Hematopoietic cell transplantation utilization and outcomes for primary plasma cell leukemia in the current era.

The outcomes of patients with primary plasma cell leukemia (pPCL) after undergoing hematopoietic cell transplantation (HCT) in the novel agent era are unknown. We report outcomes of 348 patients with pPCL receiving autologous (auto-) HCT (n = 277) and allogeneic (allo-) HCT (n = 71) between 2008 and 2015. Median age was 60 years and 56 years for auto- and allo-HCT respectively. For auto-HCT, the 4-year outcomes were: non-relapse mortality (NRM) 7% (4-11%), relapse (REL) 76% (69-82%), progression-free survival (PFS) 17% (13-23%), and overall survival (OS) 28% (22-35%). Karnofsky performance status (KPS) > 90 and ≥very good partial response (VGPR) predicted superior OS in multi-variate analysis for auto-HCT. For allo-HCT, the 4-year outcomes were: NRM 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%). Compared with prior CIBMTR pPCL patients (1995-2006), inferior survival was noted in the current cohort (3-year OS, 39% vs. 38% in allo-HCT, and 62% vs. 35% in auto-HCT) respectively. However, we noted an increased HCT utilization, from 12% (7-21%) in 1995 to 46% (34-64%) in 2009 using SEER data (available till 2009). Despite modern induction translating to higher proportion receiving HCT, the outcomes remain poor in pPCL patients, mainly derived by high relapse rates post-HCT.

Survey on Transfusion-Transmitted Cytomegalovirus and Cytomegalovirus Disease Mitigation.

CONTEXT: - Cytomegalovirus (CMV) can be transmitted by cellular blood products, leading to severe disease in immunosuppressed patients such as neonates and transplant recipients. To mitigate transfusion-transmitted CMV (TT-CMV), "CMV-safe" blood products (leukoreduced and/or CMV-seronegative) are transfused. Attempts to develop practice guidelines for TT-CMV mitigation have been limited by paucity of high-quality clinical trials. OBJECTIVE: - To assess current TT-CMV mitigation strategies across medical institutions for specific at-risk populations. DESIGN: - Supplemental questions regarding TT-CMV and CMV disease mitigation were added to a College of American Pathologists Transfusion Medicine (Comprehensive) Participant Survey in 2015, addressing whether a given institution provided CMV-safe products for 6 at-risk patient populations. RESULTS: - Ninety percent (2712 of 3032) of institutions reported providing universally leukoreduced blood products. Among institutions without universal leukoreduction, 92% (295 of 320) provided leukoreduced products on the basis of clinical criteria. Eighty-three percent (2481 of 3004) of respondents reported having availability of CMV-seronegative products; however, wide variation in policies was reported governing CMV-seronegative product use. Among all respondents, less than 5% reported using CMV prophylaxis and monitoring in high-risk patient groups. Transplant centers reported higher rates of CMV prophylaxis (25% [97 of 394] solid organ) and monitoring (15% [59 of 394] solid organ) for CMV-negative transplant recipients. CONCLUSIONS: - Universal leukoreduction is the primary strategy for mitigating TT-CMV. While most institutions have both CMV-seronegative and leukoreduced blood products available, consensus is lacking on which patients should receive these products. High-quality studies are needed to determine if CMV-seronegative and leukoreduced blood products are needed in high-risk patient populations.

Impact of predictive scoring model and e-mail messages on African American blood donors.

BACKGROUND: Expanding the African American (AA) donor pool is critical to sustain transfusion support for sickle cell disease patients. STUDY DESIGN AND METHODS: The aims were to: 1) apply cognitive computing on donation related metrics to develop a predictive model that effectively identifies repeat AA donors, 2) determine whether a single e-mail communication could improve AA donor retention and compare retention results on higher versus lower predictive score donors, and 3) evaluate the effect of e-mail marketing on AA donor retention with culturally versus nonculturally tailored message. RESULTS: Between 2011 and 2012, 30,786 AA donors donated blood at least once on whom predictive repeat donor scores (PRDSs) was generated from donor-related metrics (frequency of donations, duration between donations, age, blood type, and sex). In 2013, 28% (8657/30,786) of 2011 to 2012 donors returned to donate on whom PRDS was validated. Returning blood donors had a higher mean PRDS compared to nonreturning donors (0.649 vs. 0.268; p < 0.001). In the e-mail pilot, high PRDS (≥0.6) compared to low PRDS (<0.6) was associated with 89% higher donor presentation rate (p < 0.001), 20% higher e-mail opening rate (p < 0.001), and, specifically among those who opened the e-mail, 159% higher presentation rate (p < 0.001). Finally, blood donation rate did not differ (p = 0.79) as a function of generic (n = 9312, 1.4%) versus culturally tailored (n = 9326, 1.3%) message. CONCLUSION: Computational algorithms utilizing readily available donor metrics can identify highly committed AA donors and in conjunction with targeted e-mail communication has the potential to increase the efficiency of donor marketing.

Impact of Uniform Methods on Interlaboratory Antibody Titration Variability: Antibody Titration and Uniform Methods.

CONTEXT: -Substantial variability between different antibody titration methods prompted development and introduction of uniform methods in 2008. OBJECTIVE: -To determine whether uniform methods consistently decrease interlaboratory variation in proficiency testing. DESIGN: -Proficiency testing data for antibody titration between 2009 and 2013 were obtained from the College of American Pathologists. Each laboratory was supplied plasma and red cells to determine anti-A and anti-D antibody titers by their standard method: gel or tube by uniform or other methods at different testing phases (immediate spin and/or room temperature [anti-A], and/or anti-human globulin [AHG: anti-A and anti-D]) with different additives. Interlaboratory variations were compared by analyzing the distribution of titer results by method and phase. RESULTS: -A median of 574 and 1100 responses were reported for anti-A and anti-D antibody titers, respectively, during a 5-year period. The 3 most frequent (median) methods performed for anti-A antibody were uniform tube room temperature (147.5; range, 119-159), uniform tube AHG (143.5; range, 134-150), and other tube AHG (97; range, 82-116); for anti-D antibody, the methods were other tube (451; range, 431-465), uniform tube (404; range, 382-462), and uniform gel (137; range, 121-153). Of the larger reported methods, uniform gel AHG phase for anti-A and anti-D antibodies had the most participants with the same result (mode). For anti-A antibody, 0 of 8 (uniform versus other tube room temperature) and 1 of 8 (uniform versus other tube AHG), and for anti-D antibody, 0 of 8 (uniform versus other tube) and 0 of 8 (uniform versus other gel) proficiency tests showed significant titer variability reduction. CONCLUSION: -Uniform methods harmonize laboratory techniques but rarely reduce interlaboratory titer variance in comparison with other methods.

Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR.

Engraftment for CD34 selected stem cell products is not compromised by cryopreservation.

BACKGROUND: The coinfusion of haploidentical CD34+ selected peripheral blood stem cell products with umbilical cord blood (UCB) provides early neutrophil recovery, long-term UCB engraftment, and a lower incidence of graft-versus-host disease; however, this complex transplant presents a scheduling challenge for both the cellular therapy laboratory and the clinical team. Cryopreservation of the haploidentical product can facilitate scheduling, but has been previously shown to be associated with infusion reactions and delayed platelet (PLT) engraftment in allogeneic hematopoietic progenitor cell transplant. STUDY DESIGN AND METHODS: To test whether cryopreservation of the CD34+ selected product compromises the graft, we compared neutrophil and PLT engraftment kinetics for patients receiving freshly infused or cryopreserved products. Seventy-two products collected from haploidentical related donors were CD34+ selected and infused in a combined transplant with UCB: 32 were cryopreserved before infusion and 40 were infused fresh. RESULTS: No adverse infusion events were reported in either group and there was no difference in neutrophil and PLT engraftment time between fresh and cryopreserved products. CONCLUSION: Cryopreservation of a CD34+-selected product can be safely used in a combined transplant with UCB and does not affect engraftment time.

How we handled the dextran shortage: an alternative washing or dilution solution for cord blood infusions.

Dextran 40 is the main component of the solution used to wash or dilute thawed cord blood unit (CBU) products for stem cell transplant. Dextran 40 became unavailable in the United States as of April 2014. Like many other cellular therapy laboratories in the United States, we found ourselves with limited dextran 40 inventory, a growing CBU transplant requirement, and no alternative solution. Since there are no published alternative washing solutions for cryopreserved CBU we had to develop and validate a new solution rapidly. We chose to validate hydroxyethyl starch (HES) due to its similar ability to stabilize red blood cells and reduce sudden changes in osmolality that occur during thawing. For the validation we used 3 CBUs and thawed and washed each unit with both dextran 40- and HES-based solutions; thus, each CBU served as its own control. We observed no significant differences between the two wash solutions for all the monitored variables including cell viability, cell recovery, or potency measured by colony-forming cell assay. Based on this initial validation we began using HES-albumin for CBU washing after our supply was exhausted. Our initial experience with the first 16 CBU transplants after validation indicates safe infusion and preliminary cord engraftment.

Genetic and molecular targets in lymphoma: implications for prognosis and treatment.

Lymphomas are the most common hematologic malignancies with approximately 79,000 new cases estimated for 2013 in the USA. Despite improved outcomes, relapse or recurrence remains a common problem with conventional cytotoxic therapy. Recently, many genetic and molecular mechanisms that drive various cellular events like apoptosis, angiogenesis and cell motility have been more clearly delineated. These new findings, coupled with the advent of high-throughput screening technology have led to the discovery of many compounds that can target specific mutations and/or influence deregulated transcription. In this review, we intend to provide a concise overview of genetic and molecular events that drive cellular processes in lymphomas and represent potential therapeutic targets. Additionally, we briefly discuss the prognostic significance of select biological markers.

Taxanes: impact on breast cancer therapy.

Taxanes play an important role in the management of early-stage and advanced-stage breast cancer. Initial studies sought to determine whether there was antitumor activity in patients with metastatic disease, and identify the optimal agent, dose, and schedule. Subsequent studies established a role for both paclitaxel and docetaxel as adjuvant therapy, determined whether they should be administered concurrently or sequentially with other cytotoxic agents, and also determined the optimal agent, dose, and schedule. Taxanes have also been combined with biologic agents, including anti-HER2-directed therapy and antiangiogenic therapy. The aim of this article is to provide a review of pivotal trials evaluating taxane therapy that have informed the current approach for the use of taxanes in early-stage and advanced-stage breast cancer.

Signal transduction inhibitors in treatment of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-ß, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-ß signaling has been therapeutically targeted by small molecule inhibitor of the TGF-ß receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-ß receptor kinase inhibition, members of TGF-ß super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.

Changes in intern attitudes toward medical error and disclosure.

CONTEXT: The 2000 Institute of Medicine report, 'To Err is Human: Building a Safer Health System', focused the medical community on medical error. This focus led to educational initiatives and legislation designed to minimise errors and increase their disclosure. OBJECTIVES: This study aimed to investigate whether increased general awareness about medical error has affected interns' attitudes toward medical error and disclosure by comparing responses to surveys of interns carried out at either end of the last decade. METHODS: Two cohorts of interns for the academic years 1999, 2000 and 2001 (n = 304) and 2008 and 2009 (n = 206) at a university hospital were presented with two hypothetical scenarios involving errors that resulted in, respectively, no permanent harm and an adverse outcome. The interns were questioned regarding their likely responses to error and disclosure. RESULTS: We collected 510 surveys (100% response rate). For both scenarios, the percentage of interns who would be willing to fully disclose their mistakes increased substantially from 1999-2001 to 2008-2009 ('no permanent harm': 38% and 71%, respectively [p < 0.001]; 'adverse outcome': 29% and 55%, respectively [p < 0.001]). About two thirds of fully disclosing interns in both scenarios believed 'the patient's right to full information' to be the primary reason for their disclosure. Fear of litigation in response to error disclosure decreased (70% and 52%, respectively), the percentage of interns who felt that 'medical mistakes are preventable if doctors know enough' decreased (49% and 31%, respectively), belief that competent doctors keep emotions and uncertainties to themselves decreased (51% and 14%, respectively), and agreement with leaving medicine if one (as an intern) caused harm or death decreased (50% and 3%, respectively). Prior training about medical mistakes increased more than four-fold between the cohorts. CONCLUSIONS: This comparison of intern responses to a survey administered at either end of the last decade reveals that there may have been some important changes in interns' intended disclosure practices and attitudes toward medical error.

Role of plasmapheresis in the management of myeloma kidney: a systematic review.

Multiple myeloma complicated by acute renal failure is a diagnosis often encountered by the practicing nephrologist. The role of plasmapheresis in such patients has been of interest for decades. Three randomized controlled trials (RCTs) and multiple observational trials have evaluated the potential role of plasmapheresis in the management of this condition. This systematic review presents the results of these trials regarding survival benefits, recovery from dialysis, and improvement in renal function. A comprehensive search revealed 56 articles. Of these, only 8 articles met our inclusion criteria (3 RCTs, 1 correction of results, and 4 observational trials). Two of the 3 RCTs showed no difference in survival benefit. Two of the 3 RCTs showed a greater percentage of patients stopping dialysis in the intervention group; however, these results were not reproduced in the largest trial. All the studies showed an improvement in renal function for patients receiving plasmapheresis; however, only 2 RCTs and 1 retrospective study showed a statistically significant improvement in renal function among patients who received plasmapheresis in comparison with a control group. Our systematic review does not suggest a benefit of plasmapheresis independent of chemotherapy for multiple myeloma patients with acute renal failure in terms of overall survival, recovery from dialysis, or improvement in renal function.

Granuloma annulare.

We present a case of a 77-year-old, diabetic male with a 20-year history of a migratory erythematous, asymptomatic, generalized, nonscaly, and nonitchy rash that started over the dorsum of his left hand. On examination, there were multiple annular erythematous plaques, distributed symmetrically and diffusely over his torso and arms, with central clearing and no scales. A punch biopsy of the skin helped us to arrive at the diagnosis of a generalized granuloma annulare (GA). GA is a benign, self-limiting skin condition of unknown etiology that is often asymptomatic. The cause of this condition is unknown, but it has been associated with diabetes mellitus, infections such as HIV, and malignancies such as lymphoma. These lesions typically start as a ring of flesh-colored papules that slowly progress with central clearing. Lack of symptoms, scaling, or associated vesicles helps to differentiate GA from other skin conditions such as tinea corporis, pityriasis rosea, psoriasis, or erythema annulare centrifugum. Treatment is often not needed as the majority of these lesions are self-resolving within 2 years. Treatment may be pursued for cosmetic reasons. Available options include high-dose steroid creams, PUVA, cryotherapy, or drugs such as niacinamide, infliximab, Dapsone, and topical calcineurin inhibitors.

Intracranial tumor lysis and cerebral edema after administration of intrathecal methotrexate: a case report and discussion.

Methotrexate is a common agent used in the management of hematological malignancies, but is often associated with the development of diverse central nervous system adverse events, such as seizures. We present a case of seizures after intrathecal administration of methotrexate, during the management of diffuse large B-cell lymphoma. There was complete resolution of the CNS lesions after chemotherapy along with the interval development of diffuse cerebral edema. We hypothesize that tumor lysis is the underlying mechanism of this untoward event, resulting in the corresponding clinical presentation.

Two "childhood" malignancies in an elderly individual: a case report and discussion.

Rhabdomyosarcoma (RMS) is the most common soft-tissue tumor in childhood, but is extremely rare in elderly. We present a rare case of cardiac RMS, which developed 1 year after the diagnosis and management of acute lymphoblastic leukemia in a 68-year-old female. The occurrence of such phenomena is intriguing, especially in an individual without prior history of malignancy at a younger age. Through the review of the existing literature, we attempt to approach the pathogenesis and clinical manifestations of this rare clinical entity.