Anita D’Souza

Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.

Pharmaceutical amyloidosis associated with subcutaneous insulin and enfuvirtide administration

Abstract Protein and peptide drugs administered subcutaneously, such as insulin can be amyloidogenic and result in localized amyloid deposits at the sites of medication injections. These iatrogenic amyloidoses typically present as a localized subcutaneous nodule or skin reaction at the site of administration, and often pose diagnostic challenges. We have analyzed the amyloid proteome in 52 cases of insulin and enfuvirtide associated amyloidosis using laser microdissection/tandem mass spectrometry. We show that the deposits are composed of the drug, as well as other amyloid precursor proteins such as apolipoproteins A-I, A-IV, E and serum amyloid protein. Mass spectrometry-based amyloid sub-typing allows for accurate amyloid diagnosis with resultant therapeutic and prognostic implications. This insight into the amyloid proteome in drug-induced amyloidosis may help further understand pathogenesis of amyloid fibril formation.

Is ‘informed consent’ an ‘understood consent’ in hematopoietic cell transplantation?

Hematopoietic cell transplantation (HCT) is a complex and highly specialized medical treatment that is associated with significant risks, including death. Furthermore, transplantation is offered to patients who often have no other curative treatment alternatives. The routine-consent process for HCT typically occurs before HCT and is influenced by many factors related to patients, physicians and the transplant per se. These factors can impede the consent process and subsequently result in a failure of proper engagement in and an understanding of the procedure with resultant adverse consequences influencing patients and even the patient–physician relationship. We contend that informed consent is a dynamic and ongoing process and that better patient education can assist in the decision making, fulfill the ethical principle of respect for autonomy and engage the patient to maximize compliance and adherence to therapy. This manuscript reviews the key literature pertaining to the decision-making and consent process in HCT and proposes guidelines for improving the consent process. Strategies for improving patient comprehension, engagement and enhancing consent forms are discussed.

Autologous Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction: A Systematic Review and Meta-analysis

Importance The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction. Objective To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT. Data Sources We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: “myeloma” combined with “autologous,” “transplant,” “myeloablative,” or “stem cell.” Study Selection Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis. Data Extraction And Synthesis For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs. Main Outcomes and Measures The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes. Results A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65; P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74; P < .001) and 0.76 for OS (95% CI, 0.42-1.36; P = .20) in favor of HDT. Meta-regression showed that longer follow-up was associated with superior PFS (HR/mo, 0.98; 95% CI, 0.96-0.99; P = .03) and OS (HR/mo, 0.90; 95% CI, 0.84-0.96; P = .002). For PFS, tandem HDT/ASCT had the most favorable HR (0.49; 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR, 0.53; 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. For OS, none of the HDT/ASCT-based approaches had a significant effect on survival. Treatment-related mortality with HDT/ASCT was minimal (<1%). Conclusions and Relevance The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.

Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis

Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60 mL/min), N=1240, moderate (30–59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31–38)%, 40 (31–49)% and 27 (15–40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65–71)%, 68 (60–76)% and 60 (46–74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6–35)% and for Mel 200 was 46 (36–57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11–41) % and for Mel 200 was 32 (11–58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.

Signaling Pathways and Emerging Therapies in Multiple Myeloma.

Multiple myeloma (MM) is a devastating malignancy of antibody-producing plasma cells. In the absence of a single unifying genetic event contributing to disease manifestation, efforts have focused on understanding signaling events deregulated in myeloma plasma cells. MM cells are dependent on both cellular and non-cellular components of the tumor microenvironment such as bone marrow stromal cells, endothelial cells, and cytokines such as interleukin 6 (IL6), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF) for their growth and survival. The cumulative effect of such interactions is the aberrant activation of numerous signal transduction pathways within the MM plasma cells leading to uncontrolled growth and prevention of apoptosis. Here, we will review our current understanding of some of the key signal transduction pathways dysregulated in MM and emerging therapies targeting these pathways in MM.

CYP2C19*17 genetic polymorphism—an uncommon cause of voriconazole treatment failure

We describe an immunosuppressed, 48-year-old male, allogeneic hematopoietic stem cell transplant recipient with severe graft-versus-host disease who developed invasive pulmonary Aspergillus fumigatus infection 6 months after transplant. His lack of response to voriconazole and undetectable serum trough levels of the drug led us to establish that he had the uncommon cytochrome P450, CYP2C19*17 allele, which leads to a rapid metabolism of voriconazole but not of the other azole antifungals. We discuss the particular challenges encountered in this case.

Rehabilitation referrals and outcomes in the early period after hematopoietic cell transplantation

In a cohort of inpatient hematopoietic cell transplantation (HCT) recipients, we assessed patterns of referral to rehabilitation treatment, functional performance and short-term outcomes in patients who received post-transplant rehabilitation in comparison with those who did not. Among 201 first-time HCT recipients, 53 (26%) were referred to an inpatient rehabilitation provider, had an assessment of functional performance using the Functional Independence Measure scale and underwent rehabilitation treatments to address functional needs. Patients who received rehabilitation therapy were more likely to be females (P=0.02), older than 60 years of age (P=0.0146), employed (P=0.01), have hypertension (P=0.02), peripheral vascular disease (P=0.01) and pre-transplant Karnofsky Performance Score (KPS) <90 (P=0.02). Mean functional performance scores for transfers and ambulation increased significantly in the group with rehabilitation interventions (P=0.0022 and P<0.0001, respectively). There was no difference between the groups that did and did not receive rehabilitation treatments in 30-day re-admission rates. Patients who are 60 years of age or older, with pre-transplant KPS<90, and pre-transplant hypertension were more likely to be referred for rehabilitation treatments in the early period after HCT. Future studies should be designed to determine the optimal timing and cost effectiveness of functional assessment and rehabilitation treatments in this high-risk population.

Use of propylene glycol-free melphalan conditioning in light-chain amyloidosis patients undergoing autologous hematopoietic cell transplantation is well tolerated and effective

To the Editor: Light-chain amyloidosis (AL) is a malignant plasma cell disorder, characterized by misfolded fibrillar protein deposition in vitals organs of the body, leading to organ failure and eventually death [1]. Treatment is directed at eradicating the underlying plasma cell clone using systemic chemotherapy [2]. Autologous hematopoietic cell transplantation (auto-HCT) has been a preferred approach in transplant-eligible patients to improve long-term outcomes [3]. High-dose melphalan conditioning is the standard of care for auto-HCT in patients with plasma cell disorders [4]. The lyophilized melphalan formulation has inadequate solubility and stability after reconstitution, and propylene glycol (PG), which is used as a co-solvent to improve solubility and chemical stability of lyophilized melphalan, is associated with cardiac, neurologic, metabolic, and renal toxicities [5, 6]. A novel PG-free melphalan preparation, Evomela (PG-free melphalan), uses captisol as a solubilizing agent and thus may be less toxic than PG melphalan formulations. In a phase IIb study of multiple myeloma (MM) patients undergoing auto-HCT, PG-free melphalan showed an acceptable safety profile and comparable efficacy [7]. Consequently, PG-free melphalan was granted FDA approval for use as a conditioning regimen in patients undergoing auto-HCT. Since AL patients have increased peri-transplant complications, we sought to determine the safety and efficacy of PG-free melphalan conditioning in AL patients undergoing auto-HCT compared to PG melphalan. We switched to PG-free melphalan for auto-HCT conditioning on 15 November 2016. Herein, we compare early post-transplant outcomes of AL patients in the year before and after the change. We retrospectively analyzed AL patients who underwent auto-HCT from 31 October 2015 to 31 October 2017 at our institution (N= 18), nine each in PG melphalan and PG-free melphalan group. AL staging was determined using the 2012 revised staging system [8]. Hematologic response was defined according to the 2012updated AL response criteria [9]. Chart review was conducted to identify events in the first 100 days following auto-HCT, including arrhythmias, cardiac and/or renal failure, mucositis, engraftment syndrome, days in hospital, rehospitalization, and transfer to intensive care unit (ICU). We also reviewed charts for need of platelet and pack red blood cell (PRBC) transfusion post auto-HCT in PG melphalan and PG-free melphalan group. The threshold for PRBC transfusion was hemoglobin <7 g/dl and for platelet transfusion was <10,000/mm during this entire period. Incidence and severity of chemotherapy-induced mucositis was determined based on documentation of oral mucositis in the charts and use of opioid medications for oral, throat, or abdominal pain. We also took into account the use of intravenous dexamethasone, intubation to protect airway, and ICU transfer due to suspected oropharyngeal mucositis. Categorical variables between groups were compared using χ test. Continuous variables were compared by nonparametric t test using analysis of variance. Baseline characteristics are summarized in Table 1 and the two groups were comparable. One patient in the PG melphalan arm received BEAM (carmustine, etoposide, cytarabine and melphalan) conditioning before auto-HCT due to concurrent diagnosis of Waldenstrom macroglobulinemia with IgM AL. The median time to neutrophil and platelet engrafment was similar in both groups as well as the incidence of post-transplant cardiac or renal failure. * Anita D’Souza anitadsouza@mcw.edu

Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis

The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.