A phase 1 trial of 90Y-Zevalin radioimmunotherapy with autologous stem cell transplant for multiple myeloma.

This phase 1 study (clinical trial NCT00477815) was conducted to determine the maximum tolerated dose (MTD) of yttrium-90 ibritumomab tiuxetan (90Y-Zevalin) with high dose melphalan (HDM) therapy in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). In a 3+3 trial design, 30 patients received rituximab 250 mg/m2 with indium-111 ibritumomab tiuxetan (111In-Zevalin) for dosimetry (day -22); rituximab 250 mg/m2 with escalating doses of 90Y-Zevalin (day -14); melphalan 100 mg/m2 (days -2,-1) followed by ASCT (day 0) and sargramostim (GM-CSF, day 0) until neutrophil engraftment. Each patient's 111In-Zevalin dosimetry data were used to calculate the dose of 90Y-Zevalin (in mCi) to deliver 10, 12, 14, 16, 18 or 20 Gy to the liver. Dose limiting toxicities were seen in 3 patients. The overall response rate was 73% (22/30) with stringent complete response in 2 patients; complete response, 5; very good partial response, 12; and partial response, 3. The median PFS was 16.5 months and the median overall survival was 63.4 months. In MM, the MTD of 90Y-Zevalin with HDM is 18 Gy to the liver. The addition of radiation with novel delivery methods such as radioimmunotherapy combined with standard transplant regimens warrants further study.

Association of hematopoietic cell transplantation-specific comorbidity index with resource utilization after allogeneic transplantation.

Comorbidities affect clinical outcomes and costs in medicine. The hematopoietic cell transplantation (HCT)-specific comorbidity index (HCT-CI) predicts mortality risk after HCT. Its association with resource utilization (RU) is unknown. In this single-center, retrospective study, we examined the association of HCT-CI with RU (readmissions, length of hospital stay (LOS) and days out of hospital alive (DOHA)) in first 100 days (n=328) and 1 year (n=226) in allogeneic HCT patients from January 2010 to June 2014. Age, disease risk, conditioning and use of antithymocyte globulin were significantly different in the four groups with HCT-CI 0 to1 (n=138), 2 (n=56), 3 (n=55) or ⩾4 (n=79). Although the readmissions were higher in the first 100 days for patients with HCT-CI >0-1 (P=0.03), they were not significantly different in patients over 1 year (P=0.13). In the multivariable analysis, patients with HCT-CI score of >0 to 1 had increased LOS and fewer DOHA in both 100 days and 1 year after HCT. In this exploratory analysis, we found that HCT-CI >0 to 1 is associated with increased RU after allogeneic HCT. Recognizing predictors of RU can identify patients at risk of high utilization and help understand what drives health-care costs.

Autologous stem cell transplant for multiple myeloma patients 70 years or older.

Autologous stem cell transplant (Auto-SCT) is increasingly used in older patients with multiple myeloma (MM), despite lack of phase 3 trials in this age-defined population. For 207 consecutive MM patients who underwent Auto-SCT and were 70 years or older at transplant (study cohort), data were analyzed and compared with a younger cohort (1764 Auto-SCT patients <70 years old). The proportion of Auto-SCT in the older patients increased from 7.8% of all transplants in 1998-2006 to 12.9% in 2007-2015. Sixty percent of patients required stem cell mobilization with chemotherapy or plerixafor. Full-dose melphalan conditioning was given to 55% of the older patients compared with 93% of the younger patients (P<0.001). Older patients were more likely to be hospitalized (64% vs 55%; P=0.01), but hospitalization duration was comparable. For newly diagnosed patients, median PFS was 33.5 months for the older cohort and 33.8 months for the younger cohort (P=0.91), and median overall survival was 6.1 and 7.8 years, respectively (P=0.11). Presumably, a smaller fraction of patients, age 70-76, is selected for Auto-SCT, but the benefits are comparable to those seen for younger patients. Reduced-dose melphalan was given to approximately half the patients to avoid excessive toxicity.

Corticosteroid use as adjunct therapy for respiratory syncytial virus infection in adult allogeneic stem cell transplant recipients.

BACKGROUND: Respiratory syncytial virus (RSV) infection causes significant morbidity and mortality in allogeneic stem cell transplant (allo-SCT) recipients. Although ribavirin and immunoglobulins are common components of therapy, the role of adjunct corticosteroids is not established. OBJECTIVES: We sought to evaluate corticosteroid utilization in the setting of post-allo-SCT RSV infection in our center and assess post-transplant outcomes including pulmonary function decline. METHODS: Patients with a history of RSV infection from 2008 to 2014 seen at our institution were identified. Treatment and outcome data were retrospectively collected. Forced expiratory volume at 1 s (FEV1) and carbon monoxide diffusion capacity (DLCO) were collected pre- and post-RSV infection. RESULTS: During the observation period, RSV was isolated in 53 of 552 patients undergoing allo-SCT (10%) and 45 had evaluable therapy data. RSV-related mortality in this cohort was 4/45 (9%). Twenty-one (47%) were on corticosteroids prior to RSV diagnosis, of whom 11 (24%) had a dose increase post symptom onset. Eight (18%) patients were started on corticosteroids at the time of RSV infection. Corticosteroid therapy at symptom onset was associated with a higher rate of upper respiratory infection (URTI) to lower respiratory infection (LRTI) progression risk ratio (RR) 2.49 (1.21-5.13; P = 0.016), hospital admission RR 2.05 (1.24-3.37; P = 0.005), or intensive care unit admission RR 2.91 (1.89-5.01; P = 0.002). No significant difference was seen with FEV1 and DLCO decline (P = 0.3 and 0.24, respectively) or mortality (P = 0.26). CONCLUSION: Adjunct corticosteroid use in the setting of RSV infection did not improve RSV-related outcomes including long-term pulmonary function. Our results do not support the routine use of corticosteroids; however, this finding does need to be verified in a larger cohort of patients.

Accuracy of self-reported tobacco use status among hematopoietic SCT patients.

Tobacco use is a risk factor for adverse outcomes among hematopoietic SCT (HSCT) patients. Accurate identification of tobacco use offers a vital opportunity to treat this risk factor. The current study compared self-reported tobacco use status with serum cotinine levels among HSCT patients at the time of pre-transplant evaluation. A total of 444 participants completed both assessments; 44 participants (9.9%) were classified as tobacco users with serum cotinine concentrations >2 ng/mL vs 29 with self-reporting. Sensitivity and specificity of self-reporting were 65.9% and 100%, respectively. Positive and negative predictive values were 100% and 96.4%, respectively. Comparing tobacco use documented in the medical record with cotinine, sensitivity and specificity were 51.2% and 99.2%, respectively. Factors associated with tobacco use were male gender, single relationship status, less education and younger age. In summary, utilization of serum cotinine assays increased detection of tobacco use cases >50% over self-reporting. Results are discussed in the context of translation to care, including clinical and ethical implications, and current tobacco use treatment guidelines. When cotinine assays are not available, self-reporting of any tobacco use in the year before HSCT should trigger brief advice and cessation or relapse prevention counseling.

Phase 2 trial of intravenously administered plerixafor for stem cell mobilization in patients with multiple myeloma following lenalidomide-based initial therapy.

Initial therapy of multiple myeloma with lenalidomide-based regimens can compromise stem cell collection, which can be overcome with the addition of plerixafor. Plerixafor is typically given subcutaneously (SQ), with collection ∼11 h later for maximum yield. Intravenous administration may allow more rapid and predictable mobilization. This trial was designed to assess the efficacy and feasibility of IV plerixafor in patients receiving initial therapy with a lenalidomide-based regimen. Patients received G-CSF at 10 µg/kg/day for 4 days followed by IV plerixafor at 0.24 mg/kg/dose starting on day 5; plerixafor was administered early in the morning with apheresis 4-5 h later. Thirty-eight (97%) patients collected at least 3 × 10(6) CD34+ cells/kg within 2 days of apheresis. The median CD34+ cells/kg after 1 day of collection was 3.9 × 10(6) (range: 0.7-9.2) and after 2 days of collection was 6.99 × 10(6) (range: 1.1-16.5). There were no grade 3 or 4 non-hematological adverse events, and one patient experienced grade 4 thrombocytopenia. The most common adverse events were nausea, diarrhea and abdominal bloating. IV plerixafor is an effective strategy for mobilization with low failure rate and is well tolerated. It offers flexibility with a schedule of early-morning infusion followed by apheresis later in the day.

Long-term outcome of patients with multiple [corrected] myeloma-related advanced renal failure following auto-SCT.

Renal failure commonly complicates multiple myeloma (MM) and is associated with reduced survival. It is not clear whether auto-SCT results in improved renal function or attainment of independence from dialysis in patients with advanced renal impairment due to MM. We conducted a retrospective cohort study of all patients who underwent auto-SCT for MM complicated by advanced renal failure at our institution over a 10-year period (2000-2010). We aimed to assess the association between auto-SCT and renal outcome in patients with serum creatinine (SCr) over 3 mg/dL, attributable to MM, including those who were dialysis dependent. Thirty patients (2.8% of all auto-SCT patients) met inclusion criteria. Fourteen of 15 patients who were dialysis dependent before auto-SCT remained dialysis dependent in the long term despite hematological response (HR). Of the remaining 15 patients with SCr >3 mg/dL, an improvement in glomerular filtration rate (GFR) from 15 to 19.4 mL/min/1.73 m(2) was noted post auto-SCT (P=0.035); however, neither HR post auto-SCT or pre-existing renal function were independently associated with renal outcome. Auto-SCT was not associated with independence from dialysis in patients with renal failure due to MM at our institution. Although auto-SCT was associated with an improvement in GFR in patients with SCr >3 mg/dL, this improvement was not related to HR.

Patients with immunoglobulin light chain amyloidosis undergoing autologous stem cell transplantation have superior outcomes compared with patients with multiple myeloma: a retrospective review from a tertiary referral center.

The underlying plasma cell clones in multiple myeloma (MM) and Ig light-chain amyloidosis (AL) appear to be different not only in terms of 'tumor burden' but also in terms of their underlying biology. High-dose chemotherapy with auto-SCT is one method of reducing the clone size and thereby improving OS. Post-auto-SCT outcomes between the two diseases have never been formally compared. Among all patients with a diagnosis of AL or MM who received auto-SCT as primary therapy at the Mayo Clinic, Rochester, there were higher CR rates (40% versus 29%, P<0.0001) in the AL group. The respective median OS for the AL and MM patients was 113 and 59.5 months, respectively, P<0.0001. Among patients achieving CR, MM patients had a fivefold risk of death as compared with AL patients. Although auto-SCT cannot be offered to all patients with either AL or MM, it appears that for those well enough to be chosen for the procedure, greater benefit is derived among the AL patients. This difference in survival is most notable among those patients who achieve CR, suggesting very different plasma cell biology between the two diseases.

Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models.

Streptozotocin (STZ)-induced diabetes mellitus (DM) offers a very cost-effective and expeditious technique that can be used in most strains of rodents, opening the field of DM research to an array of genotypic and phenotypic options that would otherwise be inaccessible. Despite widespread use of STZ in small animal models, the data available concerning drug preparation, dosing and administration, time to onset and severity of DM, and any resulting moribundity and mortality are often limited and inconsistent. Because of this, investigators inexperienced with STZ-induced diabetes may find it difficult to precisely design new studies with this potentially toxic chemical and account for the severity of DM it is capable of inducing. Until a better option becomes available, attempts need to be made to address shortcomings with current STZ-induced DM models. In this paper we review the literature and provide data from our pancreatic islet transplantation experiments using single high-dose STZ-induced DM in NCr athymic nude mice with hopes of providing clarification for study design, suggesting refinements to the process, and developing a more humane process of chemical diabetes induction.

SCT without growth factor in multiple myeloma: engraftment kinetics, bacteremia and hospitalization.

SCT is important in the management of multiple myeloma. In the United States, the standard of care is administration of growth factors to accelerate neutrophil recovery after SCT. The need for growth factors after transplant has not been investigated recently. We analyzed a cohort of 166 patients at our institution who underwent autologous transplant for multiple myeloma without receiving growth factors after transplant and compared them with 498 patients who received standard filgrastim beginning on posttransplant day 5. A neutrophil count of 500/µL was achieved in a median of 12.5 days in patients receiving growth factor, compared with 13.5 days in those not receiving growth factor (P<0.001). Platelet engraftment was identical (median, 14.5 days; P=0.12) in both groups, despite a lower median number of CD34+ cells infused in patients who did not receive growth factors. Incidence of nonstaphylococcal bacteremia was identical in both groups. The median hospital stay was 3.5 days shorter in the group not receiving growth factor. It is feasible and reasonable to perform autologous SCT for multiple myeloma without administering growth factors.

Low risk of symptomatic venous thromboembolic events during growth factor administration for PBSC mobilization.

The use of erythropoietic agents has been associated with an increased risk of venous thromboembolic events (VTEs), especially in patients with underlying malignancies. However, it is not known whether there is an increased risk of VTE associated with granulocyte growth factors. We reviewed 621 patients undergoing PBSC mobilization using granulocyte growth factors, alone or in combination with CY. Patients with a diagnosis of AL amyloidosis (AL: 114; 18%), multiple myeloma (MM: 278; 44%) Hodgkin lymphoma (HL: 20; 3%) or non-Hodgkin lymphoma (NHL: 209; 33%) were included. Symptomatic VTE occurred in six (0.97%) patients: two AL, two MM and two NHL. Of the six patients, two had pulmonary embolism, one developed deep vein thrombosis and three developed symptomatic catheter related thrombosis. Two patients with AL had heparin-induced thrombocytopenia and thrombosis. We found a low incidence of VTE among patients undergoing PBSC mobilization.

The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia.

A paucity of research exists examining the potential impact of tobacco use on cancer treatment outcomes, especially among patients treated with hematopoietic SCT (HSCT). A retrospective cohort study design was used to examine the impact of smoking on duration of hospitalization and overall survival among 148 consecutive patients undergoing HSCT for treatment of acute leukemia from 1999 to 2005. Of the 148 patients, 15% reported current smoking, 30% former smoking, and 55% never used tobacco. Patients were followed for a median 3.5 years (interquartile range=2.1-5.5). Compared to no history of smoking, current smoking was associated with worse pre-HSCT pulmonary function tests (P<0.02 in each case), more days hospitalization (46.2 days versus 25.7 days, P=0.025), and poorer overall survival (hazard ratio (HR)=1.88; 95% CI 1.09-3.25). Results were similar after multivariate adjustment, although the association with overall survival attenuated slightly (HR=1.75; 95% CI 1.00-3.06). Current smoking appears to adversely affect the number of days hospitalized post HSCT and overall survival. Translational research focused on interventions to promote tobacco cessation may lead to improved HSCT outcomes.

Predicting PBSC harvest failure using circulating CD34 levels: developing target-based cutoff points for early intervention.

PBSCs are usually mobilized using G-CSF with or without chemotherapy. With the emergence of newer mobilizing agents, predicting poor mobilization may allow early intervention and prevent the costs and complications associated with remobilization. We retrospectively evaluated a cohort of 1556 patients seen between January 2000 and September 2008 with multiple myeloma (565; 36%), non-Hodgkin's lymphoma (NHL) (562; 36%), amyloidosis (345; 22%) or Hodgkin's disease (94; 6%), who were initially mobilized with single agent G-CSF. Sensitivity and specificity analysis was used to identify ideal peripheral blood CD34 count (PB-CD34) cutoff points that predicted successful collection. In patients with plasma cell disorders, a PB-CD34 count of 11, 17, 21 and 28/µL by day 4 or 5 was required to collect a target of 2, 4, 8 or 12 million cells/kg, respectively. A CD34 yield of <0.8 million cells/kg on first apheresis also predicted for <2 million CD34 cells/kg. For patients with NHL or Hodgkin's disease, a PB-CD34 count of <6 and <15/µL on day 4 or 5 predicted failure to achieve a target collection of 2 and 4 million cells/kg, respectively. This study suggests that PB-CD34 thresholds should be based on collection target to allow for early intervention and to prevent collection failures.

Stem cell transplantation in patients with autonomic neuropathy due to primary (AL) amyloidosis.

OBJECTIVES: Patients with AL amyloidosis can benefit from high-dose chemotherapy and autologous stem cell transplantation (ASCT). Transplantation can be challenging due to fluid shifts, sepsis, and cardiac dysrhythmias. Amyloidosis may present with autonomic neuropathy (AN) that renders peritransplant care problematic. The purpose of this study was to determine the outcome of patients with AN during and after ASCT. METHODS: We performed a case-control study of patients with AL amyloidosis with associated AN and compared them to a large matched cohort without AN who also underwent ASCT. RESULTS: We identified 13 patients with AN who underwent ASCT and a matched control group of 95 patients without AN. Patients with AN had more organs involved (median 2.5 vs 1, p < 0.001) and the conditioning dose of melphalan was often reduced by 30% compared to controls without AN (p = 0.0015). Median duration of hospitalization was similar for both cohorts, as were engraftment kinetics. Atrial fibrillation occurred in all patients with AN but in only 1 control patient (p < 0.0001). Median overall survival (OS) for patients with AN was 29 months but >60 months for controls (p < 0.0001). On univariate analysis, cardiac involvement (p = 0.0132), AN (p = 0.0011), glomerular filtration rate (p = 0.038), number of organs involved (p = 0.0064), and NT-pro-BNP (p = 0.039) all had an impact on OS. On multivariate analysis, AN retained an independent adverse impact on OS. CONCLUSIONS: Patients with autonomic neuropathy secondary to AL amyloidosis can undergo autologous stem cell transplantation with relative safety. Autonomic neuropathy is an independent, adverse determinant of survival in these patients.

CD34+ cell dose and establishment of full donor chimerism at day +100 are important factors for survival with reduced-intensity conditioning with fludarabine and melphalan before allogeneic hematopoietic SCT for hematologic malignancies.

The combination of fludarabine and melphalan as a reduced-intensity conditioning (RIC) regimen extends allogeneic hematopoietic SCT (HSCT) as a therapeutic option for elderly or frail patients with relapsed, refractory or other high-risk hematologic malignancies. Whether any modifiable factors exist that could improve survival before or immediately after HSCT is unknown. We reviewed the medical records of the first 50 patients at our institution to undergo fludarabine/melphalan RIC from September 2000 to September 2007 to determine factors associated with survival. A total of 25 (50%) patients had undergone prior HSCT and as such was a high-risk group of patients. On multivariate analysis, CD34(+) cell dose greater than 5.5 × 10(6) per kg (risk ratio (RR) 0.44, 95% CI 0.19-0.98, P=0.02) and full donor chimerism at day +100 (RR 0.17, 95% CI 0.06-0.64, P=0.002) remained independent prognostic factors. In our series, achievement of full donor chimerism at day +100 was associated with an approximately 70% 2-year survival, a favorable outcome in this high-risk group of patients. Although the infused CD34(+) cell dose is a modifiable variable, whether donor lymphocyte infusions or other immunologic interventions should be performed to promote the establishment of full chimerism early post transplant remains unknown.

Clinical impact and resource utilization after stem cell mobilization failure in patients with multiple myeloma and lymphoma.

High-dose chemotherapy in conjunction with auto-SCT is the preferred treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma and newly diagnosed multiple myeloma. Failure to achieve optimal stem cell mobilization results in multiple subsequent attempts, which consumes large amounts of growth factors and potentially requires antibiotics and transfusions. We retrospectively reviewed the natural history of stem cell mobilization attempts at our institution from 2001 to 2007 to determine the frequency of suboptimal mobilization in patients with hematologic malignancy undergoing autologous transplant and analyzed the subsequent resource utilization in patients with initially failed attempts. Of 1775 patients undergoing mobilization during the study period, stem cell collection (defined by the number of CD34+ cells/kg) was 'optimal' (> or = 5 x 10(6)) in 53%, 'low' (> or = 2-5 x 10(6)) in 25%, 'poor' (<2 x 10(6)) in 10%, and 'failed' (<10 CD34+ cells/microl) in 12%. In the 47% of collections that were less than optimal, increased resource consumption included increased use of growth factors and antibiotics, subsequent chemotherapy mobilization, increased transfusional support, more apheresis procedures, and more frequent hospitalization. This usually unappreciated resource utilization associated with stem cell mobilization failure highlights the need for more effective mobilization strategies.

Phase I trial of autologous hematopoietic SCT with escalating doses of topotecan combined with CY and carboplatin in patients with relapsed or persistent ovarian or primary peritoneal carcinoma.

We designed a phase I clinical trial of escalating doses of topotecan with CY and carboplatin in combination with autologous hematopoietic SCT (AHSCT) for the treatment of relapsed or persistent platinum sensitive ovarian or primary peritoneal carcinoma. After stem cell collection, 16 patients received topotecan at 1.5, 2.5, 3.5, 4.5 or 6.0 mg/m(2)/d combined with CY 1.5 g/m(2)/d and carboplatin 200 mg/m(2)/d, all by 4-day continuous infusion. Steady state pharmacokinetics of topotecan and carboplatin were examined. Pre-treatment biopsies were examined for the expression of topoisomerase (topo) I, Ki67 and Bcl-2 family members by immunohistochemistry. One of six patients at a topotecan dose of 4.5 mg/m(2)/d and two of three patients at 6.0 mg/m(2)/d had dose-limiting toxicity of grade 3 stomatitis lasting >2 weeks. There was no treatment-related mortality. As topotecan clearance was constant over the dose range examined, topotecan steady state plasma concentrations increased with dose. Median progression-free survival and overall survival were 6.5 months and 2.7 years, respectively. Shorter progression-free survival was observed in tumors with low topo expression (P=0.04). Topotecan can safely be dose escalated to 4.5 mg/m(2)/d in combination with CY, carboplatin and AHSCT. This trial is registered at ClinicalTrials.gov as NCT00652691.

Organ procurement organization compliance with 21 CFR 1271: a challenge for allogeneic pancreatic islet cell transplantation programs.

In order to protect tissue recipients, the Food and Drug Administration drafted Title 21, Section 1271 of the Code of Federal Regulations 1271 (21 CFR 1271) to address infectious disease risk. These regulations apply to tissues but not vascularized organs. Pancreatic islet cells are regulated under 21 CFR 1271. These regulations require qualification of suppliers of critical materials and services with regard to 21 CFR 1271 compliance. As part of supplier qualification, all organ procurement organizations (OPOs) in the United States were sent a questionnaire covering the key components of these regulations. Of the 57 OPOs, 29 (51%) were in compliance based upon survey results. Twelve (21%) were not compliant in one or more areas. All indicated plans to become compliant. The remaining 15 (27%) either failed or refused to complete the survey, some indicating 21 CFR 1271 did not apply to OPOs. Using 2006 data, OPOs compliant with 21 CFR 1271 recovered 50% of the organs procured in the United States. These findings represent a challenge for allogeneic islet cell transplant programs whose raw material must comply with 21 CFR 1271. OPOs should work toward understanding and complying with 21 CFR 1271. Regulatory agencies should work toward enhancing safety of the pancreas supply by facilitating compliance through harmonization of requirements.

Comparison of high-dose CY and growth factor with growth factor alone for mobilization of stem cells for transplantation in patients with multiple myeloma.

We retrospectively analyzed outcomes of 716 patients with multiple myeloma who were mobilized using CY and growth factor (n=370) or growth factor alone (n=346) before SCT. Patients receiving CY had higher stem cell yields than the growth factor only group (median number of apheresis sessions needed to achieve stem cell collection goals, two vs four sessions, respectively (P=0.001)). However, patients treated with CY required more time for engraftment of platelets and neutrophils (P<0.001 for both). For patients receiving CY, 75% achieved engraftment (defined as a platelet count of 50 x 10(9)/l) by day 39, whereas 75% of patients not receiving CY achieved engraftment by day 18. Similar results were observed for neutrophil engraftment. These differences did not affect the duration of hospitalization, but patients treated with CY had a higher incidence of post transplant nonstaphylococcal bacteremia. For CY-mobilized patients, considerably faster platelet engraftment (5 fewer days) resulted if stem cell reinfusion occurred more than 30 days after the first apheresis session. Our data suggested that CY damaged the microenvironment and slowed engraftment. By lengthening the period between the completion of apheresis and stem cell reinfusion, the microenvironment may recover and result in faster engraftment.