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  • American Society of Hematology  (21)
  • 1
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3072-3072
    Abstract: Abstract 3072 In the 1990s, the most common indication for high dose chemotherapy (HDC) and autologous hematopoietic cell transplantation (AHCT) was breast cancer. Several randomized controlled trials for metastatic breast cancer (MBC), performed to address the role of HDC and AHCT, found no survival benefit over conventional therapy. A recently published meta-analysis confirmed a lack of significant survival benefit and failed to identify any subset of patients that benefited from this approach. Many trials of HDC for MBC, however, demonstrate better than expected 10–15 year progression free and overall survival occurring in 5–15% of patients. These data prompted us to evaluate the long term results of treatment with HDC and AHCT in MBC at our institution. Two-hundred eighty five patients underwent HDC followed by AHCT for metastatic breast cancer from 1984–2000. Preparative regimens included STAMP V (cyclophosphamide [Cy], carboplatin, thiotepa [TT] ), n=98; CBT (Cy, carmustine, TT), n=79; busulfan and Cy, n=54; TT, n=27; STAMP I (Cisplatin, Cy, BCNU), n=26; and BCNU, n=1. With a median follow up of 169 months (range 77–283 months) in survivors, 34 (12%) of these patients remain alive. Of the 251 patients who died, 218 (87%) died of relapsed/metastatic disease. Other causes of death included infectious or cardiopulmonary etiologies. Incidence of death from secondary malignancies was less than 1%. Her2 status was unavailable in the majority of the patients, but comparison by age ( 〈 50 and 〉 50) and hormonal status did not demonstrate any significant differences in relapse (p=0.33 and p=0.32 respectively) or survival (p=0.13 and p=0.42). Using Cox analysis, we identified three prognostic factors for survival in multivariable analysis: number of prior chemotherapy regimens (HR 1.48 per 1 regimen increase, p 〈 0.001); disease status, (HR 1.34, p=0.029 for partial response and HR 2.66, p=0.008 for relapsed/refractory disease); and source of hematopoietic cells (HR 2.45, p=0.012 for bone marrow compared to peripheral stem cells). Data regarding number and type of metastatic sites was not available for the entire cohort. Of the 34 long term survivors identified, sufficient data was available on 28 patients. In this cohort, 10 patients had metastatic disease at presentation while 18 patients had recurrent metastatic disease. Of the 10 patients with primary metastatic disease, 4 patients had oligometastatic involvement of the ipsilateral supraclavicular lymph node which would now be classified as stage IIIC disease by current AJCC staging guidelines. Three patients had limited bone disease and 3 had oligometastatic disease that had been resected. Of the 18 patients with recurrent metastatic disease, 9 had local recurrence at the site of the incision or chest wall, and 6 had a single site of recurrence primarily in the lung or loco-regional lymph nodes, also classified as primarily oligometastatic disease. Most of these lesions were surgically resected. Of the remaining patients, one had recurrent lesions in the liver, one had bilateral breast recurrence, and one had recurrence in the lung with additional possible bone involvement. This retrospective evaluation of patients who underwent HDC and AHCT for metastatic breast cancer demonstrates long term survival in a small subset of MBC patients, primarily those with primary or recurrent oligometastatic disease. Previous studies have suggested that oligometastatic breast cancer is a distinct subgroup with long-term prognosis that is superior to MBC. While the use of HDC and AHCT has largely been abandoned in the United States, several recent long term follow up studies such as this one questions its role for select populations. The use of HDC in subsets such as oligometastatic breast cancer may be beneficial, and may warrant further study; however, overall there remains no demonstrable benefit to HDC and long term survival is rare in the population of patients with metastatic disease. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 2
    In: Blood, American Society of Hematology, Vol. 112, No. 5 ( 2008-09-01), p. 1582-1592
    Abstract: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients. We used a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 3
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5664-5664
    Abstract: Introduction Multiple myeloma (MM) is a B cell cancer mainly characterized by proliferation of malignant plasma cells in the bone marrow, presence of a monoclonal serum immunoglobulin, and occurrence of osteolytic lesions. RAS genes encode a family of small GTPase proteins ubiquitously expressed in all cell lineages and organs that transmit signals for cell growth, differentiation, and survival. Mutations in RAS genes often lead to constitutively activated RAS signaling, resulting in cancer. Various RAS mutations have been described in myeloma patients. RAS mutations are rarely found in pre-malignant stages as MGUS (monoclonal gammopathy of undetermined significance). These findings suggest that RAS mutations may play an important role in malignant transformation of MM. Rigosertib (ON 01910.Na) is an inhibitor of RAS-related signaling pathways associated with cancer cell division, growth, and survival. Rigosertib binds directly to the RAS-binding domain in RAS effector proteins resulting in disruption of RAS/effector interactions and inhibition of multiple RAS-driven signaling pathways. Clinical trials with rigosertib have been conducted in MDS and solid tumors, but the effect of rigosertib in MM has not yet been fully characterized. Methods Various mouse/human MM cell lines (5TGM1, KMS28, RPMI8226, JJN3, OPM2) were tested for their growth with treatment of rigosertib at different concentrations (1, 10, 50, 100, 500 nM) for 4 days. For a mouse MM model study, 0.5e6 Luciferase infected 5TGM1 cells were injected via tail vein into C57BL6/KaLwRij mouse. Rigosertib (100 mg/kg QD) was administrated via intraperitoneal injection from 14 days post-transplantation. The MM growths were weekly monitored by in vivo IVIS imaging after luciferin (Luciferase substrate) injection. Results All cells (5TGM1, KMS28, RPMI8226, JJN3, OPM2) tested showed growth inhibition with rigosertib in a dose-dependent manner. MM progression assessed by in vivo imaging was found to be significantly suppressed by rigosertib treatment as shown in Figure. Furthermore, a survival analysis demonstrated a positive trend towards increased life expectancy with rigosertib treatment (Median survival; control (35 days) vs treated (44.5 days)). Conclusion Our results demonstrate that rigosertib suppresses MM growth in both human/mouse cell lines and a mouse MM model and suggest additional exploration of rigosertib alone or in combination with other MM treatments. Figure 1 Figure 1. Disclosures Davies: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Hoffman:Onconova: Employment. Fruchtman:Onconova: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
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  • 4
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1784-1787
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
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  • 5
    In: Blood, American Society of Hematology, Vol. 137, No. 19 ( 2021-05-13), p. 2657-2661
    Abstract: Adult patients with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy, we analyzed induction of apoptosis by venetoclax and inotuzumab ozogamicin in terms of cytotoxicity and mode of action. Flow cytometry–based analyses of mitochondrial outer membrane permeabilization (MOMP) and ataxia telangiectasia mutated activation demonstrate rapid induction of MOMP by venetoclax and DNA damage signaling by inotuzumab ozogamicin, respectively. In primary ALL samples and patient-derived xenograft (PDX) models, venetoclax and inotuzumab ozogamicin cooperated and synergized in combination with dexamethasone in vitro in all tested samples of ALL. In murine PDX models, inotuzumab ozogamicin, but not venetoclax, induced complete remission in a dose-dependent manner but constantly failed to achieve relapse-free survival. In contrast, combination therapy with venetoclax, dexamethasone, and inotuzumab ozogamicin induced long-term leukemia-free survival and treatment-free survival in all 3 ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualify for evaluation in clinical trials.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 6
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1920-1920
    Abstract: Reduced intensity conditioning for allogeneic hematopoietic cell transplantation (alloHCT) has become a standard approach for older patients and for those with co-morbidities that prohibit myeloablative conditioning. The optimal conditioning regimen for patients with AML or MDS undergoing such transplants is not clear. Therefore we performed a single center, retrospective analysis comparing busulfan (100 mg/m2/day on days -5, -4, -3, -2) and fludarabine (40 mg/m2/day on days -5, -4, -3, -2) (BuFlu) versus fludarabine (30 m2/day on days -5, -4, -3) and 400 cGy total body irradiation (200 cGy on days -1 and 0) (FluTBI) conditioning. All of the BuFlu transplants were performed as inpatient hospitalizations while all of those with FluTBI were performed as an outpatient. A total of 71 patients in two cohorts were included. The first study cohort consisted of 38 patients (23 AML, 15 MDS) who received FluTBI from 3/2004-4/2010, and the second included 33 (20 AML, 13 MDS) patients conditioned with FluBu from 6/2010-12/2013. The groups had similar disease risk and HCT comorbidity index scores. The BuFlu patients were older (median age 65 [range, 34-73] vs. 61[range, 44-70] years, P=0.03), but there were no other differences in patient or disease characteristics. All patients received peripheral blood stem cells as the graft source. The donor sources were 53% matched related (MRD) and 47% matched unrelated (MUD) for FluTBI patients and 58% MRD and 42% MUD for BuFlu patients. The BuFlu group received more red blood cell (RBC) transfusions (median 4 vs. 2, P=0.02), but there were no differences in platelet transfusion requirements. Platelet recovery was longer for patients receiving BuFlu than FluTBI (median 16 vs. 12 days, P=0.004), but there was no difference in cumulative incidence of neutrophil recovery. The respective median number of days hospitalized in the first 100 days post-transplant was 22 vs. 10 days (P 〈 0.001) and in the first year was 40 vs. 16 days (P 〈 0.001). Post-transplant outcomes are shown in the Table. The most common causes of death were relapse and infection for both the FluTBI (44% and 13%) and BuFlu (57% and 14%) groups. Quality of life assessments using the FACT-BMT were performed pre-alloHCT, at day 100, 6 months and 1 year. There was no difference in physical, social, emotional, and functional well-beings, additional concerns, trial outcome index or total score between the two groups at baseline or any of the follow-up timepoints. We conclude that alloHCT using FluTBI or BuFlu reduced intensity conditioning regimens results in comparable outcomes in patients with AML/MDS. The greater RBC transfusion requirement and need for inpatient hospitalization with the BuFlu regimen have implications for healthcare resource utilization. Future prospective investigation comparing these regimens with larger patient cohorts and cost-effectiveness analyses are warranted. Table 1. Patient outcomes Variable FluTBI N (%) BuFlu N (%) P-value T-cell complete donor chimerism 29 (78) 26 (81) 0.83 Graft failure/rejection 3 (8) 3 (9) 0.87 Grade II-IV acute GvHD 13 (34) 17 (52) 0.24 Grade III-IV acute GvHD 3 (8) 6 (18) 0.21 Any Chronic GvHD 16 (42) 14 (42) 0.91 Extensive chronic GvHD 8 (21) 13 (39) 0.06 CMV reactivation 12 (32) 13 (39) 0.66 Fungal Infection 2 (5) 1 (3) 0.83 Relapse (2-years) 20 (53) 17 (52) 0.96 100 day mortality 13 (95% CI 6-29 ) 9 (95% CI 3-26 ) 0.59 Non-relapse mortality (2-years) 29 (95% CI 15-44) 29 (95% CI 14-45) 0.56 Relapse mortality (2-years) 34 (95% CI 20-49) 36 (95% CI 20-53) 0.86 Overall survival (2-years) 37 (95% CI 22-52) 35 (95% CI 19-51) 0.73 Disclosures Majhail: Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 7
    In: Blood, American Society of Hematology, Vol. 101, No. 5 ( 2003-03-01), p. 2067-2069
    Abstract: We studied the impact of donor cytomegalovirus (CMV) serologic status on CMV viremia and disease when prophylactic granulocyte colony-stimulating factor (G-CSF)–mobilized granulocyte transfusions (GTs) were given following allogeneic peripheral blood stem cell (AlloPBSC) transplantation. A cohort of 83 patients who received 2 prophylactic GTs from ABO-compatible stem cell donors following AlloPBSC transplantation was compared with a cohort of 142 patients who did not. AlloPBSC donors were eligible for granulocyte donation irrespective of their CMV serostatus. Recipients received no prophylactic therapy for CMV. Donor CMV serostatus had no impact on CMV viremia and disease in the 2 cohorts. Our data show that in an era of effective surveillance and preemptive therapy for CMV, AlloPBSC recipients can safely receive 2 transfusions of prophylactic G-CSF–mobilized granulocyte components from CMV-seropositive AlloPBSC donors. This knowledge may help expand the donor pool in areas with a high prevalence of CMV in the general population.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2003
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  • 8
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 422-422
    Abstract: DBA is an inherited bone marrow failure syndrome characterized by hypoproliferative anemia, congenital abnormalities and cancer predisposition. Ribosomal genes RPS19 and 24 are mutated in 25% and 3% of DBA patients respectively. To identify additional genetic abnormalities in DBA, we evaluated 2 unrelated children with DBA and sub-telomeric deletions of chromosome 3q by comparative genomic hybridization. The larger deletion spanned 11 Mb from 3q28 to the telomeric region and included 72 gene candidates. The second deletion involved 4 Mb from 3q29 to the telomeric end and included 52 known or hypothetical genes. The overlapping deletion region contained a previously reported 1.5 Mb microdeletion-associated syndrome that did not involve hematologic abnormalities, leaving 24 candidate genes. Gene expression microarray analysis from patient-derived EBV cell lines demonstrated down regulation of 7 of these candidate genes, one of which was RPL35a, a component of the large ribosomal subunit. We screened for mutations of RPL35a by direct sequencing of PCR-amplified genomic DNA from 149 DBA probands (125 sporadic, 24 familial) and 180 normal control subjects. We identified three probands with sequence changes in the RPL35a coding region: 1) an in-frame deletion in exon 3 (82-84CTT), causing a deletion of leucine at codon 28, 2) a nonsense mutation in exon 4 (298C 〉 T), leading to an Arg102Stop and a 9 amino acid C-terminal truncation and 3) a missense mutation in exon 3 (97G 〉 A) leading to a Val33Ile change. In the patient derived EBV cell line, the latter sequence change also resulted in an aberrant exon 3 splice site leading to a frame shift following codon 32. All of the probands with RPL35a mutations were sporadic cases. These sequence variations were not observed in the control subjects. Four lentiviral-based siRNA constructs targeting RPL35a were used to test the functional consequences of reduced RPL35a expression. Hematopoietic cell lines (TF-1 and UT-7/epo) transduced with the RPL35a directed siRNA constructs demonstrated decreased growth and viability compared to control siRNAs. Northern blot analysis demonstrated abnormal processing of large ribosomal subunit RNA with decreased mature 5.8S and 28S as well as decreased precursor 12S and 32S rRNA. Orthophosphate labeling confirmed a kinetic defect in large subunit rRNA processing, characterized by increased amounts of 45S and 41S rRNA with decreases of the precursors to and the mature 28S and 5.8S rRNAs. Mature 18S rRNA levels were unaffected, suggesting a defect in rRNA processing within the first internal transcribed sequence (ITS1). These data demonstrate that DBA can be caused by alterations in large as well as small ribosomal subunit proteins. These observations further support the hypothesis that altered ribosome homeostasis and function, rather than extra-ribosomal gene functions, is the central mechanism leading to DBA.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 9
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3454-3454
    Abstract: Introduction: Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of non-Hodgkin lymphoma with unique features including presentation primarily in young men, lymphomatous infiltration of the liver and spleen, frequent bone marrow involvement, B symptoms, infrequent lymphadenopathy and poor prognosis. First described by Farcet and Gaulard1, there are two larger published series in whom only 6/66 of patients (pts) were alive at the time of the reports. 2,3 4/6 surviving pts in these reports had undergone high dose therapy and autologous or allogeneic stem cell transplantation (HDT-SCT). There are no prospective studies of treatment of HSTCL but a recent review of published case reports of HSTCL treated with allogeneic SCT suggests a better outcome for that approach.4 Methods: We reviewed our T-cell lymphoma and bone marrow transplantation databases to examine our results in pts with HSTCL. We identified 9 consecutive pts with this diagnosis. This report summarizes our single center experience. Results: All pts were male with a median age of 37y (12–59). All pts had stage IV disease with hepatomegaly and/or splenomegaly. 5/9 had documented bone marrow involvement, 7 had elevated LDH, and all 9 had B symptoms. Thrombocytopenia was present at diagnosis in 5 pts, anemia in 4 pts, and leukopenia in 4 pts. Transaminases and/or alkaline phosphatase were elevated in 6 pts. 4/9 had previous autoimmune disease: 2 with ulcerative colitis and 2 with rheumatoid arthritis. Responses to induction regimens were: CHOP (PR-2, POD-1) ICE/IVAC (CR-2, PR-2), pentostatin/2-CDA (POD-2). 2/4 pt achieved a CR to ICE as second line therapy. 8/9 pts achieved at least a PR and proceeded to HDT-SCT. 6 pts received an allogeneic SCT (one after relapse from autologous SCT), and 3 pts an autologous SCT. At the time of this report, 4/9 patients are alive in remission, 20–158 mos from diagnosis; the 4 surviving patients all underwent HDT/SCT. Following autologous-SCT 2/3 pts relapsed at 5 and 35 mos. Following Allogeneic-SCT 2/6 pts relapsed at 3 and 6 mos, 1 of whom was effectively treated with donor lymphocytes and remains in remission at 20 mos. 2/6 pts undergoing allo-SCT died of treatment related toxicities without documented recurrent disease. Complete information to determine the age-adjusted international prognostic index (aaIPI) was available for 8/9 pts; the aaIPI appeared to correlate with outcome: 4/5 pts with an aaIPI of low intermediate to high intermediate risk (1–2 factors) were alive compared to 0/3 aaIPI high risk disease (3 factors). The prognostic index for PTCL (PIT) consisting of age, performance status, LDH, and bone marrow involvement was also assessed. All 8 pts had at least one risk factor; 4/6 pts with a PIT of 1–2 were alive vs 0/2 pts for PIT of ≥3. Four pts received ICE or IVAC as their initial therapy and 3/4 were alive compared to only 1/5 for those who received other initial regimens. Conclusions: In this single institution experience, use of non-CHOP induction chemotherapy regimens such as ICE or IVAC and early use of HDT-SCT consolidation appear to improve the outcome for pts with HSTCL compared to reported results with CHOP or CHOP-like regimens.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 10
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1800-1800
    Abstract: Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). We previously reported low incidences of acute GVHD in unrelated donor transplant recipients who received prophylactic HCQ in addition to standard GVHD prophylaxis (BBMT2003; 9: 714–721). We herein report results of a single-institution phase III trial, in which 95 recipients of matched sibling allogeneic peripheral blood stem cell transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ or placebo starting 21 days pre-transplant and continued until d+365. HCQ was very well tolerated and not associated with side effects. The addition of HCQ had no effects on lymphocyte subsets both pre- and post-transplant. Overall, the incidence of acute GVHD was 59% in both arms, and severe acute GVHD occurred in 11% (HCQ) and 14% (placebo) (p=0.76). Sixty-one and 46% of patients developed chronic GVHD in the placebo and the HCQ arms, respectively (p = 0.15). With a median follow-up of 18 months, relapse-free and overall survivals were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single agent CSA was not associated with a reduction of either acute or chronic GVHD; additionally, no significant effects on relapses or survival were observed.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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