Karen Sweiss

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease

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).

Encephalopathy after high-dose Ifosfamide: a retrospective cohort study and review of the literature.

AbstractBackground: Encephalopathy occurs in 10–40% of patients treated with high-dose ifosfamide. Proposed risk factors for encephalopathy include hepatic or renal dysfunction, brain metastases, electrolyte imbalances and drug-drug interactions. Objective: The purpose of this retrospective cohort study and literature review was to estimate the prevalence of encephalopathy, identify characteristics associated with encephalopathy and evaluate the effectiveness of methylthioninium chloride (methylene blue) in its prevention. Study design and methods: A total of 19 patients received high-dose ifosfamide for soft tissue sarcoma during a 4-year period at our medical centre. Eight patients developed encephalopathy based on adverse drug event (ADE) reports submitted by a clinical pharmacist. These reports incorporate the Naranjo probability scale, which is used to assess the likelihood that a change in clinical status is the result of an ADE rather than the result of other factors, such as progression of disease. The demographics, concurrent medication therapy, co-existing illnesses and laboratory parameters were documented from the medical records. We also conducted a review of the literature by searching MEDLINE (1996–October 2007). Main outcome and results: A total of 19 patients received high-dose ifosfamide; eight patients experienced encephalopathy (group I, 42%) and 11 patients did not experience encephalopathy (group II, 58%). More women than men developed encephalopathy (group I, 87.5% vs group II, 27.3%). Serum albumin (group I, 3.1 ±0.3 vs group II, 3.6 ±0.3 g/dL), haemoglobin (10.5 ±1.5 vs 12.4 ±1.7 g/dL) and total bilirubin (0.5 ±0.2 vs 0.8 ±0.3 mg/dL) levels were substantially lower in patients with encephalopathy, whereas the ratio of actual bodyweight to the ideal bodyweight (1.4 ±0.3 vs 1.1 ±0.2) was substantially higher in these patients. Five (62.5%) patients received a subsequent cycle of high-dose ifosfamide; all of these patients received methylthioninium chloride to minimize the risk of encephalopathy. All of these patients developed encephalopathy. Other reports have found that hypoalbuminaemia is associated with encephalopathy and that methylthioninium chloride does not prevent ifosfamide-induced encephalopathy. Conclusions: In summary, female sex, low total bilirubin, albumin and haemoglobin levels, and obesity appear to be associated with ifosfamide-induced encephalopathy. Methylthioninium chloride did not appear to prevent encephalopathy with subsequent doses of high-dose ifosfamide.

Reliability of a pretransplant i.v. BU test dose performed 2 weeks before myeloablative FluBu conditioning regimen

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 μM 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 μM 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=0.03). In patients who had a test dose, a significant correlation (P<0.0001) 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.

Comorbidity index does not predict outcome in allogeneic myeloablative transplants conditioned with fludarabine/i.v. busulfan (FluBu4)

The assessment of a hematopoietic stem cell transplant (HSCT)-specific comorbidity index (HCT-CI) has been developed to predict the risk of TRM in patients undergoing allogeneic HSCT. As the myeloablative fludarabine/i.v. busulfan (FluBu4) regimen has been associated with limited extra-hematologic toxicity, we analyzed whether the HCT-CI represents a useful tool in transplant patients conditioned with this regimen. Of the 52 consecutive patients who received an allogeneic HSCT with FluBu4 at our institution, 50 were evaluable for assessing pre-transplant HCT-CI. Patients were divided into three groups: score 0 (n=7); score 1–2 (n=17) and score >3 (n=26). The three groups did not differ significantly in age, diagnosis, previous lines of chemotherapy and type of donor. High-risk disease was present in 57% of low, 82% of intermediate and 85% of high HCT-CI score groups (P=ns). Two-year TRM and OS was 14.3 and 85.7% in the low score group, 23.5 and 58.8% in the intermediate score group and 15.4 and 50% in the high HCT-CI score group (P=ns). In this study, the HCT-CI lacked sensitivity to reliably predict TRM although patients with no comorbidities showed a trend for improved survival.

Melphalan 200 mg/m 2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival

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/m2 (Mel200) and autologous stem cell transplantation. Similar baseline characteristics were seen among 46 patients with creatinine clearance (CrCl) <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 <60 mL/min had longer time to neutrophil (P=0.008) and platelet engraftment (P<0.001). Diarrhea, duration of total parenteral nutrition use and infection were significantly higher in the CrCl <60 mL/min group. With a median follow-up of 35 months (range 2–132) in the CrCl <60 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 <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.

Plerixafor given before the third leukapheresis to rescue an unsuccessful stem cell mobilization with CY and G-CSF.

Plerixafor given before the third leukapheresis to rescue an unsuccessful stem cell mobilization with CY and G-CSF

Deferasirox increases BU blood concentrations

BU is commonly used in combination with fludarabine or CY for conditioning before hematopoietic SCT due to a favorable toxicity profile.1, 2 However, as the pharmacokinetics (PK) of BU can be unpredictable there is inter-patient variability in the systemic concentrations of the drug after weight-based dosing. Supra-therapeutic levels may increase the risk of non-relapse mortality,3 whereas sub-therapeutic levels may lead to disease relapse.4 Therapeutic drug monitoring has been attempted to tailor the dose for each patient and achieve a target area under the curve (AUC).5 For this reason, blood sampling strategies have been adopted to determine the BU dose required to achieve a desired target AUC.6 Although the exact mechanism of BU metabolism is unknown, it is believed that the drug undergoes glucuronidation and subsequent metabolism through the liver.7 Therefore, there is potential for drug–drug interactions that may increase or decrease the clearance of BU. Newer drugs are now being introduced into the SCT arena, but their effect on BU metabolism remains unknown. We describe a case that demonstrates the significant effect of deferasirox on BU blood concentrations.

The impact of novel influenza A (H1N1) after hematopoietic SCT

Patients with hematological malignancy who undergo hematopoietic SCT (HSCT) remain profoundly immunosuppressed for approximately 1 year, or even longer if on prolonged anti-GVHD therapy. Based on evidence from previous influenza outbreaks, these patients are likely to be at a high risk of contracting novel influenza A (H1N1) during the current pandemic and of developing severe respiratory complications. However, data relating to the course of H1N1 infection in patients after HSCT are sparse, with only four anecdotal cases reported so far. Moreover, the role of steroids in the course of influenza in these patients is still unclear. Here we describe five cases of H1N1 infection identified at our institution in the past 6 months in adult patients transplanted with peripheral blood HSC. None of them had been vaccinated against H1N1 virus. Diagnosis of H1N1 was made by real-time reverse transcriptase PCR (rRT-PCR) assay in four cases and by rapid-Ag detection in one case. Patient characteristics and outcome are shown in Table 1. Of the five patients, one patient received an autologous and four patients an allogeneic HSCT from related (n1⁄4 3) or unrelated (n1⁄4 1) donors. The time from transplant to H1N1 was on average 14 months for allo-transplant patients and 3 months for the autologous transplant case. Late infection in allotransplant cases is likely associated with the development of chronic GVHD. In fact, all the four allotransplant patients had a history of GVHD, and three were still on immunosuppression with either tacrolimus and/or prednisone or mycophenolate mofetil at the time of the H1N1 infection. Of five cases only one died. This was a patient on high-dose corticosteroids for chronic GVHD. She developed progressive pneumonia despite prolonged treatment initially with oseltamivir and then with i.v. peramivir. rRT-PCR on nasal swab and bronchoscopy specimens 9 days apart was positive for H1N1 infection; the bronchoscopy also demonstrated parainfluenza type 1 and invasive pulmonary aspergillosis. The patient required admission to the intensive care unit, intubation and mechanical ventilation. She had Rhizopus growing from sputum cultures shortly before her death. All our patients were started on early empirical treatment with oseltamivir, and this may have helped the course of symptoms in four of them. However, in the case of patients on high-dose steroids, or on multiple lines of immunosuppressive therapy due to GVHD, the risk of lethal complications remains very high. Based on these findings, our current strategies to limit infection in the transplant population include not only recommending isolation from contacts with influenza-like illness but also offering H1N1 vaccination. Although sub-optimal immune responses may be observed in these immuno-compromised patients, we believe it may still represent a useful preventive tool against lethal complications. It is worth noting that prolonged viral shedding may occur with corticosteroids use as in the case of the patient who died. Importantly, in those patients who are unable to take oral medications, transplant physicians should be aware that i.v. peramivir is available under an emergency use authorization through the Centers for Disease Control and Prevention.

Tumor necrosis factor-alpha inhibitors and risk of non-Hodgkin lymphoma in a cohort of adults with rheumatologic conditions: TNF-alpha inhibitors and risk of non-hodgkin lymphoma

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.

Decreased pulmonary function in asymptomatic long-term survivors after allogeneic hematopoietic stem cell transplant

Decreased pulmonary function in asymptomatic long-term survivors after allogeneic hematopoietic stem cell transplant