Cleveland Clinic Foundation Internal Medicine Residency Program.

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc. (ACP), and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an initiative of the Cleveland Clinic's internal medicine residents to improve diabetes care and outcomes within an underserved patient population at an East Cleveland, OH, health center.

Conditional Long-Term Survival after Autologous Hematopoietic Cell Transplantation for Diffuse Large B Cell Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with chemosensitive, relapsed, diffuse large B cell lymphoma (DLBCL). We performed a retrospective cohort study to delineate subsequent (conditional) and relative survival in 371 adult patients with DLBCL who underwent AHCT between 2000 and 2014 and had survived for 1, 2, 3, or 5 years after transplant. The probability of overall survival at 10 years after AHCT was 62%, 71%, 77%, and 86%, respectively, for the 4 cohorts, whereas that of progression-free survival (PFS) was 55%, 65%, 72%, and 81%, respectively. The respective cumulative incidence of nonrelapse mortality (NRM) at 10 years after transplantation was 13%, 12%, 11%, and 8%, respectively. In multivariable analysis, older age was associated with greater mortality risk among all but 5-year survivors; relapse within the landmark time was associated with greater mortality risk in all groups. Older age and relapse within the landmark time were associated with worse PFS in all groups. Standardized mortality ratio (SMR) was significantly higher than an age-, gender-, and race-matched general population, with the magnitude of SMR decreasing as the landmark time increased (4.0 for 1-year, 3.0 for 2-year, 2.4 for 3-year, and 1.8 for 5-year survivors). Our study provides information on long-term survival and prognosis that will assist in counseling patients with DLBCL who have received AHCT. Survival improves with longer time in remission post-transplant, although patients continue to remain at risk for NRM, underscoring the need for continued vigilance and prevention of late complications.

Reduced intensity is preferred over myeloablative conditioning allogeneic HCT in chronic lymphocytic leukemia whenever indicated: A systematic review/meta-analysis.

Despite availability of new and more effective therapies for chronic lymphocytic leukemia, presently this disease remains incurable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Recent published clinical practice recommendations on behalf of the American Society for Blood and Marrow Transplantation relegated the role of for allogeneic hematopoietic cell transplantation to later stages of the disease. To our knowledge, no randomized controlled trial has been performed to date comparing myeloablative versus reduced intensity conditioning regimens in chronic lymphocytic leukemia patients eligible for the procedure. We performed a systematic review/meta-analysis to assess the efficacy of allogeneic hematopoietic cell transplantation when using myeloablative or reduced intensity conditioning regimens. We report the results in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Based on lower non-relapse mortality and slightly better overall survival rates, reduced intensity conditioning regimens appear to be the most desirable choice whenever the procedure is indicated for this disease. It appears highly unlikely that a RCT will be ever performed comparing reduced intensity vs. myeloablative allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia. In the absence of such a study, results of this systematic review/meta-analysis represent the best available evidence supporting this recommendation whenever indicated in patients with chronic lymphocytic leukemia.

Current state of hematopoietic cell transplantation in CLL as smart therapies emerge.

Novel therapies targeting various kinases downstream of the B-cell receptor have emerged along with monoclonal antibodies and BCL-2 antagonists, and are changing the therapeutic landscape of chronic lymphocytic leukemia. However, cure remains unattainable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Access to allogeneic hematopoietic cell transplantation has expanded considerably with availability of reduced intensity conditioning regimens which is capable offering durable remissions even in poor-risk disease. Encouraging data from ibrutinib and venetoclax in Del17p is challenging the notion of disease eradication as the ultimate therapeutic goal to a new concept of merely disease control. By favoring the non-transplant approach, patients should be aware that there are no established salvage therapies, yet, to rescue disease progression after ibrutinib. When disease eradication is the desirable approach, a reduced intensity conditioning allogeneic hematopoietic cell transplant is the preferred choice at this time.

Hematopoietic Cell Transplantation for Richter Syndrome.

Treatment combining chemotherapy with immunotherapy as well as novel targeted therapies have shown limited efficacy in Richter syndrome. Overall response rates after chemoimmunotherapy range from 43% to 67%, but remissions are generally short-lived. In chronic lymphocytic leukemia (CLL), allogeneic hematopoietic cell transplantation (all-HCT) is considered a potentially curative treatment modality, yielding 3-year overall survival rates exceeding 50% and a plateau in survival curves. In Richter syndrome, efficacy of allo-HCT depends on demonstrating an objective response (complete remission or partial response) before allografting, with resulting 3-year survival rates of 41% to 75%. On the other hand, the efficacy of autologous HCT is limited, especially when considering that patients autografted for Richter syndrome might relapse with CLL in 35% of cases. Notwithstanding the scarcity of published data, we recommend that patients with Richter syndrome should be referred to transplant centers as soon as the diagnosis is confirmed to evaluate their candidacy for allo-HCT. Establishing a clonal relationship to CLL is important considering the more aggressive disease course in clonally related Richter syndrome. Moreover, achievement of a complete remission or partial response to salvage therapy must be a prerequisite before moving forward with allografting for Richter syndrome. Patients who fail to demonstrate an objective response to salvage therapy should be considered for enrollment in clinical trials.

Reduced-intensity or myeloablative allogeneic hematopoietic cell transplantation for mantle cell lymphoma: a systematic review.

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only known treatment that can offer a cure in mantle cell lymphoma, but it is unclear if regimen dose-intensity offers any advantage. We performed a systematic review/meta-analysis to assess efficacy of allo-HCT using myeloablative or reduced-intensity conditioning. We report results according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. On the basis of a relatively lower nonrelapse mortality and a slightly better progression-free survival/event-free survival and overall survival rates, reduced-intensity allo-HCT regimens appear to be the preferred choice when an allo-HCT is being considered for mantle cell lymphoma. The higher rate of relapse when offering reduced-intensity regimens cannot be ignored but certainly highlights opportunities to incorporate post-transplant strategies to mitigate this risk. A prospective comparative study is ultimately needed to generate more conclusive evidence.

Efficacy of High-Dose Therapy and Autologous Hematopoietic Cell Transplantation in Peripheral T Cell Lymphomas as Front-Line Consolidation or in the Relapsed/Refractory Setting: A Systematic Review/Meta-Analysis.

To date, no prospective randomized trials exist comparing high-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) against conventional therapy for management of peripheral T cell lymphomas either as upfront consolidation or in the relapsed/refractory setting. Available data supporting this approach are limited to single-arm prospective or retrospective studies only. Accordingly, we performed a systematic review/meta-analysis of the published literature. Our search identified 1586 publications, but only 27 (n = 1368) met our inclusion criteria. In the front-line setting, pooled analysis of only prospective studies showed rates of progression-free survival (PFS) of 33% (95% confidence interval [CI], 14% to 56%), overall survival (OS) of 54% (95% CI, 32% to 75%), relapse/progression of 26% (95% CI, 20% to 33%), and transplantation-related mortality (TRM) of 2% (95% CI, 0% to 5%); for retrospective studies, rates of PFS, OS, relapse/progression, TRM, and secondary malignancies were 55% (95% CI, 40% to 69%), 68% (95% CI, 56% to 78%), 36% (95% CI, 24% to 48%), 6% (95% CI, 2% to 11%), and 7% (95% CI, 2% to 14%), respectively. On the other hand, pooled analysis of retrospective studies evaluating HDT/auto-HCT in the relapsed/refractory setting showed pooled rates of PFS, OS, relapse/progression, and TRM of 36% (95% CI, 32% to 40%), 47% (95% CI, 43% to 51%), 51% (95% CI, 39% to 62%), and 10% (95% CI, 5% to 17%), respectively. Among the various histologic subtypes, PFS and OS rates appear to be higher in anaplastic large cell lymphoma, regardless of disease stage. In the absence of a multicenter, randomized controlled trial comparing HDT/auto-HCT to a nontransplantation strategy, the findings of this systematic review/meta-analysis may represent the best evidence supporting the role of HDT/auto-HCT for treatment of peripheral T cell lymphomas as front-line consolidation or in the relapsed/refractory setting.

Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury.

Allogeneic hematopoietic cell transplantation is a potential curative treatment option for various malignant and nonmalignant hematologic disorders. Patients undergoing an allogeneic hematopoietic cell transplant are prescribed immune-suppressant therapies to facilitate hematopoietic donor-cell engraftment and prevent graft-versus-host disease. Drug-drug interactions may occur, owing to exposure to complex multidrug regimens with narrow therapeutic windows and high toxicity profiles. Here, we describe a unique case of a 65-year-old man with poor-risk acute myeloid leukemia who underwent a matched-sibling hematopoietic cell allograft. Sirolimus and tacrolimus were used for graft-versus-host disease prophylaxis. He developed oral thrush requiring treatment with clotrimazole troches, which subsequently resulted in serious renal toxicity attributed to supratherapeutic levels of sirolimus and tacrolimus. Patient renal function improved after temporarily holding both immune suppressants, and administering phenytoin to help induce sirolimus and tacrolimus metabolism. This case highlights sudden and serious toxicities that resulted from clotrimazole-sirolimus and clotrimazole-tacrolimus drug-drug interactions, even when administered topically.

Therapeutic strategies for cytomegalovirus in allogeneic hematopoietic cell transplantation.

Cytomegalovirus (CMV) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation. Advances in surveillance of cytomegalovirus reactivation using sensitive techniques and a preemptive strategy to treat virus reactivation has reduced incidence of cytomegalovirus end organ disease. However, severe immunosuppression associated with extensive T-cell depletion resulting from graft-versus-host disease prevention for cases of mismatched or others such as haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease therapy itself create clinical challenges in managing cytomegalovirus infection. Novel anticytomegalovirus therapies including newer pharmacologic interventions, vaccines, and adoptive cellular therapies to restore anticytomegalovirus immunity appear promising and are expected to continue to shape our treatment armamentarium. Eradication of CMV disease altogether, rather than simply suppressing viremia, should be the ultimate desirable goal.