CD34+ Cell Mobilization, Autograft Cellular Composition and Outcome in Mantle Cell Lymphoma Patients.

Backgound: Autologous stem cell transplantation (ASCT) is a standard treatment in transplant-eligible mantle cell lymphoma (MCL) patients after first-line chemoimmunotherapy. Study Design and Methods: This prospective multicenter study evaluated the impact of CD34+ cell mobilization and graft cellular composition analyzed by flow cytometry on hematologic recovery and outcome in 42 MCL patients. Results: During CD34+ cell mobilization, a higher blood CD34+ cell count (>30 × 106/L) was associated with improved overall survival (median not reached [NR] vs. 57 months, p = 0.04). The use of plerixafor did not impact outcome. Higher number of viable cryopreserved graft CD34+ cells (>3.0 × 106/kg) was associated with faster platelet (median 11 vs. 15 days, p = 0.03) and neutrophil (median 9 vs. 10 days, p = 0.02) recovery posttransplant. Very low graft CD3+CD8+ cell count (≤10 × 106/kg) correlated with worse progression-free survival (PFS) (HR 4.136, 95% CI 1.547-11.059, p = 0.005). On the other hand, higher absolute lymphocyte count >2.5 × 109/L at 30 days after ASCT (ALC-30) was linked with better PFS (median NR vs. 99 months, p = 0.045) and overall survival (median NR in either group, p = 0.05). Conclusions: Better mobilization capacity and higher graft CD3+CD8+ cell count had a positive prognostic impact in this study, in addition to earlier lymphocyte recovery (ALC-30>2.5 × 106/L). These results need to be validated in another study with a larger patient cohort.

Loss of CD34+ Cells and Effect of the Number of Viable Cryopreserved CD34+ Cells in the Infused Blood Grafts on Hematologic Recovery, Progression-Free Survival and Overall Survival in NHL Patients After Autologous Stem Cell Transplantation.

PATIENTS: This post-hoc study aimed to find out factors affecting graft viable CD34+ cell loss during processing and cryopreservation in 129 non-Hodgkin lymphoma (NHL) patients receiving autologous stem cell transplantation (auto-SCT) and the impact of a low (< 2.0 × 106/kg, group A) and a decent number (≥ 2 × 106/kg, group B) of viable CD34+ cells infused on the hematologic recovery, progression-free survival (PFS) and overall survival (OS) after auto-SCT. RESULTS: The median loss of viable CD34+ cells during cryopreservation was higher in group A (47% vs. 19%, p < .001). A higher yield of CD34+ cells at the first apheresis in group B (p = .002) was linked with greater loss of viable graft CD34+ cells after cryopreservation. Filgrastim (FIL) use for mobilization seemed to associate with higher viable CD34+ cell loss compared to pegfilgrastim (PEG) or lipegfilgrastim (LIPEG) in both groups (in group A FIL 66 vs. PEG 35%, p = .006; in group B FIL 37 vs. PEG 15 vs. LIPEG 13%, p < .001). Hematologic recovery after auto-SCT was faster in group B. Neither viable CD34+ cell loss during storage nor viable CD34+ cell number < 2.0 × 106/kg infused affected on PFS or OS. CONCLUSIONS: G-CSF type used in mobilization and mobilization capacity were found to correlate with viable CD34+ cell loss during processing and storage. Most importantly, low infused viable CD34+ cell count did not seem to impact on PFS or OS.

Impact of the number of cryopreserved CD34+ cells in the infused blood grafts on hematologic recovery and survival in myeloma patients after autologous stem cell transplantation: Experience from the GOA study.

BACKGROUND: Prospective data on the impact of CD34+ cell loss during cryopreservation and the amount of cryopreserved CD34+ cells infused after high-dose therapy on hematologic recovery and post-transplant outcome in multiple myeloma (MM) are scarce. PATIENTS AND METHODS: This post-hoc study aimed to investigate factors associating with CD34+ cell loss during cryopreservation and the effects of the infusion of a very low number (<1.0 × 106 /kg, group A), low number (1-1.9 × 106 /kg, group B), and optimal number (≥2 × 106 /kg, group C) of thawed viable CD34+ cells on hematologic recovery, progression free survival, and overall survival after autologous stem cell transplantation among 127 patients with MM. RESULTS: In group C, pegfilgrastim use (P = 0.001), plerixafor use (P = 0.039), and older age ≥ 60 years (P = 0.026) were associated with less loss of CD34+ cells during cryopreservation. Better mobilization efficacy correlated with greater CD34+ cell loss in group B (P = 0.013 and P = 0.001) and in group C (P < 0.001 and P < 0.001). Early platelet engraftment was slowest in group A (20 d vs 12 d in group B vs 11 d in group C, P = 0.003). The infused viable CD34+ cell count <1.0 × 106 /kg seemed not to have influence on PFS (P = 0.322) or OS (P = 0.378) in MM patients. CONCLUSIONS: Cryopreservation impacts significantly on the CD34+ cell loss. A very low number of graft viable CD34+ cells did not affect PFS or OS.

Efficacy of conventional-dose cytarabine, idarubicin and thioguanine versus intermediate-dose cytarabine and idarubicin in the induction treatment of acute myeloid leukemia: Long-term results of the prospective randomized nationwide AML-2003 study by the Finnish Leukemia Group.

OBJECTIVES: AML-2003 study sought to compare the long-term efficacy and safety of IAT and IdAraC-Ida in induction chemotherapy of acute myeloid leukemia (AML) and introduce the results of an integrated genetic and clinical risk classification guided treatment strategy. METHODS: Patients were randomized to receive either IAT or IdAraC-Ida as the first induction treatment. Intensified postremission strategies were employed based on measurable residual disease (MRD) and risk classification. Structured questionnaire forms were used to gather data prospectively. RESULTS: A total of 356 AML patients with a median age of 53 years participated in the study. Long-term overall survival (OS) and relapse-free survival (RFS) were both 49% at 10 years. The median follow-up was 114 months. No significant difference in remission rate, OS or RFS was observed between the two induction treatments. Risk classification according to the protocol, MRD after the first and the last consolidation treatment affected the OS and RFS significantly (p < .001). CONCLUSIONS: Intensified cytarabine dose in the first induction treatment was not better than IAT in patients with AML. Intensification of postremission treatment in patients with clinical risk factors or MRD seems reasonable, but randomized controlled studies are warranted in the future.

The European Medicines Agency Review of Crizanlizumab for the Prevention of Recurrent Vaso-Occlusive Crises in Patients With Sickle Cell Disease.

Crizanlizumab is a monoclonal antibody that binds to P-selectin. On October 28, 2020, a conditional marketing authorization valid through the European Union (EU) was issued for crizanlizumab for the prevention of recurrent vaso-occlusive crises (VOCs) in patients with sickle cell disease aged 16 years or older. Crizanlizumab was evaluated in a phase 2, double-blind, placebo-controlled randomized multicenter trial comparing high-dose (5 mg/kg) crizanlizumab, low-dose (2.5 mg/kg) crizanlizumab and placebo in patients with a history of 2-10 VOCs in the previous year. Patients who were receiving concomitant hydroxycarbamide (HC) as well as those not receiving HC were included in the study. The primary endpoint of the trial was the annual rate of sickle cell-related pain crises as adjudicated by a central review committee. High-dose crizanlizumab led to a 45.3% lower median annual rate of sickle cell-related pain crises compared to placebo (P = 0.010), with no statistically significant difference for the low dose. Treatment with high-dose crizanlizumab led to similar incidences of adverse events (AEs), grade 3 AEs, and serious AEs compared to placebo. Most frequently observed AEs that occurred more often in the crizanlizumab arm compared to placebo were infusion related reactions (34.8% versus 21%), arthralgia (18.2% versus 8.1%), diarrhea (10.6% versus 3.2%), and nausea (18.2% versus 11.3%). The aim of this article is to summarize the scientific review of the application leading to regulatory approval in the EU.

Autograft cellular composition and outcome in myeloma patients: Results of the prospective multicenter GOA study.

BACKGROUND: Autologous stem cell transplantation (auto-SCT) is a widely used treatment option in multiple myeloma (MM) patients. The optimal graft cellular composition is not known. STUDY DESIGN AND METHODS: Autograft cellular composition was analyzed after freezing by flow cytometry in 127 MM patients participating in a prospective multicenter study. The impact of graft cellular composition on hematologic recovery and outcome after auto-SCT was evaluated. RESULTS: A higher graft CD34+ cell content predicted faster platelet recovery after auto-SCT in both the short and long term. In patients with standard-risk cytogenetics, a higher graft CD34+ count (>2.5 × 106 /kg) was linked with shorter progression-free survival (PFS; 28 vs. 46 months, p = 0.04), but there was no difference in overall survival (OS) (p = 0.53). In a multivariate model, a higher graft CD34+ CD133+ CD38- (>0.065 × 106 /kg, p = 0.009) and NK cell count (>2.5 × 106 /kg, p = 0.026), lenalidomide maintenance and standard-risk cytogenetics predicted better PFS. In contrast, a higher CD34+ count (>2.5 × 106 /kg, p = 0.015) predicted worse PFS. A very low CD3+ cell count (≤20 × 106 /kg, p = 0.001) in the infused graft and high-risk cytogenetics remained predictive of worse OS. CONCLUSIONS: Autograft cellular composition may impact outcome in MM patients after auto-SCT. More studies are needed to define optimal graft composition.

Haemophilia, state of the art and new therapeutic opportunities, a regulatory perspective.

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions in the Western world. However, optimizing haemophilia care remains challenging in developing countries. Several challenges and unmet needs remain in the treatment of the haemophilia limiting the QoL of patients. These challenges are now being addressed by extended half-life recombinant factors, rebalancing and substitution therapies. Gene therapy and genome editing show promise for a definite clinical cure. Here, we provide an overview of new therapeutic opportunities for haemophilia and their advances and limitations from a regulatory perspective. The database on human medicines from the European Medicines Agency (EMA) was used and data from rare disease (orphan) designations and EPARs were retrieved for the analysis. Clinical trial databases were used to query all active studies on haemophilia. Gene therapy medicinal products based on AAV and lentiviral vectors are in development and clinical trials have reported substantial success in ameliorating bleeding tendency in haemophilia patients. The prospect of gene editing for correction of the underlying mutation is on the horizon and has considerable potential. With regard to the benefit of the gene therapy medicinal products, more long-term efficacy and safety data are awaited. We are entering an era of innovation and abundance in treatment options for those affected by bleeding disorders, but issues remain about the affordability and accessibility to patients.

Mobilization characteristics, blood graft composition, and outcome in diffuse large B-cell lymphoma after autologous stem cell transplantation: Results from the prospective multicenter GOA study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a common indication for autologous stem cell transplantation (auto-SCT). STUDY DESIGN AND METHODS: This prospective noninterventional study aimed to evaluate the impact of mobilization characteristics and graft cellular content on hematologic recovery and outcome after auto-SCT among 68 patients with DLBCL. RESULTS: Better mobilization capacity as manifested by blood CD34+ cell count >32 × 106 /L and CD34+ cell yield of the first apheresis >2.75 × 106 /kg correlated with faster neutrophil (P = .005 and P = .017) and platelet (P = .002 and P < .001) recovery. A higher number of infused CD34+ cells (> 2.65 × 106 /kg) was associated with better 5-year overall survival (OS; 95% vs 67%, P = .012). The graft CD34+ CD133+ CD38- cell count >0.07 × 106 /kg was predictive of better 5-year OS (87% vs 63%; P = .008) and higher graft CD3+ cell count (>23.1 × 106 /kg) correlated also with better 5-year OS (80% vs 40%, P = .008). In multivariate analysis only disease status of CR I at auto-SCT was associated with better progression-free survival (P = .014) and OS (P = .039). CONCLUSION: The mobilization capacity of CD34+ cells impacted on early hematologic recovery in patients with DLBCL after auto-SCT. Higher graft CD34+ cell count and both CD34+ CD133+ CD38- and CD3+ cells were also associated with better OS. The effect of optimal graft cellular composition on outcome in DLBCL should be evaluated in a randomized study.

EMA Review of Belantamab Mafodotin (Blenrep) for the Treatment of Adult Patients with Relapsed/Refractory Multiple Myeloma.

On August 25, 2020, a marketing authorization valid through the European Union was issued for belantamab mafodotin monotherapy for the treatment of multiple myeloma (MM) in adult patients who have received at least four prior therapies, whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody (mAb), and who have demonstrated disease progression on the last therapy. Belantamab mafodotin is an antibody-drug conjugate that combines a mAb, which binds specifically to B-cell maturation antigen, with maleimidocaproyl monomethyl auristatin F, which is a cytotoxic agent. It was evaluated in Study 205678 (DREAMM-2), an open-label, two arm, phase II, multicenter study in patients with MM who had relapsed following treatment with at least three prior therapies, who were refractory to an IMiD, a PI, and an anti-CD38 mAb alone or in combination. Patients were randomized to receive 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) belantamab mafodotin by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Belantamab mafodotin achieved an overall response rate (ORR) of 32% (97.5% confidence interval [CI]: 22-44) with a median duration of response (DoR) of 11 months (95% CI: 4.2 to not reached). The most frequently (≥20%) reported adverse reactions grades 3-4 with belantamab mafodotin were keratopathy (31%), thrombocytopenia (22%), and anemia (21%). With regard to the corneal risks associated with belantamab mafodotin, patients would need to undergo specific ophthalmic examinations so that any findings can be promptly and adequately managed. The scientific review concluded that a 32% ORR and a median DoR of 11 months observed with belantamab mafodotin was considered clinically meaningful. Given the manageable toxicity profile and considering that belantamab mafodotin has a mechanism of action that is different from that of authorized treatments in this group of highly pretreated patients whose disease is refractory to three classes of agents, the benefit risk for belantamab mafodotin monotherapy was considered positive, although the efficacy and safety evidence were not as comprehensive as normally required. IMPLICATIONS FOR PRACTICE: Belantamab mafodotin (Blenrep, GlaxoSmithKline, St. Louis, MO, U.S.A) was approved in the European Union as monotherapy for the treatment of adult patients with refractory/relapsed multiple myeloma. Belantamab mafodotin resulted in durable response in highly pretreated patients whose disease is refractory to three classes of agents. Belantamab mafodotin is a monoclonal antibody against B-cell maturation antigen conjugated with the potent antimitotic agent maleimidocaproyl monomethyl auristatin. This is the first monoclonal antibody to target this antigen in multiple myeloma, which represents a true novelty from a pharmacological point of view.

Autograft cellular composition and outcome in NHL patients: results of the prospective multicenter GOA study.

Autologous stem cell transplantation (auto-SCT) is an established treatment option in patients with non-Hodgkin lymphoma (NHL). In this prospective multicenter study, the effect of infused blood graft cellular composition on post-transplant outcome was analyzed in 129 NHL patients. Higher graft CD34+ cell content (>2.5 × 106/kg) correlated with better progression-free survival (PFS) (p=.009) and overall survival (OS) (p=.004). Higher graft CD34+CD133+CD38- counts (>0.08 × 106/kg) were also linked with better PFS (p=.03) and OS (p=.004), and these survival benefits retained in multivariate analyses. Higher infused CD3+CD4+ cell count (>37 × 106/kg) predicted better PFS (p=.013) and OS (p=.007) in multivariate analysis. Autograft cellular composition seems to impact outcome in NHL patients. These observations regarding composition of optimal graft in autologous setting should be validated in an independent patient series or in a randomized study.

A prospective comparison of pegfilgrastim and lipegfilgrastim combined with chemotherapy in the mobilization of CD34+ cells in NHL patients.

BACKGROUND: Autologous stem cell transplantation (auto-SCT) is a treatment approach in non-Hodgkin lymphoma (NHL) patients. The options for mobilization of CD34+ cells to support high-dose therapy are granulocyte-colony stimulating factors (G-CSFs) alone or after chemotherapy. Limited data exist on the efficacy of lipegfilgrastim (LIPEG) in the mobilization field. PATIENTS AND METHODS: The present prospective nonrandomized study compared LIPEG 6 mg (n = 40) with pegfilgrastim (PEG) 6 mg (n = 37) in the mobilization of blood CD34+ cells after chemotherapy in NHL patients with comparable mobilizing chemotherapy and disease status before auto-SCT. RESULTS: Significantly higher blood CD34+ cell (B-CD34+ ) counts were observed in the LIPEG group at the start of the first apheresis (44 vs 23 × 106 /L, P = .009), in line with a higher collection yield of the first apheresis (3.3 vs 2.1 × 106 /kg, P = .086) and total yield of CD34+ cells (4.7 vs 2.9 × 106 /kg, P = .004). LIPEG proved to be a more effective G-CSF, resulting in a higher B-CD34+ cell peak (60 vs 32 × 106 /L, P = .030) and higher proportion of excellent mobilizers (33% vs 8%, P = .008). The superiority of LIPEG was confirmed in the multivarite analysis concerning the CD34+ cell yield of the first apheresis day (P = .010) and the total yield (P = .001). CONCLUSION: The mobilization of blood grafts with LIPEG added to chemotherapy was associated with higher CD34+ cell apheresis yields than with PEG. A randomized study is warranted to verify these findings.

EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes.

On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). Vyxeos was designated as an orphan medicinal product on January 11, 2012. The applicant for this medicinal product was Jazz Pharmaceuticals Ireland Limited. Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine, antineoplastic agents that inhibit topoisomerase II activity and also cause DNA damage. The strength of Vyxeos is 5 units/mL, where 1 unit equals 1.0 mg cytarabine plus 0.44 mg daunorubicin. The marketing authorization holder Jazz Pharmaceuticals had found that this was an optimal ratio for the efficacy of the product. Study CLTR0310-301, a phase III, multicenter, randomized, trial of Vyxeos (daunorubicin-cytarabine) liposome injection versus standard 3+7 daunorubicin and cytarabine in patients aged 60-75 years with untreated high-risk (secondary) AML, showed a statistically significant difference between the two groups in overall survival (OS) with a median OS of 9.56 months in the daunorubicin-cytarabine arm compared with 5.95 months for standard chemotherapy (hazard ratio, 0.69; 95% confidence interval, 0.52-0.90; one-sided p = .003). The most common side effects were hypersensitivity including rash, febrile neutropenia, edema, diarrhea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. IMPLICATIONS FOR PRACTICE: Vyxeos has demonstrated a clinically significant improvement in overall survival compared with the standard of care 7+3 in the proposed population of patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML. This is remarkable given the very poor prognosis of these patients and their unmet medical need. Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only curative treatment in AML.

CD34+ cell mobilization, blood graft composition, and posttransplant recovery in myeloma patients compared to non-Hodgkin's lymphoma patients: results of the prospective multicenter GOA study.

BACKGROUND: Autologous stem cell transplantation is an established treatment option for patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL). STUDY DESIGN AND METHODS: In this prospective multicenter study, 147 patients with MM were compared with 136 patients with NHL regarding the mobilization and apheresis of blood CD34+ cells, cellular composition of infused blood grafts, posttransplant recovery, and outcome. RESULTS: Multiple myeloma patients mobilized CD34+ cells more effectively (6.3 × 106 /kg vs. 3.9 × 106 /kg, p = 0.001). The proportion of poor mobilizers (peak blood CD34+ cell count <20 × 106 /L) was higher in NHL patients (15% vs. 3%, p < 0.001). Plerixafor was added to rescue the mobilization failure in 17 MM patients (12%) and in 35 NHL patients (26%; p = 0.002). The infused grafts contained more natural killer (NK) and CD19+ cells in MM patients. Blood platelet and NK-cell counts were higher in MM patients posttransplant. Early treatment-related mortality was low in both groups, but NHL patients had a higher late (>100 days) nonrelapse mortality (NRM; 6% vs. 0%, p = 0.003). CONCLUSIONS: Non-Hodgkin's lymphoma and MM patients differ in terms of mobilization of CD34+ cells, graft cellular composition, and posttransplant recovery. Thus, the optimal graft characteristics may also be different.

European Medicines Agency review of ixazomib (Ninlaro) for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

On 21 November 2016, the European Commission issued a marketing authorisation valid throughout the European Union for ixazomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Ixazomib was evaluated in one, randomised, double-blind, phase III study comparing ixazomib plus lenalidomide and dexamethasone (n=360; ixazomib arm) versus placebo plus lenalidomide and dexamethasone (n=362; placebo arm) in adult patients with relapsed and/or refractory multiple myeloma who had received at least one prior therapy. The median progression-free survival (PFS) in the intent-to-treat population was 20.6 months in patients treated with ixazomib compared with 14.7 months for patients in the placebo arm (stratified HR=0.742, 95% CI 0.587 to 0.939, stratified p-value=0.012). The most frequently reported adverse reactions (≥20%) within the ixazomib and placebo arms were diarrhoea (42% vs 36%), constipation (34% vs 25%), thrombocytopaenia (28% vs 14%), peripheral neuropathy (28% vs 21%), nausea (26% vs 21%), peripheral oedema (25% vs 18%), vomiting (22% vs 11%) and back pain (21% vs 16%). The scientific review concluded that the gain in PFS of 5.9 months observed with ixazomib was considered clinically meaningful. Concerning the possible uncertainty about the magnitude of the effect, this uncertainty was acceptable given the favourable toxicity profile, and considering that ixazomib is the first agent to allow oral triple combination therapy in this patient population which represents a therapeutic innovation in terms of convenience for patients. Therefore, the benefit-risk for ixazomib in combination with lenalidomide and dexamethasone was considered positive, although the efficacy evidence was not as comprehensive as normally required.

Are products with an orphan designation for oncology indications different from products for other rare indications? A retrospective analysis of European orphan designations granted between 2002-2012.

BACKGROUND: Orphan designated medicinal products benefit from regulatory and economic incentives for orphan drug development. Approximately 40% of orphan designations target rare neoplastic disorders, referring to rare cancers. In order to provide more insights in drugs for rare neoplastic disorders that are under development and to better understand the role of orphan designation in the development of oncology drugs, this study investigates the characteristics of the product, the indication and the applicants as well as the stage of development of products with an orphan designation for rare neoplastic disorders and compares them with products with an orphan designation for other rare indications. Therefore, orphan designation application files and annual reports submitted by the applicant were reviewed at the premises of the European Medicines Agency. RESULTS: At the time of application, 41.6% of products with orphan designation for rare neoplastic disorders were in pre-clinical phase; this was 65.1% for other rare conditions (p < 0.05). Thirty percent of orphan designations for rare neoplastic disorders had reached phase 1; compared to 19.3% of orphan designations targeting other rare conditions (p < 0.05). The same trend was observed for the stage of development at the time of the latest annual report. Significant benefit was more often considered for orphan designations for rare neoplastic disorders compared to orphan designations for other rare conditions. CONCLUSION: Orphan designations for rare neoplastic disorders involve products that are in a more advanced stages of development compared to orphan designations for other (non-oncology) rare conditions.

Methods, units and quality requirements for the analysis of haemoglobin A1c in diabetes mellitus.

The formation of glycohemoglobin, especially the hemoglobin A1c (HbA1c) fraction, occurs when glucose becomes coupled with the amino acid valine in the ß-chain of Hb; this reaction is dependent on the plasma concentration of glucose. Since the early 1970s it has been known that diabetics display higher values OF HbA1C because they have elevated blood glucose concentrations. Thus HbA1c has acquired a very important role in the treatment and diagnosis of diabetes mellitus. After the introduction of the first quantitative measurement OF HbA1C, numerous methods for glycohemoglobin have been introduced with different assay principles: From a simple mini-column technique to the very accurate automated high-pressure chromatography and lastly to many automated immunochemical or enzymatic assays. In early days, the results of the quality control reports for HbA1c varied extensively between laboratories, therefore in United States and Canada working groups (WG) of the Diabetes Controls and Complications Trial (DCCT) were set up to standardize the HbA1c assays against the DCCT/National Glycohemoglobin Standardization Program reference method based on liquid chromatography. In the 1990s, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) appointed a new WG to plan a reference preparation and method for the HBA1c measurement. When the reference procedures were established, in 2004 IFCC recommended that all manufacturers for equipment used in HbA1c assays should calibrate their methods to their proposals. This led to an improvement in the coefficient of variation (CV%) associated with the assay. In this review, we describe the glycation of Hb, methods, standardization of the HbA1c assays, analytical problems, problems with the units in which HbA1c values are expressed, reference values, quality control aspects, target requirements for HbA1c, and the relationship of the plasma glucose values to HbA1c concentrations. We also note that the acceptance of the mmol/mol system for HbA1c as recommended by IFCC, i.e., the new unit and reference ranges, are becoming only slowly accepted outside of Europe where it seems that expressing HbA1c values either only in per cent units or with parallel reporting of percent and mmol/mol will continue. We believe that these issues should be resolved in the future and that it would avoid confusion if mmol/mol unit for HbA1c were to gain worldwide acceptance.

Blood graft cellular composition and posttransplant recovery in non-Hodgkin's lymphoma patients mobilized with or without plerixafor: a prospective comparison.

BACKGROUND: Autologous stem cell transplantation is commonly used to treat non-Hodgkin's lymphomas (NHLs). Cellular composition of the blood grafts apparently has a role in the posttransplant hematologic and immune recovery. Plerixafor increases the mobilization of CD34+ cells and higher amounts of various lymphocyte subsets have been reported in the grafts. Limited prospective data are available in regard to graft cellular composition, hematologic and immune recovery, and patient outcomes in NHL patients who receive plerixafor added to chemomobilization. STUDY DESIGN AND METHODS: Forty-one patients with NHL participated in this prospective study. All patients received chemomobilization and 15 poor mobilizers also received plerixafor. CD34+ cell subsets and lymphocyte subsets of cell grafts, posttransplant hematologic and immune recovery, and outcome were evaluated. RESULTS: Blood grafts in the plerixafor group contained a significantly higher proportion of CD34+133+CD38- cells and more lymphocytes of all major subsets except B lymphocytes. Neutrophil engraftment was comparable and platelet recovery slightly slower in the plerixafor group. Natural killer cell recovery was significantly faster in patients mobilized with plerixafor. Otherwise hematologic and immune recovery as well as short-time outcome were comparable even though there was a trend for progression-free survival and overall survival benefit in the plerixafor group. CONCLUSIONS: In poorly mobilizing NHL patients, plerixafor added to chemomobilization is safe and effective. It also modifies the blood graft composition in many ways, some of which have been linked to better outcomes in previous studies. Larger sets of patients and longer follow-up are needed to see whether plerixafor-mobilized grafts are associated with superior outcome of the patients.