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  • 1
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    Phosphodiesterase Inhibition Increases Fetal Hemoglobin in Sickle Cell Disease; L-Arginine Supplementation Does Not.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 3396-3396
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3396-3396
    Abstract: Nitric oxide- and cyclic nucleotide-linked pathways have been proposed to regulate fetal hemoglobin expression in sickle cell disease (SCD), and phosphodiesterase-5 (PDE5) inhibition and arginine supplementation can enhance these pathways. In an open-label gender-biased study (due to earlier concerns about sildenafil-induced priapism), we examined HbF and markers of disease activity in 12 patients with SCD (HbSS,) who had confirmed hematologic stability on hydroxyurea therapy and who had been treated with three months of thrice daily L-arginine supplementation (0.1–0.2 g/Kg, n=6, 4 male) or sildenafil (PDE5 inhibitor, 25–100 mg, n=6, all female). An additional 12 patients received study drug but did not have stable lead-in HbF levels; their data, where available, is included in analyses of amino acid levels, tricuspid regurgitant (TR) jet measurements, and 6-minute walk (6MW) distance. 25 mg of sildenafil increased cGMP by an average of 2 pM/ml at 2 hours (n=5). Statistics between groups are 2-way repeated measures ANOVA, while within groups are 1-way RMA, from data collected every 2 weeks. L-arginine increased serum arginine and ornithine concentrations while sildenafil did not. Percent change in HbF (%) and F-cells (%) from baseline rose with sildenafil, but did not change with L-arginine. Reticulocytes (K/μL) and arginase, markers of hemolysis, dropped with sildenafil, but LDH(IU/L) and MCHC rose with both treatments, although only modestly. TR jet velocity and 6-MW distance improved markedly in patients treated with sildenafil, whose parameters had suggested somewhat more severe disease at the start of therapy. We conclude that HbF and F-cell levels are modestly increased in patients on HU who also receive sidlenafil, consistent with prior studies suggesting that HU in part operates via NO-cGMP signaling pathways. Sildenafil, but not L-Arginine, improves physiologic, and some hematologic, parameters in SCD. These clinical data, while limited by small numbers, support earlier genetic data from other investigators that implicate members of the PDE family in the modulation of HbF in SCD. Measurement L-Arg, baseline L-Arg, week 12 Sildenafil, baseline Sildenafil, week 12 Arginine [mM], 47±16 96±58 35.0±15.6 28.6±11.3 p 〈 .005 2-way RMA n=7 n=8 Ornithine [mM], 74±13 128±77 68±11 61±7 p 〈 .05 2-way RMA n=7 n=8 TR jet (m/s) 2.57±0.32 2.72±0.40 2.79±0.38 2.68±0.32 n=9, p=n.s., 1-way RMA n=13, p 〈 .05, 1-way RMA 6-minute walk (meters) 494±109 511±116 400±89 491±110 n=9, p=n.s., 1-way RMA n=13, p 〈 .05, 1-way RMA HbF (% Total Hgb) % change from baseline 0±0 2.9±16.1 0±0 9±16 n=6, p=n.s., 1-way RMA n=6, p 〈 .05 1-way RMA F-cells (% total RBCs), % change 0±0 4.2±16.8 0±0 11±17 n=6, p=n.s., 1-way RMA n=6, p 〈 .05 1-way RMA Reticulocytes, K/μL 186±38 190±23 244±129 177±92 n=6, rose and fell, p 〈 .05 1-way RMA n=6, p 〈 .05 1-way RMA LDH (IU/L) 305±96 327±62 324±153 351±260 n=6, p 〈 .05 1-way RMA n=5, p 〈 .05 1-way RMA Mean corpuscular Hgb concentration, MCHC (g/dL) 34.4±0.9 34.8±1.0 35.1±1.6 35.6±2.7 n=6, p 〈 .05 1-way RMA n=6, p 〈 .05 1-way RMA
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.3396.3396
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 2
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    In Patients With Chronic Lymphocytic Leukemia (CLL) Ibrutinib Effectively Reduces Clonal IgM Paraproteins and Serum Free Light Chains While Increasing Normal IgM, IgA Serum Levels, Suggesting a Nascent Recovery Of Humoral Immunity
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4182-4182
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4182-4182
    Abstract: The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib induces objective clinical responses in the majority of CLL patients (Byrd et al., NEJM 2013). Ibrutinib covalently binds to BTK and with once daily dosing (420 mg, PO) results in 〉 90% inhibition of kinase activity. Germline inactivating mutations in BTK lead to an immunodeficiency syndrome first described by the pediatrician Dr. Bruton in boys suffering from recurrent bacterial infections. These kids, diagnosed with what is now known as Bruton’s agammaglobulinemia, have a severe defect in B cell maturation resulting in the virtual absence of immunoglobulins. Hypogammaglobulinemia is a common complication of CLL and likely is a significant contributor to the increased rate of infections that are a leading cause of death in CLL. Thus, to what degree ibrutinib affects normal B cell function and immunoglobulin levels may in part determine the safety profile of continuous treatment with this agent. Patients and Methods Here we present data from a phase II trial (NCT01500733) of ibrutinib 420 mg daily on 28 day cycles for relapsed/refractory (RR) and treatment naïve (TN) CLL/SLL patients (pts). Serum immune globulins (IgG, IgM, IgA), serum free light chains, and immunofixation electrophoresis were obtained at baseline, and every 6 months thereafter. For statistical analysis of pre-treatment to on-treatment measurements the paired Student t-test was used. Results Here we report on 25 patients (10 TN, 15 RR) who completed 〉 12 months on ibrutinib and never received immunoglobulin replacement therapy. By 6 and 12 months, there was a non-statistically significant trend toward decreased IgG levels (ref. range 642-1730) from a pre-treatment median of 601 to 587 mg/dL (at 6 months) and 495 mg/dL (at 12 months; P = 0.14). In contrast, median serum IgA (ref. range 91-499) rose from 42 (baseline) to 58 (at 6 mo) to 61 mg/dL by 12 months (P 〈 0.005). Three patients had a clonal IgM on electrophoresis, which decreased with treatment. In the remaining 22 patients IgM (ref. range 34-342) rose from 16 (baseline) to 25 (6 months) to 23 mg/dL by 12 months (P 〈 0.01). TN patients had higher IgA and IgM levels at baseline and achieved the higher absolute increase by 12 months. However, the relative rate of increase from baseline was similar for both groups, suggesting that ibrutinib enables a recovery of IgA and IgM levels equally in both TN and RR patients. In 20 patients serum free light chain measurements were available, with an abnormal pre-treatment kappa/lambda ratio in 17. In 11 patients the CLL cells were kappa clonal by flow cytometry and in 9 they were lambda clonal. Eight of 11 pts with a kappa CLL clone had kappa serum free light chain (KSFLC, ref. range 0.57 – 2.22 mg/dL) levels 〉 upper limit of normal (median 5.7 mg/dl). At 6 and 12 months there was a 76% and 72% reduction of the KSFLC (P 〈 0.01), and in 7 pts the level normalized by 6 months. In contrast, prior to therapy the lambda serum free light chains (LSFLC, ref. range 0.66-2.32 mg/dL) were low (median 0.62 mg/dL) in these patients and increased by 68% (P 〈 0.005) to normal levels by 6 months in all of them. Conversely, 8 of 9 patients with lambda clonal CLL by flow cytometry had LSFLC 〉 upper limit of normal (median 8.4 mg/dL), which decreased on ibrutinib by 〉 80% (P 〈 0.03) and normalized in 88% of pts by 12 months. The KSFLC in most of these patients was in the low normal range and only increased by 19% from baseline by 12 months. Thus, ibrutinib effectively reduces the clonal light chain, a correlate of tumor control, while the non-clonal light chains, presumably in part reflecting normal B-cells, are low pre-treatment and increase during treatment. Conclusion Consistent with other reports we see little change in IgG levels in the first 12 months. Importantly, ibrutinib leads to a significant increase in both IgA and IgM serum levels, suggesting a beginning recovery of humoral immunity. The reduction of clonal light chains, a tumor marker, correlates with clinical response. In contrast, the increasing levels of the non-clonal light chain may herald a recovery of the normal B-cell (and possibly plasma cell compartment) raising the possibility that ibrutinib may selectively target CLL cells while allowing the re-growth of normal B-cells. We are currently investigating this further. Supported by the Intramural Research Program of NHLBI. We thank our patients for participating and acknowledge Pharmacyclics for providing study drug. Disclosures: Off Label Use: Ibrutinib not FDA approved for CLL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4182.4182
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 3
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    Early Predictors of Fetal Hemoglobin Response to Hydroxyurea in Sickle Cell Disease.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2344-2344
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2344-2344
    Abstract: We investigated the kinetics of hematologic change in patients with sickle cell disease (SCD, HbSS, n=6) or SC disease (HbSC, n=1) who had been newly started on hydroxyurea (HU), with the intention of identifying early correlates to fetal hemoglobin (HbF) responsiveness. We found that HbF increased in all patients on HU, and that the half-maximal degree of HbF response could be estimated by 2 months, in patients’ whose MCVs had risen ≥ 10% above baseline. All 7 patients were treated with HU and followed closely for 6 months or more, until hematologic stability. Hematologic stability was apparent by ≥ 5 months. White blood cell count (WBC), absolute neutrophil count (ANC), reticulocyte (retic) count, % HbF, and mean corpuscular volume (MCV) were examined at bi-weekly intervals. Baseline values (1 or 2 values averaged) were compared with mean values obtained during weeks 2 to 8 (3 or 4 values averaged). As expected, by 2 months WBC and ANC had fallen 30 +/− 8% and 26 +/− 8%, respectively. Change in total hemoglobin (5.8 +/−6.7%), total platelet count (less 11 +/− 10.8%), and LDH (5.3 +/− 8.7%) was not consistent during this two month interval. By eight weeks after initiation of HU, retic counts had dropped in all six SS patients, from 15 to 52% less than baseline while MCV rose 9–21% above baseline; in general, rise in MCV preceded the rise in HbF. Overall, by the time of hematologic stability, all patients had increased their percent HbF, at between 3–8.5-fold relative to baseline; baseline percent HbF of total hemoglobin (Hgb) ranged from 0.7 to 8.3% and, after stabilization, from 5.2% to 24.9%. Maximal percentage of Hgb that was accounted for by HbF at stabilization was arbitrarily set at 100; at 8 weeks, all patients had achieved ≥ 42% of their maximal HbF level, mean 55 +/− 9.4% of maximum HbF. Two additional patients in whom extensive lab data were available, but who were suspected to be non-compliant or sub-therapeutically treated, had a & gt;10% rise in MCV that was temporally associated with an inflection upward for HbF. Patient 8 had mean bi-weekly MCVs of 94, 91, 93, and, after a family conference, 102 (p=.003); Concurrent HbF was 7, 6, 6 and then 10 (p=.046). Patient 9 had mean bi-weekly MCVs on low-dose HU of 97, 96, and, after dose adjustment, 109(p=.003); HbF was 2%, 3%, and then 5 (p=.0094). We speculate that, in many patients, an increase in MCV above baseline of ≥ 10% is a marker of adequate HU dosing, and that HbF levels at that time approximate half-maximal response. A larger series will be necessary to confirm this relationship; a predictive model, correlating MCV and HbF responsiveness, could be used to determine sufficiency of, and compliance to, HU therapy, and to early identify patients who are at high-risk from SCD (e.g. with pulmonary hypertension) whose HbF responsiveness may not be adequate from HU alone. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2344.2344
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 4
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    Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
    Springer Science and Business Media LLC ; 2003
    In:  Nature Medicine Vol. 9, No. 12 ( 2003-12), p. 1498-1505
    Details
    In: Nature Medicine, Springer Science and Business Media LLC, Vol. 9, No. 12 ( 2003-12), p. 1498-1505
    Type of Medium: Online Resource
    ISSN: 1078-8956 , 1546-170X
    URL: Article
    DOI: 10.1038/nm954
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2003
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  • 5
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    Severity of pulmonary hypertension during vaso-occlusive pain crisis and exercise in patients with sickle cell disease
    Wiley ; 2007
    In:  British Journal of Haematology Vol. 136, No. 2 ( 2007-01), p. 319-325
    Details
    In: British Journal of Haematology, Wiley, Vol. 136, No. 2 ( 2007-01), p. 319-325
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.2007.136.issue-2
    DOI: 10.1111/j.1365-2141.2006.06417.x
    RVK:
    XA 34100
    Language: English
    Publisher: Wiley
    Publication Date: 2007
    detail.hit.zdb_id: 1475751-5
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  • 6
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    Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality
    Wiley ; 2005
    In:  British Journal of Haematology Vol. 130, No. 6 ( 2005-09), p. 943-953
    Details
    In: British Journal of Haematology, Wiley, Vol. 130, No. 6 ( 2005-09), p. 943-953
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.2005.130.issue-6
    DOI: 10.1111/j.1365-2141.2005.05701.x
    RVK:
    XA 34100
    Language: English
    Publisher: Wiley
    Publication Date: 2005
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  • 7
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    Effective Inhibition Of Tumor Microenvironment Interactions In CLL Patients Treated With The BTK Inhibitor Ibrutinib Results In Sustained Inhibition Of Tumor Proliferation and Survival Pathways
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 118-118
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 118-118
    Abstract: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, tissue resident CLL cells show an increase in both B-cell receptor (BCR) and NF-κB signaling; pathways known to regulate survival, proliferation and migration of CLL cells. One key signaling molecule in this pathway is Bruton’s tyrosine kinase (BTK) that is activated directly downstream of the BCR and known to be up-regulated in CLL cells (Herman et al., Blood 2011). Ibrutinib, a covalent BTK inhibitor currently in clinical trials for CLL, has been shown to induce apoptosis and inhibit proliferation and tumor burden both in vitro and in mouse models of CLL (Herman et al., Blood 2011; Ponader et al., Blood 2012, Herman et al., Leukemia 2013). Recently, in a multicenter study, ibrutinib has been shown to induce objective clinical responses and reduce lymphadenopathy in the majority of patients, regardless of the presence of adverse prognostic markers (Byrd et al., NEJM 2013). It has been shown that CLL cells in the lymph node and bone marrow microenvironments demonstrate higher levels of BCR and NF-κB signaling as well as increased cell activation and proliferation (Herishanu et al., Blood 2011). We therefore sought to determine the in vivo effect of ibrutinib on tumor cell activation and proliferation in these microenvironmental niches. We have previously demonstrated that ibrutinib inhibits BCR and NF-κB in the lymph node microenvironment within the first 24 hours after initiation of therapy (Herman et al., ASH 2012). We here expand our previous results by evaluating the long term effects of ibrutinib in the tissue compartment. Because repeat sampling of lymph node tissue on therapy is not practical, we assessed changes in the bone marrow compartment. We obtained bone marrow aspirates pre-treatment and after two cycles of ibrutinib (Day 56). We first evaluated the BCR gene signature using a previously validated set of BCR regulated genes (Herishanu et al., 2011). We found that BCR signaling was significantly inhibited in CLL cells sampled from the bone marrow in 8/8 patients evaluated (P = 0.01). Similarly we also found inhibition of the NF-κB gene signature in all patients evaluated (P = 0.01). In fact, every patient evaluated demonstrated a reduction in both signatures, but there was substantial variation among patients in the extent to which these pathways were inhibited. This variability did not appear to correlate with clinical and prognostic factors, such as IGHV mutation status, deletion of chromosome 17p, or prior treatment status. However, the degree of inhibition of NF-κB signaling was strongly correlated with the degree of inhibition of BCR signaling (r = 0.96, P 〈 0.001), suggesting that the BCR (and/or a second equally BTK dependent pathway) plays a major role in activating NF-κB also in bone marrow resident CLL cells. To confirm our results we next evaluated the phosphorylation of proteins activated downstream of the BCR. We found that CLL cells showed a significant reduction in both PLCγ2 and ERK phosphorylation (mean reduction 52.9% and 71.2%, respectively; P 〈 0.01). Next, using the proliferation marker Ki67 we found a significant reduction in tumor proliferation in the bone marrow on ibrutinib (from a median of 6.6% KI67+ CLL cells pre-treatment to 1.1% on Day 56, P = 0.003). Lastly, we also found a significant reduction in the cell surface expression of the activation markers CD69 and CD86 (mean reduction of 57% (P = 0.001) and 82% (P = 0.03), respectively). In conclusion, our data demonstrate that ibrutinib effectively inhibits BCR, NF-κB, and ERK signaling. This occurs very quickly as demonstrated in the lymph node and is sustained on treatment as shown in the bone marrow. The strong and sustained reduction in proliferation and activation of CLL cells in the tissue microenvironment suggests that BTK is indeed a central hub mediating the nourishing and protective effects of the tumor microenvironment. This work was supported by the Intramural Research Program of NHLBI, NIH. We thank our patients for donating blood and tissue samples to make this research possible. We acknowledge Pharmacyclics for providing study drug. Disclosures: Off Label Use: Ibrutinib in chronic lymphocytic leukemia.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.118.118
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Hematologic, biochemical, and cardiopulmonary effects of l ‐arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy
    Wiley ; 2009
    In:  European Journal of Haematology Vol. 82, No. 4 ( 2009-04), p. 315-321
    Details
    In: European Journal of Haematology, Wiley, Vol. 82, No. 4 ( 2009-04), p. 315-321
    Abstract: Objectives:  Fetal hemoglobin (HbF) induction involves NO‐cGMP signaling pathways. l ‐arginine, an NO precursor, and the phosphodiesterase (PDE) 5 inhibitor sildenafil, which potentiates cGMP, were studied in adults with sickle cell disease (SCD) who were stably on HU. Methods:  Twenty four courses of l ‐arginine (0.1–0.2 g/kg divided TID) or sildenafil (25–100 mg TID), assigned based on gender due to concerns about sildenafil‐related priapism, were successfully completed. Biochemical assays, pulmonary pressures, and cardiopulmonary exercise capacity are reported from patients in whom serial values are available. Hematologic responses are reported in 14 subjects with HbSS who had stable baseline HbF levels. Results:  l ‐arginine increased plasma arginine and ornithine, but not citrulline, suggesting diversion by plasma arginase from NO, and citrulline, generation. Glutathione increased only in patients on l ‐arginine. Sildenafil increased plasma cGMP and citrulline, but not other amino acids. Pulmonary pressures and 6‐min walk distances improved only in patients on sildenafil. In subjects with stable baseline HbF levels, HbF levels changed little from a normalized baseline on l ‐arginine, decreasing by 2.9 ± 16.1%, n  = 6; P  = n.s., but increased on sildenafil, by 7.5 ± 11.7%, n  = 8, P   〈  0.05. Absolute reticulocyte counts initially decreased in patients on sildenafil. Conclusions:  l ‐arginine, at doses that increase plasma arginine levels, altered redox potential in red cells. The lack of clinically detectable efficacy of l ‐arginine may be due to increased arginine metabolism in SCD patients. In vivo augmentation of the cyclic nucleotide pathway by PDE inhibition may induce HbF slightly, but strikingly improves hemodynamic and functional status in SCD.
    Type of Medium: Online Resource
    ISSN: 0902-4441 , 1600-0609
    URL: Issue
    URL: Article
    DOI: 10.1111/ejh.2009.82.issue-4
    DOI: 10.1111/j.1600-0609.2009.01210.x
    Language: English
    Publisher: Wiley
    Publication Date: 2009
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  • 9
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    Pulmonary vascular effects of red blood cells containing S -nitrosated hemoglobin
    American Physiological Society ; 2004
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 287, No. 6 ( 2004-12), p. H2561-H2568
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 287, No. 6 ( 2004-12), p. H2561-H2568
    Abstract: The role of S-nitrosated hemoglobin (SNO-Hb) in the regulation of blood flow is a central and controversial question in cardiopulmonary physiology. In the present study, we investigate whether intact human red blood cells (RBCs) synthesized to contain high SNO-Hb levels are able to export nitric oxide bioactivity and vasodilate the pulmonary circulation, and whether SNO-Hb dependent vasodilation occurs secondary to an intrinsic oxygen-linked, allosteric function of Hb. RBCs containing supraphysiological concentrations (100–1,000× normal) of SNO-Hb (SNO-RBCs) were synthesized and added to isolated, perfused rat lungs during anoxic or normoxic ventilation, and during normoxic ventilation with pulmonary hypertension induced by the thromboxane mimetic U-46619. SNO-RBCs produced dose-dependent pulmonary vasodilation compared with control RBCs during conditions of both normoxic (U-46619) and hypoxic pulmonary vasoconstriction. These effects were associated with a simultaneous, rapid, and temperature-dependent loss of SNO from Hb. Both vasodilatory effects and the rate of SNO-Hb degradation were independent of oxygen tension and Hb oxygen saturation. Furthermore, these effects were not affected by inhibition of the RBC membrane band 3 protein (anion exchanger-1), a putative membrane facilitator of NO export from RBCs. Whereas these data support observations by multiple groups that synthesized SNO-Hb can vasodilate, this effect is not under intrinsic oxygen-dependent allosteric control, nor likely to be relevant in the pulmonary circulation at normal physiological concentrations.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00310.2004
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    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2004
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  • 10
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    A Pilot Study Of Rituximab In Patients With Moderate Aplastic Anemia, Diamond-Blackfan Anemia and Pure Red Cell Aplasia
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2479-2479
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    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2479-2479
    Abstract: Pure red cell aplasia (PRCA), Diamond-Blackfan anemia (DBA) and moderate aplastic anemia (MAA) are all bone marrow failure syndromes that are immune-mediated or may respond to immunosuppressive therapies (IST). Anti-thymocyte globulin, cyclosporine and corticosteroids have been used with some success but have significant toxicities. The humanized monoclonal antibody to the interleukin-2 receptor on T cells, daclizumab, showed efficacy in MAA and PRCA patients with some patients achieving transfusion independence (Sloand et al, Haematologica 2010). However, this agent has since been withdrawn from the market. It is increasing recognized that the anti-CD20 chimeric monoclonal antibody, rituximab, may modulate T cell immunity in addition to its known depletion of B cells (Staci, Seminars in Hematology 2010). There are anecdotal case reports of rituximab, showing benefit in PRCA. Here, we summarize our experience using rituximab in PRCA, DBA and MAA. Design and Methods We enrolled 11 patients with PRCA (n = 7), DBA (n = 1), and MAA (n = 3) who had failed at least one prior immunosuppressive regimen to receive rituximab 375 mg/m2intravenous infusions weekly times 4 doses (NCT00229619). Responses were evaluated at 3, 6 and 12 months. Patients with MAA, DBA or PRCA were eligible for trial participation. MAA was defined as a hypocellular marrow without evidence of an underlying disease process and depression of at least two of three cell lines (an absolute neutrophil count (ANC) ≤ 1200/µL, a platelet count ≤ 70,000/µL, and a hemoglobin ≤ 8.5 g/dL or absolute reticulocyte count (ARC) ≤ 60, 000/µL in transfusion-dependent patients) but who do not fulfill criteria for severe aplastic anemia (i.e. bone marrow cellularity 〈 30% and depression of two of the three peripheral counts: ANC 〈 500/µL, a platelet count 〈 20,000/µL and an ARC 〈 60,000/µL). DBA and PRCA were defined as anemia, reticulocytopenia (ARC ≤ 50, 000/µL) and absent or decreased marrow erythroid precursors. Patients with Fanconi’s anemia, other congenital bone marrow failure syndromes, cytologic abnormalities indicating myelodysplasia or recent/ongoing parvovirus infection were excluded. Complete response (CR) was defined as return of blood counts to normal. Partial response (PR) for MAA was defined as improvement in two of the three depressed blood counts that qualified patient for participation. PR for DBA/PRCA was defined as an increase in hemoglobin by 1.5 g/dl of blood and or ARC ≥ 50,000/µL but not meeting criteria for normal counts. Results Overall, 5/11 (45%) patients responded to rituximab, all achieving PR. At 3 months, one patient with PRCA had responded. At 6 months, two additional patients responded (one with PRCA, one with MAA). At 12 months, an additional two responses were confirmed (one PRCA, one MAA). One PRCA patient lost his response between the 6 and 12 month endpoint. Among the three responding PRCA patients, the mean reticulocyte count at study initiation was 4400/µL; this increased to 54,000/µL at 6 months and further increased to 61,000/µL at 12 months (including patient who lost his response). The study was terminated early for poor accrual; many eligible patients received alternate treatments at home. Due to early study termination, the duration of responses for majority of the patients is unknown. Given the reports of daclizumab efficacy in these diseases, 90% of our patients were previously treated with daclizumab. Notably, 3 of the patients responding to rituximab had previously not responded to daclizumab. Safety The most common toxicity of rituximab observed was an infusion related reaction affecting (8/11) 73% of patients with the first infusion of rituximab. One patient developed serum sickness after the third cycle which precluded the administration of the last dose. An expected decrease in quantitative immunoglobulin levels was observed; at the 6 month evaluation there was an 11% decrease in IgG and IgA; a greater decrease (48%) was observed in IgM. Conclusions Rituximab is a viable treatment option in the armamentarium for patients with PRCA and MAA. Rituximab is safe, effective, and easily administered. Responses can be delayed to beyond 6 months therefore we suggest observation for at least 6 months after rituximab administration. Disclosures: Off Label Use: Rituximab is not FDA approved for the treatment of Pure Red Cell Aplasia, Diamond-Blackfan Anemia or Moderate Aplastic Anemia.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2479.2479
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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