Pritesh R. Patel

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.

Strength Training to Enhance Early Recovery after Hematopoietic Stem Cell Transplantation

Intensive cancer treatment followed by hematopoietic stem cell transplantation (HCT) results in moderate to severe fatigue and physical inactivity, leading to diminished functional ability. The purpose of this study was to determine the efficacy of an exercise intervention, strength training to enhance early recovery (STEER), on physical activity, fatigue, muscle strength, functional ability, and quality of life after HCT. This single-blind, randomized clinical trial compared strength training (n = 33) to usual care plus attention control with health education (UC + AC with HE) (n = 34). Subjects were stratified by type of transplantation and age. STEER consisted of a comprehensive program of progressive resistance introduced during hospitalization and continued for 6 weeks after hospital discharge. Fatigue, physical activity, muscle strength, functional ability, and quality of life were assessed before HCT hospital admission and after intervention completion. Data were analyzed using split-plot analysis of variance. Significant time × group interactions effects were noted for fatigue (P = .04). The STEER group reported improvement in fatigue from baseline to after intervention whereas the UC + AC with HE group reported worsened fatigue from baseline to after intervention. Time (P < .001) and group effects (P = .05) were observed for physical activity. Physical activity declined from baseline to 6 weeks after hospitalization. The STEER group was more physically active. Functional ability tests (timed stair climb and timed up and go) resulted in a significant interaction effect (P = .03 and P = .05, respectively). Subjects in the UC + AC with HE group were significantly slower on both tests baseline to after intervention, whereas the STEER groups time remained stable. The STEER group completed both tests faster than the UC + AC with HE group after intervention. Study findings support the use of STEER after intensive cancer treatment and HCT. Strength training demonstrated positive effects on fatigue, physical activity, muscle strength, and functional ability. The exact recovery patterns between groups and over time varied; the STEER group either improved or maintained their status from baseline to after intervention (6 weeks after hospital discharge) whereas the health education group generally declined over time or did not change.

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

Improved outcomes with novel agents and auto-SCT for multiple myeloma in African-American patients

Improved outcomes with novel agents and auto-SCT for multiple myeloma in African-American patients

Barriers and Facilitators of Medication Adherence in a Diverse Sample of Patients With Multiple Myeloma: Are Sensored Medication Devices an Option? (Preprint)

Background Many recently approved medications to manage multiple myeloma (MM) are oral, require supportive medications to prevent adverse effects, and are taken under complex schedules. Medication adherence is a concern; however, little attention has been directed toward understanding adherence in MM or associated barriers and facilitators. Advanced sensored medication devices (SMDs) offer opportunities to intervene; however, acceptability among patients with MM, particularly African American patients, is untested. Objective This study aimed to explore patients’ (1) perceptions of their health before MM including experiences with chronic medications, (2) perceptions of adherence barriers and facilitators, and (3) attitudes toward using SMDs. Methods An in-person, semistructured, qualitative interview was conducted with a convenience sample of patients being treated for MM. Patients were recruited from within an urban, minority-serving, academic medical center that had an established cancer center. A standardized interview guide included questions targeting medication use, attitudes, adherence, barriers, and facilitators. Demographics included the use of cell phone technology. Patients were shown 2 different pill bottles with sensor technology—Medication Event Monitoring System and the SMRxT bottle. After receiving information on the transmission ability of the bottles, patients were asked to discuss their reactions and concerns with the idea of using such a device. Medical records were reviewed to capture information on medication and diagnoses. The interviews were audio-recorded and transcribed. Interviews were independently coded by 2 members of the team with a third member providing guidance. Results A total of 20 patients with a mean age of 56 years (median=59 years; range=29-71 years) participated in this study and 80% (16/20) were African American. In addition, 18 (90%, 18/20) owned a smartphone and 85% (17/20) were comfortable using the internet, text messaging, and cell phone apps. The average number of medications reported per patient was 13 medications (median=10; range=3-24). Moreover, 14 (70%, 14/20) patients reported missed doses for a range of reasons such as fatigue, feeling ill, a busy schedule, forgetting, or side effects. Interest in using an SMD ranged from great interest to complete lack of interest. Examples of concerns related to the SMDs included privacy issues, potential added cost, and the size of the bottle (ie, too large). Despite the concerns, 60% (12/20) of the patients expressed interest in trying a bottle in the future. Conclusions Results identified numerous patient-reported barriers and facilitators to missed doses of oral anticancer therapy. Many appear to be potentially mutable if uncovered and addressed. SMDs may allow for capture of these data. Although patients expressed concerns with SMDs, most remained willing to use one. A feasibility trial with SMDs is planned.

Steps to Enhance Early Recovery After Hematopoietic Stem Cell Transplantation: Lessons Learned From a Physical Activity Feasibility Study

Aims: This pilot study tested and refined a free-living physical activity intervention. The investigators evaluated the acceptability and feasibility of the intervention after hematopoietic stem cell transplantation and determined preliminary effects on physical activity, fatigue, muscle strength, functional ability, and quality of life. Design: This pilot study used a 1-group, pretest-posttest design. Methods: The free-living physical activity intervention consisted of an education component and 6 weeks of gradually increasing physical activity after discharge from the hospital. The intervention was designed to increase steps by 10% weekly. Subjects were assessed before transplantation and during the seventh week after discharge from the hospital after completing the intervention. Pretest-posttest scores were analyzed with paired t tests. Results: Subject wore the physical activity tracker for an average of 38 of 42 days and met their physical activity goals 57% of the time. Subjects reported significantly less physical fatigue after the free-living physical activity intervention compared with baseline (P = .05). Improvements in quality of life approached significance (P = .06). Conclusion: The findings demonstrate that the free-living physical activity intervention implemented during the very early recovery period after transplantation is feasible and acceptable. The intervention potentially reduces fatigue and improves quality of life. The positive results must be interpreted cautiously given the pilot nature of the study. The evidence supports continued investigation.