-related mortality and is effective in the treatment of patients with NHL. Bone Marrow Transplantation (2000) 25, 1243-1248.

An effective mobilization strategy for lymphoma patients after failed upfront mobilization with plerixafor.

In an otherwise eligible patient, inadequate mobilization of PBSCs is a limiting factor to proceeding with an auto-ASCT. In such situations, plerixafor is commonly added to improve PBSC collection yields along with cytokine (G-CSF alone) or chemomobilization (chemotherapy+G-CSF). Individually, both strategies are proven to be safe and effective. Here we report six patients who underwent successful mobilization with combination chemomobilization plus plerixafor after upfront failure of cytokine mobilization plus plerixafor. The median CD34(+) cell yield after chemomobilization was 2.48 × 10(6)/kg (range 0.99-8.49) after receiving one to two doses of plerixafor. All patients subsequently underwent ASCT without major unforeseen toxicities and engrafted successfully. No significant delays in time to neutrophil recovery were observed. Our experience highlights the safety and effectiveness of chemomobilization with plerixafor after G-CSF plus plerixafor (G+P) failure and suggests this is a viable salvage strategy after initial failed G+P mobilization.

The hematopoietic stem cell transplant comorbidity index can predict for 30-day readmission following autologous stem cell transplant for lymphoma and multiple myeloma.

Patients who undergo autologous stem cell transplant (ASCT) for hematologic malignancies frequently have multiple comorbidities. The hematopoietic cell transplantation comorbidity index (HCT-CI), a transplant-specific modification of the Charlson comorbidity index, can predict risk of readmission following allogeneic stem cell transplant. Its utility in the autologous setting is unknown. We evaluated 620 patients who underwent ASCT at the Ohio State University from 2007 to 2012 for lymphoma or multiple myeloma (MM) to identify factors associated with readmission. Univariable and multivariable logistic regression were used to estimate the odds of readmission within 30 days of discharge following ASCT. A Cox proportional hazards model was used to evaluate OS. Sixty-four patients were readmitted within 30 days; the most common indications were fever and prolonged gastrointestinal toxicity. MM compared with lymphoma (odds ratio (OR) 1.89, 95% confidence interval (95% CI): 1.06-3.38, P=0.03), HCT-CI⩾3 (OR 1.74, 95% CI: 1.03-2.96, P=0.04) and length of hospitalization ⩾28 days (OR 3.14, 95% CI: 1.26-7.83, P=0.01) remained significantly associated with 30-day readmission in a multivariable model. While the model had excellent fit (P>0.75), its ability to predict individual patients who would be readmitted was less than acceptable (receiver-operator curve=0.64, 95% CI: 0.57-0.71). In a multivariable proportional hazards model, 30-day readmission (hazards ratio (HR) 1.81, 95% CI: 1.04-3.18, P=0.04), length of hospitalization ⩾28 days (HR 4.93, 95% CI: 2.65-9.18, P<0.001) and chemorefractory disease (HR 3.08, 95% CI: 1.74-5.43, P<0.001) were independently associated with inferior OS, but HCT-CI was not. Evaluation of other assessment tools may allow better prediction of outcomes following ASCT.

Association of pre-transplantation positron emission tomography/computed tomography and outcome in mantle cell lymphoma.

Positron emission tomography/computed tomography (PET/CT)-positive findings before autologous SCT (auto-SCT) are associated with inferior PFS and OS in patients with relapsed Hodgkin's and diffuse large B-cell lymphoma. We classified pre-transplant PET/CT performed before auto-SCT as positive or negative to evaluate the impact of pre-transplant PET/CT in mantle cell lymphoma (MCL). In 29 patients, 17 were PET/CT(-) and 12 were PET/CT(+). PET/CT(+) patients were younger (P=0.04), had lower MCL International Prognostic Index (MIPI, P=0.04) scores, but increased bulky adenopathy >5 cm (45% vs 13%, P=0.09). With a median follow-up of 27 months (range: 5-55 months), 7 patients relapsed (4 in the PET/CT(-) group and 3 in the PET/CT(+) group) with 2 deaths in the PET/CT(+) group without a documented relapse. The estimated 2-year PFS was 64% (95% confidence interval (CI): 0.30-0.85) vs 87% (95% CI: 0.57-0.97) in PET/CT(+) and PET/CT(-) patients, respectively (P=0.054). OS was significantly decreased in PET/CT(+) patients (P=0.007), with 2-year estimates of 60% (95% CI: 0.23-0.84) vs 100% in PET/CT(-) patients. A positive pre-transplant PET/CT is associated with a poor prognosis in patients with MCL. Additional factors may impact the prognostic value of PET/CT, as several PET/CT(+) patients remain in remission.

Effects of chemistry, manufacturing and concentration of the dye basic fuchsin regarding its use in quantitative cytophotometry.

Four separately manufactured preparations of basic fuchsin were compared to determine the effects of concentration, chemistry, and the manufacturing process for their quantitative value in the nuclear Feulgen reaction. In order to make the necessary comparisons, the two wavelength method of quantitative cytophotometry was employed to analyse each stain application regarding DNA measurements. Chicken erythrocytes, and myxamoebae and plasmodia of Didymium iridis were employed as experimental tissues. Results indicated that all four preparations of the stains yielded acceptable and valid quantitative data in relative DNA values. Differing manufacturers and dye concentrations had no appreciable effect on relative quantitative measurements. However, the maximum staining intensity was affected by differences both in the chemical structure of the individual stains and by the products from various manufacturers. The maximum dye intensity and accurate quantitative absolute values for DNA measurement were best obtained by the use of basic fuchsin having the same colour index (Cl) 42510 as that manufactured by Fisher Scientific Incorporated.

Emotion management skills in sexually maltreated and nonmaltreated girls: a developmental psychopathology perspective.

Research has demonstrated that children who experience familial sexual maltreatment are at risk for developing psychological difficulties characterized by emotional and behavioral dysregulation. Surprisingly, however, little attention has been directed toward identifying processes in emotional development that differ in maltreated and nonmaltreated children. From a developmental psychopathology perspective, the present study examined emotion management skills (i.e., emotional understanding, emotion regulation) in 21 sexually maltreated girls and their nonmaltreated peers to determine how the experience of sexual maltreatment may interfere with normative emotional development. Findings indicated that sexually maltreated girls, in comparison to their nonmaltreated peers, demonstrate lower emotional understanding and decreased ability to regulate their emotions in accordance with cultural expectations. Further, maltreated girls expected less emotional support and more relational conflict from parents in response to sadness displays and from parents and peers in response to anger displays. These findings will be discussed from the functionalist approach to emotional development, emphasizing the importance of social context (e.g., maltreating, nonmaltreating) in the development of children's emotion management skills.