Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely performed in adult patients with sickle cell disease (SCD). We utilized the chemotherapy-free, alemtuzumab/total body irradiation 300 cGy regimen with sirolimus as post-transplantation immunosuppression in 13 high-risk SCD adult patients between November 2011 and June 2014. Patients received matched related donor (MRD) granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, including 2 cases that were ABO incompatible. Quality-of-life (QoL) measurements were performed at different time points after HSCT. All 13 patients initially engrafted. A stable mixed donor/recipient chimerism was maintained in 12 patients (92%), whereas 1 patient not compliant with sirolimus experienced secondary graft failure. With a median follow-up of 22 months (range, 12 to 44 months) there was no mortality, no acute or chronic graft-versus-host disease (GVHD), and no grades 3 or 4 extramedullary toxicities. At 1 year after transplantation, patients with stable donor chimerism have normalized hemoglobin concentrations and improved cardiopulmonary and QoL parameters including bodily pain, general health, and vitality. In 4 patients, sirolimus was stopped without rejection or SCD-related complications. These results underscore the successful use of a chemotherapy-free regimen in MRD HSCT for high-risk adult SCD patients and demonstrates a high cure rate, absence of GVHD or mortality, and improvement in QoL including the applicability of this regimen in ABO mismatched cases (NCT number 01499888).

Purpose: We hypothesized that a multidisciplinary collaborative physician-pharmacist multiple myeloma clinic would improve adherence to treatment and supportive care guidelines as well as reduce delays in receiving oral antimyeloma therapy. Methods: From March 2014 to February 2015, an oncology pharmacist provided consultation for all patients in a specialist myeloma clinic. This included reviewing medications, ensuring physician adherence to supportive care guidelines, managing treatment-related adverse effects, and navigating issues involving access to oral specialty medications (collaborative clinic). Results: Outcome measures were retrospectively compared with those of patients being treated by the same physician during the previous year, in which ad hoc pharmacist consultation was available upon request (traditional clinic). The collaborative clinic led to significant improvements in adherence to supportive medications, such as bisphosphonates (96% v 68%; P < .001), calcium and vitamin D (100% v 41%; P < .001), acyclovir (100% v 58%; P < .001), and Pneumocystis jirovecii pneumonia prophylaxis (100% v 50%; P < .001). Appropriate venous thromboembolism prophylaxis in immunomodulatory drug–treated patients was prescribed in 100% versus 83% of cases ( P = .0035). The median time to initiation of bisphosphonate (5.5 v 97.5 days; P < .001) and P jirovecii pneumonia prophylaxis after autologous transplantation was shortened in the collaborative clinic (11 v 40.5 days; P < .001). Furthermore, the number (85% v 21%; P < .001) and duration (7 v 15 days; P = .002) of delays in obtaining immunomodulatory drug therapy were also significantly reduced. Conclusion: Our collaborative clinic model could potentially be applied to other practice sites to improve the management of patients with multiple myeloma. Prospective studies analyzing clinical outcomes, patient satisfaction, and cost effectiveness of this approach are warranted.

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 10/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.

A pretransplant test dose of i.v. BU was previously used in pediatric patients undergoing a reduced-intensity allogeneic hematopoietic SCT (HSCT). Here, we used a BU test dose in 23 adult patients who were not pancytopenic and underwent a myeloablative allogeneic HSCT prepared with fludarabine and i.v. BU (FluBU). Pharmacokinetics (PK) of BU were calculated after a test dose (0.8 mg/kg) was performed 2 weeks before transplant. Targeted BU area under the curve (AUC) range was 4800-5200 lM min. The mean BU dose calculated after the test dose was 3.5 ± 0.5 mg/kg. To validate the test dose, PK studies were repeated in 17 patients after the first dose of BU during the conditioning regimen. An AUC below the therapeutic value of 4000 lM min was observed in 23% of the patients receiving a wt-based dose and in 0% of patients whose dose was calculated on the basis of the test dose (P ¼ 0.03). In patients who had a test dose, a significant correlation (Po0.0001) between the first and subsequent doses of BU during the conditioning regimen was observed. Our findings may allow more centers to pursue transplant strategies with targeted BU by overcoming the time limitation for PK studies during the conditioning regimen.

Here we examined the addition of intensity-modulated total marrow irradiation (TMI) delivered using a linear accelerator to a myeloablative chemotherapy conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT). In this phase I study, we enrolled 14 patients with high-risk hematologic malignancies who received escalating doses of TMI at 3 Gy (n = 3), 6 Gy (n = 3), 9 Gy (n = 6), and 12 Gy (n = 2) in combination with intravenous (i.v.) fludarabine 160 mg/m(2) and targeted busulfan (area under the curve, 4800 μM*minute). Peripheral blood mobilized stem cells were obtained from HLA-matched related (n = 9) or unrelated (n = 4) or 1 antigen-mismatched unrelated (n = 1) donors. All patients rapidly engrafted and recovered their immune cells. Overall, Bearman extrahematologic toxicity were limited to grades 1 or 2, with oral mucositis grade 1 in 64% and grade 2 in 36% of the patients. With a median follow-up of 1126 days (range, 362 to 1469) for living patients, the overall survival was 50% and relapse-free survival was 43%. Of 7 deaths, 3 were due to relapse and 4 to transplantation-related complications. We conclude that 9 Gy TMI can be combined with myeloablative chemotherapy in the design of new preparative regimens for HSCT. This study was registered at clinicaltrials.gov as NCT00988013.

Based on limited evidence, the U.S. Food and Drug Administration (FDA) issued a black box warning for the use of tumor necrosis factor-alpha inhibitors (TNFIs) and risk of non-Hodgkin lymphoma (NHL). Our objective was to determine the risk of NHL associated with TNFI use by duration and type of anti-TNF agent. We performed a nested case-control study within a retrospective cohort of adults with rheumatologic conditions from a U.S. commercial health insurance database between 2009 and 2015. Use of TNFIs (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol) and conventional-synthetic disease-modifying antirheumatic drugs (csDMARDs) was identified, and conditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL. From a retrospective cohort of 55,446 adult patients, 101 NHL cases and 984 controls matched on age, gender and rheumatologic indication were included. Compared to controls, NHL cases had greater TNFI use (33% vs. 20%) but were similar in csDMARD use (70% vs. 71%). TNFI ever-use was associated with nearly two-fold increased risk of NHL (OR = 1.93; 95% CI: 1.16-3.20) with suggestion of increasing risk with duration (P-trend = 0.05). TNF fusion protein (etanercept) was associated with increased NHL risk (OR = 2.73; 95% CI: 1.40-5.33), whereas risk with anti-TNF monoclonal antibodies was not statistically significant (OR = 1.77; 95% CI: 0.87-3.58). In sensitivity analyses evaluating confounding by rheumatologic disease severity, channeling bias was not likely to account for our results. Our findings support the FDA black box warning for NHL. Continued surveillance and awareness of this rare but serious adverse outcome are warranted with new TNFIs and biosimilar products forthcoming.

Data on the effectiveness and toxicity of high-dose melphalan in patients with renal impairment (RI) are lacking. We evaluated the impact of RI on outcomes of patients with multiple myeloma treated with melphalan 200 mg/m 2 (Mel200) and autologous stem cell transplantation. Similar baseline characteristics were seen among 46 patients with creatinine clearance (CrCl) o 60 mL/min (median 50 mL/min, range 20-59) and 103 patients with CrCl ⩾ 60 mL/min (median 83 mL/min, range 60-128). Patients with CrCl o60 mL/min had longer time to neutrophil (P = 0.008) and platelet engraftment (P o 0.001). Diarrhea, duration of total parenteral nutrition use and infection were significantly higher in the CrCl o 60 mL/min group. With a median follow-up of 35 months (range 2-132) in the CrCl o60 mL/min group and 47 months (range 1-45) in the CrCl ⩾ 60 mL/min group, overall survival was comparable between the two groups. Median treatment-free survival was longer in the RI group (37 vs 17 months, P = 0.0025). Multivariate analysis showed CrCl o 60 mL/min (hazard ratio (HR) 3.5), and prior proteasome inhibitor therapy (HR 2.441) both predicted longer treatment-free survival. We consider Mel200 safe and effective in patients with CrCl between 30 and 60 mL/min.

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