Venetoclax: Bcl-2 inhibition for the treatment of chronic lymphocytic leukemia.

Venetoclax (ABT-199) is a small-molecule selective oral inhibitor of the antiapoptotic protein Bcl-2 that promotes programmed cell death of chronic lymphocytic leukemia (CLL) cells regulating the release of proapoptotic factors, such as Smac/Diablo, apoptosis-inducing factor (AIF) and cytochrome c. In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval to venetoclax for patients diagnosed with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. This review will focus on the mechanism of action, preclinical studies and clinical development of venetoclax both as a monotherapy and in combination with other drugs for CLL in the current milieu of therapy dominated by novel tyrosine kinase inhibitors such as ibrutinib and idelalisib.

PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Minimal residual disease negativity in elderly patients with acute myeloid leukemia may indicate different postremission strategies than in younger patients.

In the present analysis, we evaluated whether in elderly acute myeloid leukemia (AML) patients (>60 years), minimal residual disease (MRD) assessed by flow cytometry may have a role in guiding choice of postremission strategies. We analyzed 149 young and 61 elderly adults who achieved morphological CR after induction course of EORTC/GIMEMA protocols. Elderly patients reached a postconsolidation MRD negative status less frequently than younger ones (11 vs 28 %, p = 0.009). MRD negativity resulted in a longer 5-year disease-free survival (DFS) both in elderly (57 vs 13 %, p = 0.0197) and in younger patients (56 vs 31 %, p = 0.0017). Accordingly, 5-year cumulative incidence of relapse (CIR) of both elderly (83 vs 42 %, p = 0.045) and younger patients (59 vs 24 % p = NS) who were MRD positive doubled that of MRD negative ones. Nevertheless, CIR of MRD negative elderly patients was twofold higher than that of younger MRD negative ones (42 vs 24 %, p = NS). In conclusion, elderly patients in whom chemotherapy yields a MRD negative CR have duration of DFS and rate of CIR significantly better than those who remain MRD positive. Nonetheless, the high CIR rate observed in the elderly suggests that MRD negativity might have different therapeutic implications in this population than in the younger counterpart.

High numbers of mobilized CD34+ cells collected in AML in first remission are associated with high relapse risk irrespective of treatment with autologous peripheral blood SCT or autologous BMT.

The faster hematopoietic recovery after autologous peripheral blood SCT (APBSCT) in patients with AML may be offset by an increased relapse risk as compared with autologous BMT (ABMT). The EORTC and GIMEMA Leukemia Groups conducted a trial (AML-10) in which they compared, as second randomization, APBSCT and ABMT in first CR patients without an HLA compatible donor. A total of 292 patients were randomized. The 5-year DFS rate was 41% in the APBSCT arm and 46% in the ABMT arm with a hazard ratio (HR) of 1.17; 95% confidence interval=0.85-1.59; P=0.34. The 5-year cumulative relapse incidence was 56% vs 49% (P=0.26), and the 5-year OS 50% and 55% (P=0.6) in the APBSCT and ABMT groups, respectively. APBSCT was associated with significantly faster recovery of neutrophils and platelets, shorter duration of hospitalization, reduced need of transfusion packed RBC and less days of intravenous antibiotics. In both treatment groups, higher numbers of mobilized CD34+ cells were associated with a significantly higher relapse risk irrespective of the treatment given after the mobilization. Randomization between APBSCT and ABMT did not result in significantly different outcomes in terms of DFS, OS and relapse incidence.

Clofarabine in combination with a standard remission induction regimen (cytosine arabinoside and idarubicin) in patients with previously untreated intermediate and bad-risk acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): phase I results of an ongoing phase I/II study of the leukemia groups of EORTC and GIMEMA (EORTC GIMEMA 06061/AML-14A trial).

This study aims to determine the maximum tolerated dose (MTD) of clofarabine combined with the EORTC-GIMEMA 3 + 10 induction regimen (idarubicin + cytosine arabinoside) in adults with untreated acute myelogenous leukemia or high-risk myelodysplastic syndrome. In this phase I trial, 25 patients (median age 56 years) received 5 days of clofarabine as 1-h infusion (arm A) or push injection (arm B) at the dose level of 5 × 10 or 5 × 15 mg/m(2)/day in an algorithmic dose escalation 3 + 3 design. A consolidation course (intermediate dose cytosine arabinoside, idarubicin) was planned for patients in complete remission (CR). Primary endpoint was safety and tolerance as measured by dose limiting toxicity (DLT); secondary endpoints were response rate, other grade III/IV toxicities, and hematological recovery after induction and consolidation. Five DLTs were observed (in arm A: one DLT at 10 mg/m(2)/day, three at 15 mg/m(2)/day; in arm B: one DLT at 15 mg/m(2)/day). Three patients receiving 15 mg/m(2)/day were withdrawn due to adverse events not classified as DLT. Prolonged hypoplasia was observed in five patients. CR + complete remission with incomplete recovery were achieved in 21 patients (11/12 (92 %) receiving clofarabine 10 mg/m(2)/day; 10/13 (77 %) receiving clofarabine 15 mg/m(2)/day). Clofarabine, 5 × 10 mg/m(2)/day, resulted in one DLT and no early treatment withdrawals. MTD of clofarabine combined with cytosine arabinoside and idarubicin is 5 × 10 mg/m(2)/day.

Anelastic phenomena associated to water loss and collagen degradation in human dentin.

This work describes the anelastic and dynamic Young modulus behaviour of human dentin from room temperature up to 673 K. Human molars, extracted from individuals (males 55-70 years old) as part of their dental treatment, were cut to obtain bar-shaped samples subsequently used for mechanical spectroscopy experiments. In addition, thermo-gravimetric analysis (TGA) has been performed to assess a possible weight loss occurring in the same temperature range of mechanical spectroscopy tests. A broad and asymmetric internal friction (Q(-1)) maximum at 500 K has been observed during the heating of the as-prepared samples. This maximum is absent during the following cooling down to room temperature. It is therefore due to the occurrence of an irreversible transformation in the sample. TGA shows a remarkable weight loss in the same temperature range. This effect has been related to loss of fluids and degradation of collagen. Another set of samples, previously kept for 36 h under a vacuum of 10(-2)Pa, were submitted at room temperature to test at increasing strain from 6×10(-6) to 7×10(-4). The results show transient and fully recoverable Q(-1) increase and dynamic modulus (E) decrease. The phenomenon has been ascribed to the breaking of weak H-bonds between polypeptide chains forming the triple-helix with consequent increase of the mean length of vibrating chain segments.

Nucleophosmin/B26 regulates PTEN through interaction with HAUSP in acute myeloid leukemia.

PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a bona fide dual lipid and protein phosphatase with cytoplasmic (Cy) and nuclear localization. PTEN nuclear exclusion has been associated with tumorigenesis. Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia (AML) and displays Cy localization in mutated nucleophosmin (NPMc+) AML. Here we show that NPM1 directly interacts with herpes virus-associated ubiquitin specific protease (HAUSP), which is known as a PTEN deubiquitinating enzyme. Strikingly, PTEN is aberrantly localized in AML carrying NPMc+. Mechanistically, NPM1 in the nucleus opposes HAUSP-mediated deubiquitination and this promotes the shuttle of PTEN to the cytoplasm. In the cytoplasm, NPMc+ prevents HAUSP from deubiquitinating PTEN, causing the latter to stay in the cytoplasm where it is polyubiquitinated and degraded. Our findings delineate a new NPM1-HAUSP molecular interaction controlling PTEN deubiquitination and trafficking.

Treating older patients with AML.

The treatment of older patients with acute myeloid leukemia is a difficult challenge. Older adults are more likely to have comorbidities that can limit treatment options, the disease tends to be more aggressive biologically and outcomes are worse than those in younger patients. Deciding which older patients would benefit from intensive chemotherapy is difficult, and efforts are underway to improve existing risk-assessment tools. Treatment should be individualized and may include standard chemotherapy for those patients who have none or at most one adverse factor, or investigational agents for those presenting with multiple poor-risk features. Low-intensity therapies are recommended for those patients who are deemed too frail to tolerate myelosuppressive regimens.

Comparative molecular analysis of therapy-related and de novo acute promyelocytic leukemia.

Therapy-related acute promyelocytic leukemia (t-APL) has been reported as a late complication of exposure to radiotherapy and/or chemotherapeutic agents targeting DNA topoisomerase II. We have analyzed in t-APL novel gene mutations recently associated with myeloid disorders. Unlike previous reports in acute myeloid leukemia (AML), our results showed neither IDHs nor TET2 mutations in t-APL. However we found an R882H mutation in the DNMT3A gene in a patient with t-APL suggesting a possible role of this alteration in the pathogenesis of t-APL.

Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia.

Apoptosis plays a key role in the control of rapidly renewing tissues, such as the hematopoietic system and leukemia cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells and the development of drug resistance. These defects are also frequently associated with a low rate of response to standard chemotherapy and with a poor survival in acute myeloid leukemia (AML). The major form of apoptosis proceeds through the mitochondrial pathway, with the mitochondrial outer membrane permeabilization, leading to the release of proteins normally found in the space between the inner and outer mitochondrial membranes (cytochrome C, AIF and others). Higher levels of anti-apoptosis proteins bcl-2, bcl-x(L), Mcl-1 block permeabilization of the membrane and are reported in AML patients presenting a poor outcome. On the contrary, activated pro-apoptotic bax or bad proteins allow this permeabilization and are correlated to a good prognosis in AML. Defects in the mitochondrial pathway induce multidrug-resistance and confer important prognostic information in AML. High ratios of bcl-2 to bax protein confer a poor prognosis with decreased rates of complete remission and overall survival. The prognostic information from the ratio of the proteins is greater than bcl-2 levels alone. Recently, we confirmed the impressive impact of the bax/bcl-2 ratio, determined by flow cytometry, on AML prognosis (complete remission and overall survival) in 255 AML patients. Bcl-2 down regulation might lower the apoptotic threshold of leukemic cells and, through this mechanism, favor response to chemotherapy. Phase II studies of oblimersen (antisense Bcl-2), cytarabine and daunorubicin or oblimersen plus gentuzumab, a cytotoxic antibody directed against CD33+ cells in relapsed AMLs, showed promising results. Defects in apoptosome proteins, such as APAF-1, are frequent in AML and treatment with 5-aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, restored APAF-1 expression in leukemic cells. In conclusion, targeted therapies that are designed to induce apoptosis in leukemic cells, are the most promising anti-leukemia strategies. The elucidation of the apoptotic machinery and of its defects in AML lays the basis for developing new drugs able to trigger apoptosis and overcome therapy resistance.

Diagnosis of acute foetal distress does not preclude banking of umbilical cord blood units.

Clinical diagnosis of acute foetal distress (AFD) is based on several parameters such as abnormal foetal heart rate (FHR) pattern and/or meconium liquid staining (MLS). Standards for cord blood (CB) banking indicate that AFD should be considered as exclusion criteria for CB collection, but precise guidelines on how to proceed with CB collection in the presence of AFD signs during labour are not available. We evaluated whether the presence of FHR abnormality and/or MLS during labour 1) reduced the CB collection activity; 2) were associated with the infant's acidaemia or asphyxia and 3) deteriorated the biological characteristics of CB units. Thirty-three units of CB were evaluated for biological parameters, gas values and newborn's Apgar score. The results were compared with a control group of 33 consecutive units previously banked. No differences were observed between the two groups and all but one newborn showed normal Apgar score and absence of metabolic acidaemia. The results showed that 1) AFD reduced the CB collection activity by 10% each year; 2) the majority of CB units collected in the presence of abnormal FHR and/or meconium have biological characteristics eligible for banking; 3) FHR alterations or meconium in the presence of normal gas analysis do not represent certain diagnosis of AFD.

Non-infusional vs intravenous consolidation chemotherapy in elderly patients with acute myeloid leukemia: final results of the EORTC-GIMEMA AML-13 randomized phase III trial.

In this trial, acute myeloid leukemia patients (pts) aged 61-80 years received MICE (mitoxantrone, etoposide and cytarabine) induction chemotherapy in combination with different schedules of granulocyte colony-stimulating factor administration. Pts in complete remission were subsequently randomized for two cycles of consolidation therapy: mini-ICE regimen (idarubicin, etoposide and cytarabine) given according to either an intravenous (i.v.) or a 'non-infusional' schedule. Among the 346 pts randomized for the second step, 331 pts received consolidation-1 and 182 consolidation-2. A total of 290 events (255 relapses, 35 deaths in first CR) have been reported. The median follow-up was 4.4 years. No significant differences were detected in terms of disease-free survival (median 9 vs 10.4 months, P=0.15, hazard ratio (HR) =1.18, 95% confidence interval (CI) 0.94-1.49) - primary end point - and survival (median 15.7 vs 17.8 months, P=0.19, HR=1.17, 95% CI 0.92-1.50). In the 'non-infusional' arm grade 3-4 vomiting (10 vs 2%; P=0.001) and diarrhea (10 vs 4%; P=0.03) were higher than in the 'i.v.' arm, whereas time to platelet recovery >20 x 10(9)/l (median: 19 vs 23 days; P=0.02) and duration of hospitalization (mean: 15 vs 27 days; P<0.0001) was shorter. The 'non-infusional' consolidation regimen resulted in an antileukemic effect similar to the intravenous regimen, which was less myelosuppressive and associated with less hospitalization days.

The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia.

UNLABELLED: We assessed by multiparametric flow cytometry the levels of minimal residual disease (MRD) in 100 adult patients with acute myelogenous leukemia (AML) achieving complete remission after intensive chemotherapy. The aim of the study was to determine the optimal threshold, in terms of residual leukemic cells, and the time point of choice, that is, post-induction (post-Ind) or post-consolidation (post-Cons), able to better predict outcome. By applying the maximally selected log-rank statistics, the threshold discriminating MRD- from MRD+ cases was set at 3.5 x 10(-4) residual leukemic cells, a level that allowed the identification of distinct subgroups of patients, both at post-Ind and post-Cons time points. Post-Cons MRD- patients had a superior outcome in terms of relapse rate, overall survival (OS) and relapse-free survival (RFS) (P<0.001, for all comparisons), regardless of the MRD status after induction. In particular, patients entering MRD negativity only after consolidation showed the same outcome as those achieving early negativity after induction. Multivariate analysis, including karyotype, age, MDR1 phenotype, post-Ind and post-Cons MRD levels, indicated that the post-Cons MRD status independently affected relapse rate, OS and RFS (P<0.001, for all comparisons). IN CONCLUSION: (1) the threshold of 3.5 x 10(-4) is valid in discriminating risk categories in adult AML and (2) post-Cons MRD assessment is critical to predict disease outcome.

Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab.

OBJECTIVE: Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be quite effective in the treatment of immune disorders resulting from autoantibodies. We prospectively studied the long-term effects of rituximab in 10 patients with anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis refractory to conventional therapy (n=3) or in second or subsequent relapse (n=7). METHODS: The median age of patients was 53 yrs (range 38-70 yrs). Eight were classified as Wegener's granulomatosis, and two as microscopic polyangiitis. Clinical activity was assessed using the Birmingham Vasculitis Activity Score modification for Wegener's granulomatosis. Treatment consisted of intravenous infusions of rituximab given at the dose of 375 mg/m2 weekly for four consecutive weeks. RESULTS: All patients experienced a rapid clinical improvement following the administration of rituximab, with nine complete responses and one partial response at 6 months. With a median follow-up of 33.5 months (range 26-45 months), three patients have thus far relapsed. Retreatment with the monoclonal antibody at the same dose and schedule resulted in a new sustained response in all these patients. Rituximab therapy resulted in prolonged B-cell depletion. The ANCA titres decreased significantly in all patients, with eight out of 10 becoming ANCA-negative and three remaining ANCA-negative even after B-cell recovery. Infusion-related side effects were observed in one patient, but were of mild intensity and did not require discontinuation of treatment. CONCLUSIONS: Rituximab is an effective and well-tolerated treatment for patients with ANCA-associated vasculitis and should be strongly considered in severely affected patients who do not respond to standard therapy or in those in whom cytotoxic therapy bears a high risk of morbidity.

O6-(4-bromothenyl)guanine (PaTrin-2), a novel inhibitor of O6-alkylguanine DNA alkyl-transferase, increases the inhibitory activity of temozolomide against human acute leukaemia cells in vitro.

Anti-tumour activity of triazene compounds of clinical interest [i.e. dacarbazine and temozolomide (TMZ)] relies mainly on the generation of methyl adducts to purine bases of DNA. Two DNA repair enzyme systems, i.e. the O6-guanine-alkyl-transferase (MGMT) and mismatch repair (MMR), play a predominant role in conditioning the cytotoxic effects of triazenes. In particular, high levels of MGMT associated with target cells are responsible of resistance to triazenes. On the contrary, the presence of MMR is required for the cytotoxic effects of these compounds. Previous studies performed by our group and a more recent clinical investigation reported by Karen Seiter, pointed out that triazene compounds could play an important role in the treatment of refractory acute leukaemia. Leukaemia blasts, especially of lymphoblastic leukaemia, show frequently high levels of MGMT activity. Therefore, it reasonable to hypothesize that combined treatment of leukaemia patients with triazene compounds along with MGMT inhibitors could lead to a better control of the disease. PaTrin-2 (O6-(4-bromothenyl)guanine, PAT) is a potent and scarcely toxic MGMT inhibitor recently introduced in clinical trials. This drug is used in combination with triazene compounds in order to augment their anti-tumour efficacy against neoplastic cells endowed with high MGMT activity. The present report describes, for the first time, pre-clinical in vitro studies on the cytotoxic activity of combined treatment with PAT+TMZ against long-term cultured leukaemia cells and primary leukaemia blasts obtained from patients with acute lymphoblastic leukaemia or acute myeloblastic leukaemia. The results point out that, both in long-term cultured leukaemia cell lines and in primary blast samples, PAT could improve dramatically the sensitivity of malignant cells to the cytotoxic effects of TMZ. This sensitizing effect is detectable when leukaemia cells show resistance mechanisms based on a MGMT-proficient phenotype. On the contrary, when resistance to TMZ is dependent on MMR deficiency, no influence of PAT can be detected in various experimental conditions. In conclusion, these results appear to provide disease-oriented rational basis to design novel clinical protocols for the treatment of acute leukaemia with combined administration of PAT and triazene compounds.

Low-dose cytosine arabinoside (LD-AraC) vs LD-AraC plus granulocyte/macrophage colony stimulating factor vs LD-AraC plus Interleukin-3 for myelodysplastic syndrome patients with a high risk of developing acute leukemia: final results of a randomized phase III study (06903) of the EORTC Leukemia Cooperative Group.

In this randomized phase III study of the EORTC Leukemia Cooperative Group, patients with myelodysplastic syndromes (MDS) with 10-30% bone marrow blasts and hematopoietic failure were treated with low-dose cytosine arabinoside (LD-AraC) (2 x 10 mg/m2/day subcutaneously (s.c.) days 1-14) either alone or in combination with rhGM-CSF or interleukin-3 (IL-3) both given s.c. at a dose of 150 microg/day from day 8 to 21. A total of 180 evaluable patients with a median age of 65 years and refractory anemia with an excess of blasts (RAEB, n = 107) or RAEB in transformation (RAEBt, n = 73) were randomized. There were no differences among the three treatment regimens with respect to numbers of courses applied or treatment delays. Hemorrhage occurred in approximately 40% in all arms, whereas infection rates were higher in the granulocyte/macrophage colony stimulating factor (GM-CSF)- or IL3-containing arm. The overall response rate was 38.6% with no statistically significant difference among the three arms. In summary, a substantial proportion of patients had achieved relatively durable responses in all the three arms. No influence of either growth factor was detected on the grade of cytopenia. Thus, the combination of LD-AraC with GM-CSF or IL-3 cannot be recommended for routine use in a high-risk MDS population.

Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes.

BACKGROUND: The hematological and quality of life (QoL) changes associated with darbepoetin alfa (DA) therapy were assessed in anemic patients with previously untreated low- and intermediate-1-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Fifty-three patients received DA administered subcutaneously once a week for 24 weeks. Treatment was initiated at 150 microg fixed dose and was doubled if after the first 12 weeks there was no or suboptimal erythroid response. RESULTS: The final response rate was 24/53 (45%), with 21 major and three minor responses. Most of the responses (21/24; 87.5%) were obtained at the dose of 150 microg. With a median follow-up of 9.4 months, 17 patients maintain their response. Treatment was well tolerated with no relevant side-effects. MDS progression was observed in one case. Increases in hemoglobin levels were positively correlated with improved QoL scores using both the linear analog scale assessment (energy level, r = 0.429, P = 0.036; daily activities, r = 0.653, P < 0.001; overall well-being, r = 0.457, P = 0.024) and the Functional Assessment of Cancer Therapy-Anemia questionnaire (r = 0.247, P = 0.025). In multivariate analysis, only low levels (<200 IU/l) of endogenous erythropoietin predicted response to DA therapy. CONCLUSIONS: DA is an active, safe and well tolerated treatment for anemia in a substantial proportion of patients with low- and intermediate-1-risk MDS, and has a positive impact on the patients' QoL.

Placental/umbilical cord blood: experience of st. Eugenio Hospital collection center.

BACKGROUND: Umbilical cord blood (UCB) contains stem cells and may be an alternative source to bone marrow and peripheral blood stem cells for allogeneic transplantation for the treatment of hematologic malignancies and genetic disorders. Many UCB banks have been established worldwide to quickly provide high quality materials for transplantation. Moreover, a detailed set of standards for cord blood banking have been drawn to guarantee the quality of the products. STUDY DESIGN AND METHODS: The aim of this study was to analyze our activity between 1998 and 2001, seeking to improve the number of suitable UCB units. Written informed consent was obtained from healthy women with an uncomplicated pregnancy. RESULTS: During the study period, we collected 1060 UCB units; 328 (31%) were banked, whereas 732 (69%) were discarded. The collections were performed in 73% vaginal deliveries and 27% of cesarean sections. The main reason for the exclusion was biological; in fact, a low number of nucleated cells and a low volume accounted for 71% of the total discarded units. Moreover, 20% of the units were discarded because of parental clinical reasons. CONCLUSIONS: Our study shows that maternal history must be completely reviewed before labor and obstetrical factors should be considered to improve the number of UCB units.