HLA-DR-DQ associations, combined with PLASMIC score, are reliable predictors of acquired thrombotic thrombocytopenic purpura (aTTP) and aid in differentiating aTTP from other thrombotic microangiopathies.

BACKGROUND: Thrombotic microangiopathies (TMA) are a group of disorders with overlapping clinical features that require urgent intervention. Treatment is based on the recognition of the TMA type, which is often challenging. The aim of this study was to identify specific HLA associations with different TMA types to aid rapid diagnosis and appropriate treatment, since the HLA assay can be completed within five hours. METHODS: All 86 consecutive patients who presented to the University of Arkansas for Medical Sciences between May 2013 and January 2021 with a presumptive diagnosis of TMA were included in this study. HLA typing was performed and correlated with other clinical and laboratory studies. RESULTS: In comparison with other types of TMA, patients with acquired thrombotic thrombocytopenic purpura (aTTP) showed increased frequencies of HLA-DRB1*11, HLA-DQB1*03:01/19, HLA-DRB1*08 and HLA-DRB3. Combining the presence of these HLA associations with a PLASMIC score of 6 or more achieved a higher positive predictive value (90%) for identifying aTTP than the PLASMIC score alone (69%). In comparison with other TMA types, patients with aTTP showed decreased frequencies of HLA-DRB4, HLA-DRB1*07, HLA-DQB1*02. The HLA-DRB1*07/DQB1*02 was not observed in any aTTP patients (negative predictive value: 100%), and thus the presence of this haplotype essentially rules out aTTP. Further, HLA-DRB1*11/DQB1*03:01/19 was absent in atypical hemolytic uremic syndrome patients. CONCLUSION: HLA alleles can be used as an adjunct for the rapid assessment of TMA and can help to differentiate it from other primary and secondary forms of TMA, allowing for earlier definitive therapy.

Three years of maintenance with VRD in multiple myeloma: results of total therapy IIIB with a 15-year follow-up.

ABSTRACT: The total therapy (TT) IIIB phase 2 study incorporated bortezomib into tandem melphalan-based hematopoietic stem cell transplantation with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide for induction/consolidation and bortezomib, lenalidomide, and dexamethasone (VRD) for maintenance in patients with newly diagnosed multiple myeloma (MM). This updated analysis presents a 15.4-year median follow-up. Of 177 patients, 21% patients had gene expression profile (GEP)-defined high-risk MM. 15-year progression free survival (PFS) was 27.9%. Median PFS was better in GEP-defined low-risk patients at 7.8 years and in International Staging System stage 1 patients at 8.7 years. Overall, median OS was 9.1 years, and 15-year overall survival (OS) was 35.9%. GEP-defined low-risk patients' median OS was 11.2 years, and that of GEP-defined high-risk patients was 2.8 years. There was no difference in OS between TT IIIB and TT IIIA. This study includes the longest follow-up of patients treated with maintenance VRD reported to date. In patients with GEP-defined low-risk, nearly half and one-third of patients without ongoing treatment showed no signs of progression at 10 and 15 years, respectively. One-third of patients survived more than 15 years, but 3 years of VRD maintenance did not improve outcomes for patients with GEP-defined high-risk MM. The study was registered on www.clinicaltrials.gov as #NCT00572169.

Barriers and facilitators to cord blood banking among pregnant women at a university obstetric clinic.

BACKGROUND: Cord blood (CB) is a cell source for hematopoietic stem cell transplantation. In 2019, the percentage of births with CB collected for banking was only 3% nationally and 0.05% in our state. To increase CB donations, we need to understand pregnant women's awareness and knowledge of, plus barriers and facilitators to, CB banking (CBB). STUDY DESIGN AND METHODS: We recruited 289 women in their third trimester from an academic obstetric clinic between October 2020 and May 2021. Women attending this clinic come from all parts of the state in addition to local city residents. After agreeing to participate, participants completed a survey using Research Electronic Data Capture (REDCap). Data were analyzed using SAS version 9.4. RESULTS: Exactly 58.9% of participants had heard of CBB, but only 26.53% understood its purpose; 10.03% indicated someone had discussed CBB with them, and 61.3% were undecided about it. The preferred source of information was the clinic provider (82.1%), followed by CB bank staff (36.8%). The requested mode for receiving information was face-to-face with their provider, including written materials. Income, education, and marital status did not have a significant influence on information preferences. DISCUSSION: Lack of knowledge continues to be a major barrier to CBB. Developing educational interventions based on womens' preferences may increase understanding of CBB. Study participants preferred that the healthcare provider deliver this information. This study was done in a primarily rural, southern state, while previous studies were in larger metropolitan areas, yet results are comparable.

A hands-on resident umbilical cord blood educational curriculum compared to online education of post-residency obstetricians: comparison of the volume of collected cord blood units.

BACKGROUND: Umbilical cord blood unit (CBU) volume is a predictor of its later clinical utility. Many studies suggest the need to increase the volume of CBU collected, but most obstetrical providers receive no formal collection training. STUDY DESIGN AND METHODS: We designed and implemented an educational curriculum for obstetrics residents aimed at improving collection methods and increasing CBU volumes (CBUV). Residents were required to attend grand rounds and interactive didactic sessions on CBU collection followed by work with a simulated collection kit and then performed training collections under observation by a trained collector. Residents completed a self-assessment after each collection and received immediate personal feedback. Outside providers (non-UAMS physicians) received written instructional materials with the collection kits and had access to online training materials. They received feedback regarding their collection via standard mail. CBU donated to Cord Blood Bank of Arkansas for public use from 2014-2016 were analyzed. CBUV from residents were compared to those from outside providers. RESULTS: After adjusting for maternal age and race, infant gender, gestational age, and birth weight, the least-squared mean CBUV was 92.1 mL for UAMS collections and 65.5 mL for outside provider collections. The improved CBUV of UAMS providers is statistically significant (p < 0.0001). CONCLUSION: Our educational intervention was successful, and we believe that it can be replicated in other obstetrical residency programs. Cord blood collection education involving hands-on training with a model and immediate feedback improves CBUV, decreases kit waste, increases likelihood of CBU storage, and, therefore, inventory for transplantation.

Complement Regulatory Genetic Mutations in the Setting of Autoimmune Thrombotic Thrombocytopenic Purpura: A Case Series.

OBJECTIVE: To explore the benefits of adding eculizumab for the treatment of refractory autoimmune thrombotic thrombocytopenic purpura (iTTP) with complement dysregulation. PATIENTS AND METHODS: From January 1, 2014, through July 1, 2017, we identified patients with iTTP defined by ADAMTS13 (disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) levels less than 5% and the presence of ADAMTS13 inhibitor. Patients who progressed after receiving standard of care management for iTTP were subjected to a comprehensive evaluation to look for evidence of complement activation. Herein, we share our single-institute experience regarding the clinical course and treatment algorithm for 3 patients with refractory iTTP. RESULTS: All the patients had clinical deterioration despite treatment with plasma exchange, corticosteroids, rituximab, and vincristine, which prompted us to look for evidence of complement activation and associated genetic mutations. Complement-related genetic aberrations were present in all 3 patients, who had had different degrees of complement activation. The first 2 patients did not benefit from eculizumab when treatment was started before complete clearance of inhibitors to ADAMTS13. However, they had durable remissions when eculizumab was introduced after clearance of ADAMTS13 inhibitors. The third patient started eculizumab therapy after inhibitor levels were undetectable. CONCLUSION: We found eculizumab therapy to be effective in all 3 patients. However, its efficacy was prominent only after clearance of antibodies against ADAMTS13 via therapeutic plasma exchange.

ADAMTS13 Testing Methodologies and Thrombotic Thrombocytopenic Purpura (TTP): Conflicting Results Can Pose a Clinical Dilemma.

ADAMTS13 testing plays a critical role in confirming the clinical diagnosis of acquired idiopathic thrombotic thrombocytopenic purpura (TTP) and distinguishing it from other forms of thrombotic microangiopathies (TMA). Serial measurements of ADAMTS13 activity and inhibitor levels are also helpful in determining response to treatment and/or subsequent relapses. Numerous ADAMTS13 assays have been developed recently, including some with rapid turnaround times. Despite the good inter-assay correlation of different ADAMTS13 methodologies in published case studies, discrepancies have been shown to occur. Here we present a case where discrepant results were obtained using two different assays, posing a clinical treatment dilemma.

Optia® continuous mononuclear collection (CMNC) system is a safe and efficient system for hematopoietic progenitor cells-apheresis (HPC-a) collection and yields a lower product hematocrit (HCT%) than the COBE® spectra system: A retrospective study.

PURPOSE: We evaluated the Optia® continuous mononuclear collection (CMNC) system for hematopoietic progenitor cell-apheresis (HPC-A) collection (Terumo BCT, Lakewood, CO) compared to the COBE® Spectra (Terumo BCT, Lakewood, CO), including both large volume leukapheresis (LVL) and non-LVL collections. METHODS: We performed a retrospective data analysis of all autologous HPC-A collections with the Optia® CMNC system (n = 93; LVL = 59, non-LVL = 34) since implementation at our institution and compared it with a similar number of concurrent collections utilizing the COBE® Spectra (n = 96; LVL = 68, non-LVL = 28). The population studied included multiple myeloma (62 patients/171 collections) and lymphoma (5 patients/18 collections). Mobilization was achieved using chemotherapy + G-CSF (n = 108), chemotherapy + G-CSF + plerixafor (n = 67), G-CSF alone (n = 10), or G-CSF + plerixafor (n = 4). Based on our minimum predicted collection formula and the collection goal, 7-30 L of whole blood was processed. Per protocol, a minimum of 2 days of collection was performed. RESULTS: HPC-A collected on Optia® CMNC had lower %HCT than those collected on COBE® Spectra (3.7 versus 4.3%, P = .029). There were no statistically significant differences between the two devices for other variables examined, including preapheresis WBC count and CD34+ cell count, procedure time, whole blood volume processed, collection efficiency (CE2), % platelet loss and throughput. CE2 for both devices was higher when <30 L of whole blood volume was processed. A linear correlation was noted between the preapheresis CD34+ cell count and CD34+ cells collected. No adverse events or bleeding episodes were noted, even when acetyl salicyclic acid (ASA) was given. CONCLUSIONS: Optia® CMNC system is equivalent to the COBE® Spectra, with significantly lower product HCT%.

M1 and M2 macrophages differentially regulate hematopoietic stem cell self-renewal and ex vivo expansion.

Uncovering the cellular and molecular mechanisms by which hematopoietic stem cell (HSC) self-renewal is regulated can lead to the development of new strategies for promoting ex vivo HSC expansion. Here, we report the discovery that alternative (M2)-polarized macrophages (M2-MΦs) promote, but classical (M1)-polarized macrophages (M1-MΦs) inhibit, the self-renewal and expansion of HSCs from mouse bone marrow (BM) in vitro. The opposite effects of M1-MΦs and M2-MΦs on mouse BM HSCs were attributed to their differential expression of nitric oxide synthase 2 (NOS2) and arginase 1 (Arg1), because genetic knockout of Nos2 and Arg1 or inhibition of these enzymes with a specific inhibitor abrogated the differential effects of M1-MΦs and M2-MΦs. The opposite effects of M1-MΦs and M2-MΦs on HSCs from human umbilical cord blood (hUCB) were also observed when hUCB CD34+ cells were cocultured with M1-MΦs and M2-MΦs generated from hUCB CD34- cells. Importantly, coculture of hUCB CD34+ cells with human M2-MΦs for 8 days resulted in 28.7- and 6.6-fold increases in the number of CD34+ cells and long-term SCID mice-repopulating cells, respectively, compared with uncultured hUCB CD34+ cells. Our findings could lead to the development of new strategies to promote ex vivo hUCB HSC expansion to improve the clinical utility and outcome of hUCB HSC transplantation and may provide new insights into the pathogenesis of hematological dysfunctions associated with infection and inflammation that can lead to differential macrophage polarization.

Acetylsalicylic Acid During Leukapheresis Reduces the Incidence of Clotting in Hematopoietic Progenitor Cell Products.

INTRODUCTION: Clots may be seen during hematopoietic progenitor cell (HPC) collection or on product arrival to the cell therapy processing laboratory. We have always given one 81 mg acetylsalicylic acid (ASA) when clotting is seen during collection if there is no allergy, but hypothesized that the incidence of clotting would decrease if ASA was given to all autologous collectors with a platelet count of ≥80×109/L prior to collection (pre-emptively). METHODS: Autologous HPC were collected using the Spectra Optia instrument or Cobe Spectra instrument (Terumo BCT®, Lakewood, CO) with heparinized citrate. A retrospective review was performed to determine the total number of HPC products, including products with clots, collected between September 2010 and August 2013 (group 1). All autologous HPC collectors from September 2013 onwards were given ASA pre-emptively if their platelet count was ≥80×109/L (group 2), and a similar review was performed in this group. We included the cell density and platelet count of the HPC products and the platelet count of the patient in the data collected. We reviewed procedure notes for adverse events or bleeding. RESULTS: A total of 2574 HPC products were collected between September 2010 and August 2013; clotting was observed in 66 HPC products (66/2574; 2.56%). A total of 1906 HPC products were collected between November 2013 and October 2016; clotting was observed in 24 HPC products (24/1906; 1.25%). Thus an overall reduction was seen in incidence of clotting between groups 1 and 2 (2.56% versus 1.25; P=0.002). Since not all collectors in group 2 received pre-emptive ASA, we reviewed the incidence of clotting within this group. A decrease in incidence of clots was noted with preemptive ASA (group 2A) (5/512, 0.97%) versus no ASA (group 2B) (19/1394, 1.36%), but this was not statistically significant. The mean cell density of the HPC products did not differ significantly between these two groups (group 2A and 2B) but a higher platelet count was observed in the pre-emptive ASA group as expected (group 2A) (P=0.004). Multivariate logistic analysis after adjusting for platelet count of the HPC products showed a trend towards reduced incidence of clotting in the pre-emptive ASA group (group 2A); however no association was seen after adjusting for the cell density of HPC products, nor was an association between patient's platelet count and incidence of clotting seen. None of the collectors who received ASA suffered any adverse events, including bleeding. CONCLUSION: We observed an overall reduction in the incidence of clotting in our HPC products after initiating pre-emptive ASA usage (2.56% versus 1.25%; P=0.002). A trend towards lower incidence of clotting was noted when further analysis was performed to include pre-emptive ASA usage and platelet count of the HPC products. Although the overall incidence of clotting was very small (<3.0%), giving ASA pre-emptively further reduced the incidence of clotting and thus prevented wastage/cell loss of HPC products.

Percent cPRA (Calculated Panel Reactive Antibody) Value Predicts Percent of Positive Platelet Crossmatches.

BACKGROUND: Platelet refractoriness or lack of platelet increase after platelet transfusion is seen in patients receiving chronic platelet transfusion support. Antibodies may develop against human platelet antigens (HPA) and/or against HLA class I antigens. Crossmatch (XM) compatible platelets or HLA-identical or HLA-compatible platelets are typically used to manage transfusion refractoriness. We aimed to determine if percent calculated Panel Reactive Antibody (% cPRA) against class I HLA antigens could predict percent positive platelet XM when looking for compatible transfusion products. METHODS: A retrospective review of all platelet XM performed at our institution between 2008-2012 was performed, and patient characteristics recorded. For each patient, the percentage of all positive platelet XM performed was calculated and compared with the corresponding % cPRA levels against class I HLA antigens. RESULTS: Mean and median % positive platelet XM for all 50 patients tested in the period 2008-2012 were 61% and 60% (range 0-100%), respectively. Mean and median % cPRA levels were 66% and 68% (range 0-100%), respectively. No correlation was seen between age, sex, race, or diagnosis and positive platelet XM results. CONCLUSION: The results of our study indicate that the % cPRA correlates well with the % positive platelet XM. Thus, a higher % cPRA alerts the blood bank that additional platelets will be required for XM and/or that it would be beneficial to request HLA-identical or compatible units.

Acquired thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome successfully treated with eculizumab.

Acquired idiopathic thrombotic thrombocytopenic purpura is a life-threatening disease with a mortality of up to 90%, if not promptly recognized and treated. We report a 64-year-old woman with this condition who presented with left-sided weakness and seizure-like activity preceded by headache and easy bruising. She did not achieve optimal response to plasma exchange, corticosteroids, rituximab, and vincristine. We initiated treatment with eculizumab, following which she had durable remission that continued for 30 months after discontinuation of the drug. We later found that our patient has homozygous deletion in two closely related genes, complement factor H-related 1 and complement factor H-related 3.

Adverse Metaphase Cytogenetics Can Be Overcome by Adding Bortezomib and Thalidomide to Fractionated Melphalan Transplants.

Purpose: To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy.Experimental Design: A total of 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed one instead of two inductions and consolidations. To compensate for potential loss of efficacy of TT4-L, bortezomib and thalidomide were added to fractionated melphalan 50 mg/m2/d for 4 days.Results: Grade ≥3 toxicities and treatment-related mortalities were not reduced in TT4-L. Complete response (CR) rates were virtually identical (P = 0.2; TT4-S, 59%; TT4-L, 61% at 2 years), although CR duration was superior with TT4-S (P = 0.05; TT4-S, 87%; TT4-L, 81% at 2 years). With a median follow-up of 4.5 years, there was no difference in overall survival (OS) and progression-free survival (PFS). Whereas metaphase cytogenetic abnormalities (CAs) tended to be an adverse feature in TT4-S, as with predecessor TT trials, the reverse applied to TT4-L. Employing historical TT3a as training and TT3b as test set, 51 gene probes (GEP51) significantly differentiated the presence and absence of CA (q < 0.0001), seven of which function in DNA replication, recombination, and repair. Applying the GEP51 model to clinical outcomes, OS and PFS were significantly inferior with GEP51/CA in TT4-S; such a difference was not observed in TT4-L.Conclusions: We identified a prognostic CA-linked GEP51 signature, the adversity of which could be overcome by potentially synergizing anti-multiple myeloma effects of melphalan and bortezomib. These exploratory findings require confirmation in a prospective randomized trial. Clin Cancer Res; 23(11); 2665-72. ©2016 AACR.

Flow Cytometric Panel-Reactive Antibody Results and the Ability to Find Transfusion-Compatible Platelets after Antibody-Desensitization for Allogeneic Bone Marrow Transplant.

BACKGROUND: Panel reactive antibody (PRA) reduction protocols are used to decrease anti-HLA antibodies with concomitant PRA monitoring as a measure of successful treatment prior to organ and haploidentical blood and marrow transplant (BMT). We hypothesized that the more sensitive flow cytometry (FC) based assays for PRA [FlowPRA® and Luminex® based Single Antigen Bead (SAB)] would also correlate with the ability to find compatible platelets for allosensitized recipients. METHODS: A female patient with myelodysplastic syndrome and a high HLA class I PRA [>90% PRA and cPRA by complement-dependent cytotoxicity (CDC) assay and Flow PRA] required allogeneic BMT. Baseline HLA Class I and class II antigen typing was performed and a matched sibling donor was identified. Although baseline anti-HLA class I and class II antibodies measured by FC and CDC revealed no donor specific antibodies (DSA), the decision was made to attempt antibody desensitization to facilitate platelet transfusion during BMT. FC and CDC assays were performed to determine anti-HLA class I antibodies and cPRA/%PRA prior to starting desensitization and at the end of desensitization. Over the course of desensitization and BMT, a total of 194 apheresis platelet units underwent cross-match (XM) using Capture-P®. We compared temporally-related PRA results with platelet XM results. RESULTS: High PRA by FC or CDC assays correlates with a high % of XM-positive (incompatible) platelet units. When the CDC PRA fell to 2% after desensitization, platelet XM incompatibility fell from 100% to 63% positive (incompatible). When the FC PRA fell to 5% the positive platelet XM fell to 5%. CONCLUSIONS: Antibody desensitization facilitated platelet transfusion. PRA determination by FC appeared better correlated than determination by CDC with the ability to find XM-compatible platelets.

Hemoglobin Variants Acquired Post-Exchange Transfusion in Pediatric Sickle Cell Disease (SCD) Patients.

BACKGROUND: Many SCD patients receive chronic transfusions for prevention or treatment of disease related complications. Complications of the chronic transfusion noted in these patients include allergic reactions, transfusion transmitted infections, iron overload, and alloantibody formation. Even though hemoglobin (Hb) variants are prevalent in the general population, reports of transfusion-acquired Hb variants are rare. We performed a retrospective analysis on all SCD patients who underwent red cell exchange (RBCEx) transfusions at our institution during 2011-2013 to identify the presence of Hb variants acquired as a result of RBCEx. RESULTS: We found 66 occurrences of acquired Hb variants in 30 SCD patients during the period examined. The most commonly acquired Hb variant was Hemoglobin C (HbC) (64/66 occurrences). More than half of the patients (19/30) acquired HbC on multiple occasions (2-6 times). One patient acquired HbJ and another patient acquired HbD/G in addition to HbC. The segments from donor units were available in some of these cases and hemoglobin electrophoresis (HBE) was performed to confirm the presence of the variant Hb in the donor segments corresponding to that seen on the post-RBCEx sample. CONCLUSIONS: Heterozygous donors are asymptomatic and show no abnormalities during donor screening. Since HBE is not routinely performed on the donor specimen, it may go unrecognized until the post-transfusion recipient results pose diagnostic difficulties. There are no definitive guidelines on deferring these donors; hence one should be cognizant of these findings to prevent misdiagnosis. In a population where HbS negative blood is routinely requested, the effect of other Hb variants remains unknown. None of the patients in our study showed any adverse events due to the acquired Hb variants; however, this is of special concern in the pediatric population where a single RBC unit can contribute a significant portion of the exchanged blood volume. Additionally, donor centers may need mechanisms to confirm the findings and counsel the donors as needed.

Rituximab and intermediate-purity plasma-derived factor VIII concentrate (Koate®) as adjuncts to therapeutic plasma exchange for thrombotic thrombocytopenic purpura in patients with an ADAMTS13 inhibitor.

Thrombotic thrombocytopenic purpura (TTP) results from a congenital or acquired deficiency of the von Willebrand factor (vWF)-cleaving protease ADAMTS13. The disease can be fatal and hence treatment should be initiated promptly. Therapeutic plasma exchange (TPE) remains the standard treatment along with adjunct therapies including steroids and immunosuppressive drugs. Addition of rituximab to TPE has been shown to be beneficial in refractory/relapsing TTP; however, TPE results in removal of rituximab from the circulation requiring more frequent dosing of rituximab to achieve a favorable outcome. The intermediate-purity plasma-derived Factor VIII concentrate (FVIII) Koate® contains the highest amount of ADAMTS13 activity yet reported and has been used successfully in treating congenital TTP. Here we report our experience with addition of this FVIII concentrate to rituximab, corticosteroids and TPE in three TTP patients with an ADAMTS13 inhibitor to permit withholding TPE for 48 h after rituximab infusion.

Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients.

Highly activated/expanded natural killer (NK) cells can be generated by stimulation with the human leukocyte antigen-deficient cell line K562, genetically modified to express 41BB-ligand and membrane-bound interleukin (IL)15. We tested the safety, persistence, and activity of expanded NK cells generated from myeloma patients (auto-NK) or haploidentical family donors (allo-NK) in heavily pretreated patients with high-risk relapsing myeloma. The preparative regimen comprised bortezomib only or bortezomib and immunosuppression with cyclophosphamide, dexamethasone, and fludarabine. NK cells were shipped overnight either cryopreserved or fresh. In 8 patients, up to 1×108 NK cells/kg were infused on day 0 and followed by daily administrations of IL2. Significant in vivo expansion was observed only in the 5 patients receiving fresh products, peaking at or near day 7, with the highest NK-cell counts in 2 subjects who received cells produced in a high concentration of IL2 (500 U/mL). Seven days after infusion, donor NK cells comprised >90% of circulating leukocytes in fresh allo-NK cell recipients, and cytolytic activity against allogeneic myeloma targets was retained in vitro. Among the 7 evaluable patients, there were no serious adverse events that could be related to NK-cell infusion. One patient had a partial response and in another the tempo of disease progression decreased; neither patient required further therapy for 6 months. In the 5 remaining patients, disease progression was not affected by NK-cell infusion. In conclusion, infusion of large numbers of expanded NK cells was feasible and safe; infusing fresh cells was critical to their expansion in vivo.

Autologous Graft versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma.

Autologous graft versus host disease (autoGVHD) is a rare transplant complication with significant morbidity and mortality. It has been hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through dysregulation of the immune response resulting from either their disease, the immunomodulatory agents (IMiDs) used to treat it, or transplant conditioning regimen. Hematopoietic progenitor cell (HPC) products were available from 8 multiple myeloma patients with biopsy-proven autoGVHD, 16 matched multiple myeloma patients who did not develop autoGVHD, and 7 healthy research donors. The data on number of transplants prior to developing autoGVHD, mobilization regimens, exposure to proteasome inhibitors, use of IMiDs, and class I human leukocyte antigen types (HLA A and B) were collected. The HPC products were analyzed by flow cytometry for expression of CD3, CD4, CD8, CD25, CD56, and FoxP3. CD3(+) cell number was significantly lower in autoGVHD patients compared to unaffected controls (P = 0.047). On subset analysis of CD3(+) cells, CD8(+) cells (but not CD4(+) cells) were found to be significantly lower in patients with autoGVHD (P = 0.038). HLA-B55 expression was significantly associated with development of autoGVHD (P = 0.032). Lower percentages of CD3(+) and CD8(+) T-cells and HLA-B55 expression may be predisposing factors for developing autoGVHD in myeloma.

Analysis of CD34+ cell collection using two mobilization regimens for newly diagnosed multiple myeloma patients reveals the separate impact of mobilization and collection variables.

Mobilization regimens for CD34+ cells have generally been judged successful based on the number of cells collected without evaluating mobilization separately from collection. Using retrospective data for patients who collected CD34+ cells on Total Therapy protocols 3a/3b (VTD-PACE) and Total Therapy 4/5 using a novel regimen that added low dose melphalan to VTD-PACE (MVTD-PACE), we analyzed mobilization and collection variables separately. A significant difference favoring MVDT-PACE was found in mean CD34+ cells/µL on day 2 of collection and in mean ratio of CD34+ cells/µL on day 2 to day 1. However, because apheresis variables and growth factor dose during collection were manipulated to optimize individual collections, the two regimens were not significantly different when the mean total CD34+ cells ×10(6) /kg collected was compared. Thus, when evaluating a chemotherapy regimen or new growth factor for mobilization, it is important to realize that total CD34+ cells collected is dependent on both mobilization and collection variables.

Risk factors for MDS and acute leukemia following total therapy 2 and 3 for multiple myeloma.

Lenalidomide has been linked to myelodysplastic syndrome (MDS) after autotransplants for myeloma. Total therapy trials (TT; TT2(-/+) thalidomide) and TT3 (TT3a with bortezomib, thalidomide; TT3b with additional lenalidomide) offered the opportunity to examine the contribution of these immune-modulatory agents to MDS-associated cytogenetic abnormalities (MDS-CA) and clinical MDS or acute leukemia ("clinical MDS/AL"). Of 1080 patients with serial cytogenetic studies, MDS-CA occurred in 11% and clinical MDS/AL in 3%. Risk features of MDS-CA included TT3b, age ≥65 years, male gender, levels of ß-2-microglobulin >5.5 mg/L, and multiple myeloma relapse. Clinical MDS/AL occurred less frequently in the control arm of TT2 and more often with TT3a and TT3b. Since MDS-CA often antedated clinical disease, periodic cytogenetic monitoring is recommended. Larger CD34 quantities should be collected upfront as the risk of MDS could be reduced by applying higher CD34 doses with transplant. Thus, treatment, host, and myeloma features could be linked to MDS development after therapy for this malignancy. This trial was registered at www.clinicaltrials.gov: TT3A: NCT00081939, TT3B: NCT00572169.