Non-chemotherapy Options for Newly Diagnosed Mantle Cell Lymphoma.

OPINION STATEMENT: Mantle cell lymphoma is a rare and incurable non-Hodgkin lymphoma with a heterogenous clinical presentation. Typically, treatment consists of frontline chemoimmunotherapy induction with or without autologous stem cell transplant (ASCT) as consolidation. However, this approach has the propensity to increase short- and long-term toxicities, such as secondary malignancies, without being curative. Genomic profiling of MCL will allow for greater impact of new targeted therapies in the future and may become a helpful tool to guide treatment. Based on the data discussed, use of non-chemotherapy options may become the preferred approach for frontline therapy as opposed to conventional chemotherapy and hematopoietic stem cell transplants.

Adjuvant Radiotherapy in Early-Stage Breast Cancer: Evidence-Based Options.

BACKGROUND: Patients with a diagnosis of early-stage breast cancer are offered the option of either mastectomy or breast-conserving therapy (BCT) secondary to multiple randomized trials demonstrating equivalent long-term outcomes. Traditionally, BCT has used standard whole-breast irradiation (SWBI) after breast-conserving surgery, although several alternatives have emerged during the past few decades. METHODS: This report reviews key studies supporting each radiation technique and its respective eligibility criteria to assist clinicians in deciding which adjuvant radiotherapy options are appropriate for their patients. RESULTS: In the past, completion of SWBI required 5-7 weeks of daily treatments. During the past two decades, alternatives to SWBI have emerged including hypofractionated whole-breast irradiation (3-4 weeks), accelerated partial-breast irradiation (1-3 weeks), and endocrine therapy alone. Multiple randomized trials have established the equivalence of these alternative strategies to SWBI for appropriately selected patients. Additionally, the current guidelines for patient selection demonstrate a large amount of overlap in the selection criteria for each technique. CONCLUSION: Clinicians must evaluate patient and pathologic criteria and engage in informed discussions with patients when determining which adjuvant radiation techniques are appropriate. Future strategies being explored include using tumor genetics to identify low-risk patients and switching from paradigms that omit radiotherapy to those that omit endocrine therapy.

Cardiovascular Risk Stratification of Patients Undergoing Hematopoietic Stem Cell Transplantation: The CARE-BMT Risk Score.

BACKGROUND: Evidence guiding the pre-hematopoietic stem cell transplantation (HSCT) cardiovascular evaluation is limited. We sought to derive and validate a pre-HSCT score for the cardiovascular risk stratification of HSCT candidates. METHODS AND RESULTS: We leveraged the CARE-BMT (Cardiovascular Registry in Bone Marrow Transplantation) study, a contemporary multicenter observational study of adult patients who underwent autologous or allogeneic HSCT between 2008 and 2019 (N=2435; mean age at transplant of 55 years; 4.9% Black). We identified the subset of variables most predictive of post-HSCT cardiovascular events, defined as a composite of cardiovascular death, myocardial infarction, heart failure, stroke, atrial fibrillation or flutter, and sustained ventricular tachycardia. We then developed a point-based risk score using the hazard ratios obtained from Cox proportional hazards modeling. The score was externally validated in a separate cohort of 919 HSCT recipients (mean age at transplant 54 years; 20.4% Black). The risk score included age, transplant type, race, coronary artery disease, heart failure, peripheral artery disease, creatinine, triglycerides, and prior anthracycline dose. Risk scores were grouped as low-, intermediate-, and high-risk, with the 5-year cumulative incidence of cardiovascular events being 4.0%, 10.3%, and 22.4%, respectively. The area under the receiver operating curves for predicting cardiovascular events at 100 days, 5 and 10 years post-HSCT were 0.65 (95% CI, 0.59-0.70), 0.73 (95% CI, 0.69-0.76), and 0.76 (95% CI, 0.69-0.81), respectively. The model performed equally well in autologous and allogeneic recipients, as well as in the validation cohort. CONCLUSIONS: The CARE-BMT risk score is easy to calculate and could help guide referrals of high-risk HSCT recipients to cardiovascular specialists before transplant and guide long-term monitoring.

Cardiovascular Events After Hematopoietic Stem Cell Transplant: Incidence and Risk Factors.

Background: Hematopoietic stem cell transplantation (HSCT) is associated with various cardiovascular (CV) complications. Objectives: We sought to characterize the incidence and risk factors for short-term and long-term CV events in a contemporary cohort of adult HSCT recipients. Methods: We conducted a multicenter observational study of adult patients who underwent autologous or allogeneic HSCT between 2008 and 2019. Data on demographics, clinical characteristics, conditioning regimen, and CV outcomes were collected through chart review. CV outcomes were a composite of CV death, myocardial infarction, heart failure, atrial fibrillation/flutter, stroke, and sustained ventricular tachycardia and were classified as short-term (≤100 days post-HSCT) or long-term (>100 days post-HSCT). Results: In 3,354 patients (mean age 55 years; 40.9% female; 30.1% Black) followed for a median time of 2.3 years (Q1-Q3: 1.0-5.4 years), the 100-day and 5-year cumulative incidences of CV events were 4.1% and 13.9%, respectively. Atrial fibrillation/flutter was the most common short- and long-term CV event, with a 100-day incidence of 2.6% and a 5-year incidence of 6.8% followed by heart failure (1.1% at 100 days and 5.4% at 5 years). Allogeneic recipients had a higher incidence of long-term CV events compared to autologous recipients (5-year incidence 16.4% vs 12.1%; P = 0.002). Baseline CV comorbidities were associated with a higher risk of long-term CV events. Conclusions: The incidence of short-term CV events in HSCT recipients is relatively low. Long-term events were more common among allogeneic recipients and those with pre-existing CV comorbidities.

Novel Salvage Therapy Options for Initial Treatment of Relapsed/Refractory Classical Hodgkin's Lymphoma: So Many Options, How to Choose?

The treatment landscape for relapsed/refractory classical Hodgkin's lymphoma (cHL) has evolved with the introduction of several novel agents. Historically, the standard of care for relapsed cHL was salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, many patients are ineligible for ASCT or will have poor responses to salvage chemotherapy and ASCT. Brentuximab vedotin (BV) and checkpoint inhibitors (nivolumab/pembrolizumab) were initially approved in the post-ASCT setting. However, as a result of excellent responses and durable outcomes in this setting, they are now being studied and explored in earlier lines of therapy. Additionally, these agents are also being studied for post-transplant consolidation and maintenance with promising results in improving progression-free survival. We will review current salvage therapy options involving these novel agents and provide comparisons between regimens to aid the clinician in selecting the appropriate salvage regimen for patients who progress after first-line therapy.

Divergent paths: management of early relapsed follicular lymphoma.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States and Western Europe. Overall outcomes for patients with FL have continued to improve over the last several decades-most notably, with the addition of the CD20 monoclonal antibody rituximab to the treatment armamentarium. More recently, we have seen advances in the management of patients with relapsed/refractory FL with the approval of several new treatments including lenalidomide, axicabtagene ciloleucel, copanlisib, umbralisib, and tazemetostat. Unfortunately, there remains a group of patients for which treatment outcomes, especially overall survival (OS), are suboptimal. This group has been identified as patients who relapse within 24 months (POD24) of completion of chemoimmunotherapy (CIT). Data indicate that patients who relapse within this window have a 5-year OS of around 50%, compared to 80% for those who remain in remission beyond 24 months. POD24 patients have been included and evaluated in the studies of the novel agents mentioned. While not specifically designed to treat this high-risk group, early data suggest that outcomes are not significantly impacted by this designation, unlike CIT. While to date the optimal management of POD24 patients has not been elucidated, the future appears bright with the continued use of the approved agents and several others in clinical development.

Revising the Treatment Pathways in Lymphoma: New Standards of Care-How Do We Choose?

Diffuse large B-cell lymphoma and follicular lymphoma are the most commonly encountered non-Hodgkin lymphomas in clinical practice. Both are biologically heterogeneous, with management strategies that are becoming increasingly complex. Diffuse large B-cell lymphoma typically exhibits aggressive behavior but can be cured in the majority of cases with immunochemotherapy. While R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard of care for decades, the recent combination of polatuzumab-vedotin-R-CHP (rituximab plus cyclophosphamide, doxorubicin, and prednisone) has demonstrated improved progression-free survival for patients with intermediate- and intermediate-high-risk disease. Numerous novel therapies, including targeted agents and immunotherapy-based approaches, have recently been approved for relapsed/refractory disease and have led to improved outcomes. Follicular lymphoma is an indolent lymphoma that remains incurable with standard approaches. Overall survival in most patients is excellent, although a proportion of patients will have early relapsing disease and poorer outcomes. The availability of novel agents in the relapsed/refractory setting has shifted the treatment algorithm, which requires thoughtful consideration of sequencing. This article will review recent developments in the treatment of diffuse large B-cell lymphoma and relapsed/refractory follicular lymphoma.

Real world outcomes in patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic stem cell transplantation-A single institution experience.

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with a worse prognosis compared to Ph negative ALL. Tyrosine kinase inhibitor (TKI) therapy has led to an improvement in response rates and survival, thus becoming a critical component of therapy. We performed a retrospective cohort study of Ph+ ALL patients treated at the University of Michigan who received TKI therapy pre- and post-allogeneic hematopoietic stem cell transplant (HSCT) from April 2007 to November 2019. The study included 40 patients with Ph+ ALL (47.5% female) with a median age of 54 (24-69) years. Median event-free survival (EFS) was not reached, with a 5-year EFS of 61%. Median overall survival (OS) was not reached, with a 5-year OS of 71%. There was no difference in 2-year EFS or OS for patients on pre-transplant imatinib or dasatinib (p = 0.16, 0.09, respectively), though definitive conclusions are challenging as post-transplant TKI therapy was variable. The incidence of any grade acute graft-versus-host disease (GVHD) was 62.5% (25/40) and any grade chronic GVHD was 77.5% (31/40). Complete molecular remission (CMR) was achieved in 57.5% of patients pre-transplant with no significant difference when stratified by induction TKI (p = 1). Achievement of CMR pre-HSCT showed a trend towards improved 2-year EFS (p=0.0198) but did not significantly change 2-year OS (p = 1). Patients receiving 1st and 2nd generation TKIs pre- and post-HSCT seem to have favorable outcomes, although type of TKI (pre-HSCT) did not significantly impact EFS or OS. In addition, attaining a CMR pre-transplant improved EFS, but did not change OS.

A diagnosis of discernment: Identifying a novel ATRX mutation in myelodysplastic syndrome with acquired α-thalassemia.

Myelodysplastic syndromes (MDS) are a heterogeneous category of myeloid neoplasms that represent the most common class of acquired bone marrow failure syndromes in adults. MDS is typically associated with a hypoproliferative macrocytic anemia, but atypical findings on initial diagnostic evaluations can raise concern for a distinct pathophysiological process and lead to the investigation of alternative etiologies. Here, we report a case of MDS with a concomitant hypoproliferative microcytic and hypochromic anemia that led to the identification of acquired hemoglobin H due to a novel somatic ATRX mutation.

Radiation Therapy in the Management of Soft Tissue Sarcoma: A Clinician's Guide to Timing, Techniques, and Targets.

Radiation therapy represents a vital component in the multidisciplinary management of soft tissue sarcomas. Combined with limb-preserving surgery, radiation therapy represents a standard of care treatment option for patients with high-grade sarcomas. Radiation therapy for soft tissue sarcoma continues to evolve with changes in timing, techniques, and targets. Over the past 2 decades, increasing data have supported the role of preoperative radiotherapy with the potential for lower total doses of radiation and improved long-term function coming at the cost of increased wound complications for certain locations. Retroperitoneal sarcomas represent a location where preoperative treatment is becoming the standard of care based on anatomic constraints and challenges with delivering postoperative radiotherapy. Multiple radiation therapy techniques exist to deliver treatment; currently both 3-dimensional conformal radiotherapy and intensity-modulated radiation therapy (IMRT) are appropriate options, although increasing data support the role of IMRT in reducing dose to critical structures (bone, bowel, kidneys, vessels) while maintaining target coverage. Traditional target volumes have included larger fields; however, recent prospective data have demonstrated that image guidance in conjunction with smaller treatment volumes may reduce toxicity while not increasing marginal failures, although follow-up is short. Because of the toxicity associated with treatment, novel radiotherapy strategies are being used such as stereotactic radiotherapy as well as the use of tumor genetics to identify patients most likely to benefit most from radiotherapy.

The associations of 25-hydroxyvitamin D levels, vitamin D binding protein gene polymorphisms, and race with risk of incident fracture-related hospitalization: Twenty-year follow-up in a bi-ethnic cohort (the ARIC Study).

BACKGROUND: Deficient levels of 25-hydroxyvitamin D [25(OH)D] have been associated with increased fracture risk. Racial differences in fracture risk may be related to differences in bioavailable vitamin D due to single nucleotide polymorphism (SNP) variations in the vitamin D binding protein (DBP). METHODS: We measured 25(OH)D levels in 12,781 middle-aged White and Black participants [mean age 57 years (SD 5.7), 25% Black] in the ARIC Study who attended the second examination from 1990-1992. Participants were genotyped for two DBP SNPs (rs4588 and rs7041). Incident hospitalized fractures were measured by abstracting hospital records for ICD-9 codes. We used Cox proportional hazards models to evaluate the association between 25(OH)D levels and risk of fracture with adjustment for possible confounders. Interactions were tested by race and DBP genotype. RESULTS: There were 1122 incident fracture-related hospitalizations including 267 hip fractures over a median of 19.6 years of follow-up. Participants with deficient 25(OH)D (<20 ng/mL) had a higher risk of any fracture hospitalization [HR=1.21 (95% CI 1.05-1.39)] and hospitalization for hip fracture [HR=1.35 (1.02-1.79)]. No significant racial interaction was noted (p-interaction=0.20 for any fracture; 0.74 for hip fracture). There was no independent association of rs4588 and rs7041 with fracture. However, there was a marginal interaction for 25(OH)D deficiency with rs7041 among Whites (p-interaction=0.065). Whites with both 25(OH)D deficiency and the GG genotype [i.e., with predicted higher levels of DBP and lower bioavailable vitamin D] were at the greatest risk for any fracture [HR=1.48 (1.10-2.00)] compared to Whites with the TT genotype and replete 25(OH)D (reference group). CONCLUSIONS: Deficient 25(OH)D levels are associated with higher incidence of hospitalized fractures. Marginal effects were seen in Whites for the DBP genotype associated with lower bioavailable vitamin D, but result inconclusive. Further investigation is needed to more directly evaluate the association between bioavailable vitamin D and fracture risk.