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  • 1
    In: Leukemia, Springer Science and Business Media LLC, Vol. 37, No. 2 ( 2023-02), p. 465-472
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2008023-2
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  • 2
    In: Blood, American Society of Hematology, Vol. 121, No. 3 ( 2013-01-17), p. 440-446
    Abstract: Patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) have a poor prognosis with conventional chemotherapy. In the present study, we retrospectively analyzed the outcome of patients with BPDCN who underwent allogeneic stem cell transplantation (allo-SCT) or autologous stem cell transplantation (auto-SCT). A total of 39 patients (allo-SCT, n = 34; auto-SCT, n = 5) were identified in the European Group for Blood and Marrow Transplantation registry. The 34 allo-SCT patients had a median age of 41 years (range, 10-70) and received transplantations from sibling (n = 11) or unrelated donors (n = 23) between 2003 and 2009. MAC was used in 74% of patients. Nineteen allo-SCT patients (56%) received transplantations in first complete remission. The 3-year cumulative incidence of relapse, disease-free survival, and overall survival was 32%, 33%, and 41%, respectively. By univariate comparison, being in first remission at allo-SCT favorably influenced survival, whereas age, donor source, and chronic GVHD had no significant impact. We conclude that high-dose therapy followed by allo-SCT from related or unrelated donors can provide durable remission even in elderly patients with BPDCN. However, it remains to be shown if graft-versus-malignancy effects can contribute significantly to BPDCN control after allo-SCT.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    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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  • 3
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 565-565
    Abstract: In order to refine the indications for NST in CLL, we analyzed prognostic factors for various endpoints of the CLL3X trial. CLL3X was a phase-2 trial investigating in a multicenter setting feasibility, toxicity and efficacy of NST in patients with poor-risk CLL. Patients & lt;65 years were eligible if they had progressive disease in the presence of an unfavorable VH status, were fludarabine refractory, or had failed autoSCT. Central genetic work-up including FISH karyotyping was mandatory. Conditioning was based on fludarabine and cyclophosphamide. Centers could opt for routine addition of in-vivo T-cell depletion with alemtuzumab (TCD). Donors were HLA-matched (6/6) siblings or unrelated volunteers. Prospective longitudinal monitoring of minimal residual disease (MRD) was done centrally by MRD-flow or RQ-PCR. MRD results were communicated to the investigators for preemptive immunomodulation (restriction of immunosuppression or donor lymphocyte infusions). Results: Between June 2001 and March 2007, 113 patients were accrued in 16 centers. Thirteen patients had to be excluded due to ineligibility, and 10 patients did not proceed to NST because they lacked a donor, died or developed Richter’s transformation prior to NST, or refused NST. The 90 patients remaining had received 4 (1–11) pre-transplant regimens. 39/71 (55%) had an unfavorable FISH karyotype (del 11q- (37%) or del 17p- (18%)). 42/90 (47%) were fludarabine refractory, but only 24% had uncontrolled disease at NST. Allografts were obtained from related (39%) or unrelated donors (61%). TCD was performed in 12 patients. Due to logistical reasons, continuous sampling for prospective MRD monitoring was possible in only 4 centers representing 58% of the patients. With a median follow-up of 28 (6–80) months, 3-year non-relapse mortality, relapse incidence (REL), event-free survival (EFS) and overall survival (OS) from NST was 23% (95%CI 12%–34%), 42% (29%–56%), 42% (30%–54%), and 66% (55%–78%), respectively. Univariate log rank comparisons identified refractory disease at NST and TCD; but not age, fludarabine resistance, donor, and del 17p- as adverse factors for EFS. Three-year EFS was 43% (95%CI 14%–71%) with del 17p- vs 41% (27%–55%) without del 17p-. Cox regression models (adjusting for age, del 17p-, fludarabine resistance, remission status at NST, TCD, and donor) confirmed younger age (hazard ratio (HR)/year 0.94 (95%CI 0.89–0.99) and TCD (HR 3.68 (1.36–9.92)) as significant prognostic variables for REL; refractory disease at NST (HR 4.08 (1.9–8.74)) and TCD (HR 3.26 (1.53–6.94)) for EFS; and refractory disease at NST (HR 3.87 (1.62–9.25)) for OS. Three-year EFS was 57% (43%–72%) in patients who had sensitive disease at NST and no TCD employed, with no relapse occurring after the 3-year landmark. Only one relapse was observed in 25 patients (5 with del 17p-) who were MRD negative at month +12; and 15 out of 16 patients event-free more than 3 years after NST with MRD values available were MRD negative at last assessment. Conclusions: T-replete NST from related or unrelated donors results in sustained MRD-negative EFS in a significant proportion of patients with poor-risk CLL including those with del 17p-. NST should be performed before disease has become refractory. The potential benefit of preemptive post-transplant immunomodulation guided by real-time MRD monitoring remains to be settled.
    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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  • 4
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3159-3159
    Abstract: INTRODUCTION: T-prolymphocytic leukemia (T-PLL) is a rare T cell malignancy with an aggressive clinical course. Preliminary clinical data suggest that allogeneic stem cell transplantation (alloSCT) may provide long-term disease control in a proportion of patients. However, direct evidence that graft-versus-leukemia (GVL) activity is indeed effective in T-PLL is lacking. We sought to investigate GVL in T-PLL by correlating minimal residual disease (MRD) kinetics with immune modulatory interventions (immunosuppression tapering, donor lymphocyte infusions (DLI), chronic graft-versus-host disease (cGvHD)), and T cell receptor (TCR) repertoire diversity alterations after alloSCT. METHODS: The study sample consisted of 10 consecutive patients who received alloSCT for T-PLL at the University of Heidelberg between 2007 and 2015. Quantitative MRD monitoring was performed using clone-specific real-time quantitative PCR (RQ-PCR) of clonal TCR beta (TRB) and/or gamma (TRG) gene rearrangements. Data interpretation followed EuroMRD guidelines. In selected patients, TCR repertoire diversity was analyzed longitudinally by next-generation sequencing (NGS). TRBV-TRBD-TRBJ gene rearrangements were amplified according to BIOMED2 protocol on genomic DNA. PCR products were sequenced on Illumina's MiSeq platform. NGS data were analyzed through a purpose-built bioinformatics immunoprofiler (EuroClonality-NGS consortium). Rearrangements with very similar junctional amino acid sequences and identical TRBV and TRBJ gene usage were defined as clonotypes. RESULTS: Patients underwent alloSCT in remission after first-line (8) or salvage (2) alemtuzumab-based therapy. 5 patients were allografted with an unrelated donor, 4 with a related donor, and one received haploidentical alloSCT. Conditioning was fludarabine with cyclophosphamide and/or total body irradiation-based. All patients had a cytological complete response (CR) after alloSCT. 2 patients died early because of acute GvHD, and one had no MRD marker, leaving 7 patients for MRD monitoring. Of these, 3 were MRD- at alloSCT, whereas 5 patients remained or became MRD+ early after alloSCT. In all of these 5 patients, immunosuppression tapering (3) or DLI (2) resulted in significant reduction of MRD levels (range 1-3 log) and was accompanied by cGvHD in 3 patients. However, durable MRD- was obtained in only 2 patients (alive 81+ and 12+ months post transplant), whilst MRD re-increased in 3 patients after 5-28 months despite ongoing cGvHD in one of them. NGS of the TCR repertoire was performed longitudinally in 3 patients with the longest follow-up. A total of 104 samples (blood (n=91) and BM (n=10) plus 3 donor blood samples) were sequenced. The sample at diagnosis showed one or two major clonotypes in all 3 sequenced T-PLLs, predominantly reflecting a mono- or biallelic leukemic TRB gene rearrangement. Kinetics of this leukemic clonotype followed kinetics of RQ-PCR MRD measurement, demonstrating that NGS can be used to quantify MRD in T cell lymphoma. Immediately after transplantation, the TRB repertoire was heavily skewed in all 3 patients, but recovered over time. Also in all 3 patients, MRD responses were reproducibly associated with a shift from a clonal, T-PLL-driven profile to a polyclonal signature. This corresponded to the donor clonotype repertoire and disappeared with increasing MRD levels. In each of the samples after alloSCT, several expanded non-leukemic clonotypes were observed at a maximum frequency from 3% to 54% of total TRB sequences. However, during MRD response, novel dominant clonotypes that could explain a clonal GVL effect did not emerge. Figure 1 shows an example of a patient repeatedly showing MRD response to immune interventions. Currently, 5 patients are alive and in cytological CR (4-81 months after alloSCT), translating into a median relapse-free survival of 40 months. CONCLUSIONS: The MRD responses to immune interventions observed here provide the first direct evidence for the efficacy of GVL in T-PLL. However, the GVL effect in T-PLL appears to be often only limited or transient. It also does not seem to be caused by the emergence of novel dominant T cell clones but is rather relying on a poly-/oligoclonal T cell response. Figure 1. Example for MRD kinetics in relation to immune interventions. Figure 1. Example for MRD kinetics in relation to immune interventions. 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: 2015
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  • 5
    In: Blood, American Society of Hematology, Vol. 116, No. 14 ( 2010-10-07), p. 2438-2447
    Abstract: The purpose of this prospective multicenter phase 2 trial was to investigate the long-term outcome of reduced-intensity conditioning allogeneic stem cell transplantation (alloSCT) in patients with poor-risk chronic lymphocytic leukemia. Conditioning was fludarabine/ cyclophosphamide-based. Longitudinal quantitative monitoring of minimal residual disease (MRD) was performed centrally by MRD-flow or real-time quantitative polymerase chain reaction. One hundred eligible patients were enrolled, and 90 patients proceeded to alloSCT. With a median follow-up of 46 months (7-102 months), 4-year nonrelapse mortality, event-free survival (EFS) and overall survival (OS) were 23%, 42%, and 65%, respectively. Of 52 patients with MRD monitoring available, 27 (52%) were alive and MRD negative at 12 months after transplant. Four-year EFS of this subset was 89% with all event-free patients except for 2 being MRD negative at the most recent assessment. EFS was similar for all genetic subsets, including 17p deletion (17p−). In multivariate analyses, uncontrolled disease at alloSCT and in vivo T-cell depletion with alemtuzumab, but not 17p−, previous purine analogue refractoriness, or donor source (human leukocyte antigen-identical siblings or unrelated donors) had an adverse impact on EFS and OS. In conclusion, alloSCT for poor-risk chronic lymphocytic leukemia can result in long-term MRD-negative survival in up to one-half of the patients independent of the underlying genomic risk profile. This trial is registered at http://clinicaltrials.gov as NCT00281983.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3077-3077
    Abstract: Abstract 3077 Blastic plasmacytoid dendritic cell neoplasm (BPDC), formerly known as blastic NK cell lymphoma, is a rare hematopoietic malignancy preferentially involving the skin, bone marrow and lymph nodes. The overall prognosis of BPDC is dismal. Most patients show an initial response to acute leukemia-like chemotherapy, but relapses with subsequent drug resistance occur in virtually all patients resulting in a median overall survival of only 9–13 months. However, anecdotal long-term remissions have been reported in young patients who received early myeloablative allogeneic stem cell transplantation (alloSCT). We therefore performed a retrospective analysis of patients identified in the EBMT registry in order to evaluate the outcome of autologous stem cell transplantation (autoSCT) or alloSCT for BPDC. Eligible were all patients who had been registered with a diagnosis of BPDC or Blastic NK cell lymphoma and had received autologous stem cell transplantation (autoSCT) or alloSCT in 2000–2009. Centres were contacted to provide a written histopathology and immunophenotyping report and information about treatment and follow-up details. Patients who did not have a diagnostic score ≥ 2 as proposed by Garnache-Ottou et al. (BJH 2009) were excluded. RESULTS: Overall, 139 patients could be identified in the database who fulfilled the inclusion criteria (alloSCT 100, autoSCT 39). Of 74 patients for whom the requested additional information could be obtained, central review confirmed the diagnosis of BPDC in 39 patients (34 alloSCT, 5 autoSCT). The 34 patients who had undergone alloSCT had a median age of 41 years (range: 10–70 years), were transplanted from a related (n=11) or unrelated donor (n=23); received peripheral blood stem cells (n=9), bone marrow stem cells (n=19) or cord blood (n=6); and had been treated with a reduced intensity conditioning regimen (RIC, n=9) or myeloablative conditioning (MAC, n=25). Nineteen of 34 patients were transplanted in CR1. After a median follow up time of 28 months (range: 4–77+ months), 11 patients relapsed (median time to relapse: 8 months, range: 2–27 months) of whom 8 died due to disease progression. 9 patients died in the absence of relapse. No relapse occurred later than 27 months after transplant. Median disease free survival (DFS) was 15 months (range: 4–77+ months) and median overall survival (OS) was 22 months (range: 8–77+ months; Figure 1a). However, long-term remissions of up to 77 months after alloSCT could be observed. Patients allografted in CR1 tended to have a superior DFS (p=0.119) and OS (p=0.057; Figure 1b). MAC was associated with a better OS (p=0.001) which was attributable to the significantly higher non-relapse mortality (NRM) rate of patients after RIC (p=0.014), who had been significantly older (age RIC: 56 years, age MAC: 36 years, p=0.0014). The relapse rate was not different in patients after RIC and MAC, respectively. However, there was no survivor after RIC. Median age in the autoSCT group was 47 years (range: 14–62 years). Three of 5 patients were transplanted in CR1 of whom 1 patient relapsed after 8 months, 1 patient experienced treatment related mortality and 1 patient remained in CR for 28 months. The 2 remaining patients had more advanced disease at autoSCT and relapsed 4 and 8 months thereafter. CONCLUSION: AlloSCT is effective in BPDC and might provide curative potential in this otherwise incurable disease, especially when performed in CR1. However, it remains to be shown by prospective studies if the potential benefit of alloSCT in BPDC is largely due to conditioning intensity, or if there is a relevant contribution of graft-versus-leukemia activity. Disclosures: Tilly: Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses; Genentech: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Janssen Cilag: Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 7
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2357-2357
    Abstract: Abstract 2357 There is ample evidence that poor-risk CLL, as defined by fludarabine refractoriness or the presence of deletion 17p-, can be successfully treated by allogeneic stem cell transplantation (alloSCT). It is unknown, however, whether alloSCT can also overcome the treatment resistance associated with TP53 mutations seen under conventional fludarabine combination therapy. Therefore we have assessed the impact of TP53 mutations on the outcome of alloSCT with the patient cohort enrolled on the CLL3X trial of the German CLL Study Group. Patients and Methods: The CLL3X trial included 90 patients with poor-risk CLL who were allografted with unmanipulated blood stem cells from related or unrelated donors after nonmyeloablative conditioning. With a median follow-up of 46 months, 4-year event-free (EFS) and overall survival (OS) was 42% and 65%, respectively (Blood July 1, 2010). PFS and OS of 13 patients with deletion 17p- were similar to that of patients without this abnormality. TP53 mutations were identified by denaturating high-performance liquid chromatography (DHLPC) (exons 4–10). In addition, cases with deletion 17p- where no TP53 mutation was detected were also directly sequenced. Results: The TP53 mutational status could be obtained in 72 of 90 patients who had informative DNA samples from the time of study entry available. Of these, 19 (26%) showed TP53 mutations; 7 (10%) with a concurrent deletion 17p-, and 9 (12%) in the absence of deletion 17p-. 17p- status was not available in three TP53-mutated patients (4%). Three additional patients (4%) had 17p- without TP53 mutation. Four-year EFS and OS was 46% and 56% with TP53 mutation vs 38% and 66% without TP53 mutation (Figure). Within the TP53-mutated group, 4-year EFS and OS was 44% and 56% for patients without deletion 17p- vs 38% and 50% for patients with concurrent deletion 17p-. None of these differences were statistically significant. Among the patients who were event-free 12 months post alloSCT and had results of minimal residual disease (MRD) assessment available, the probability of being MRD-negative at this landmark was 71% with TP53 mutations and 63% without (p = 1.0). Finally, multivariate analysis using Cox regression modeling (adjusting for age, deletion 17p-, remission status at alloSCT, and T cell depletion) did not show a significant impact of TP53 mutations on EFS (Hazard ratio (HR) 0.71; 95%CI 0.31–1.61) and OS (HR 1.13; 95%CI 0.41–3.12). Conclusions: AlloSCT can provide long-term EFS in about 40% of patients with poor-risk CLL with TP53 mutation independent from the presence of concurrent deletion 17p-. Disease control appears to be similar in patients with and without TP53 mutation, suggesting that alloSCT can overcome the treatment resistance associated with this abnormality. Disclosures: Stilgenbauer: Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 8
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 26, No. 9 ( 2020-09), p. 1575-1580
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
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  • 9
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3328-3328
    Abstract: Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Molecular Systems Biology, EMBO, Vol. 18, No. 8 ( 2022-08)
    Type of Medium: Online Resource
    ISSN: 1744-4292 , 1744-4292
    Language: English
    Publisher: EMBO
    Publication Date: 2022
    detail.hit.zdb_id: 2193510-5
    SSG: 12
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