Eltrombopag for Refractory Severe Aplastic Anemia: Dosing Regimens, Long-Term Follow-up, Clonal Evolution and Somatic Mutation Profiling

Abstract Eltrombopag (EPAG) received FDA approval for treatment of refractory severe aplastic anemia (rSAA) in 2014, based on our phase I/II dose escalation trial of single agent EPAG at 50-150 mg daily over a period of 12 weeks (Olnes NEJM 2012; Desmond Blood 2014). Two observations warranted further investigation of EPAG in this unique patient population. First, cell count kinetics and lack of acute toxicities suggested that extended administration of EPAG at a fixed dose of 150mg could speed and improve response rates. Second, 19% of patients developed new cytogenetic abnormalities on EPAG, raising concerns that EPAG might promote progression to MDS/AML. We conducted a subsequent phase II study of EPAG given at a fixed daily dose of 150mg for 6 months in patients with rSAA (NCT01891994). Thirty-nine patients enrolled between July 2013 and April 2017. Primary endpoint was hematologic response at 6 months. Responding participants could continue EPAG treatment. Secondary endpoints included response at 3 months and the rate of clonal cytogenetic evolution. Nineteen of 39 (49%) patients met criteria for hematologic response at 6 months. Of these, 5/19 (26%) patients would have been deemed non-responders at 3 months of treatment. EPAG was continued in 18 patients on the extension arm. EPAG was discontinued for robust response in 13/18 (72%) after a median duration of drug administration of 12 months (6-27.5 months). EPAG was re-initiated for relapse in 3/13 patients, and all 3 recovered response. At median follow up of 6 months (range 2 - 39 m), 6/39 patients (15%) developed marrow cytogenetic abnormalities, a rate comparable to our previous cohort. Given the similar rates of response and clonal evolution in our two consecutive studies, we analyzed the relationship between outcomes and cytogenetic progression for all patients (n=83) at up to 8 years of follow-up. Sixteen of 83 (18%) patients clonally evolved (Table 1). Clonal evolution was an early event after EPAG initiation. Evolution occurred within 6 months in 13/16 evolvers (81%), and in 6/6 evolvers with high risk chromosome 7 abnormalities (5/6 within 3 months). The frequency of high risk clonal evolution 24 months post intervention is comparable to historic controls with rSAA. However, direct temporal comparisons of evolution events are limited by differences in the sequence of cytogenetic tests. Non-chromosome 7 cytogenetic abnormalities were often transient, and not associated with dysplasia. Two evolvers continued EPAG off the rSAA protocol and cytogenetics normalized (UPN 71,14). The acquisition and selection of somatic mutations, particularly of myeloid candidate genes recurrently mutated in MDS/AML, has been proposed to be an initiating step in clonal evolution. We performed whole exome sequencing (WES) on samples obtained pre-EPAG treatment and at the primary response endpoint and/or time of clonal evolution in 21 responding patients and in 11 patients with cytogenetic evolution. Candidate gene mutations were detected in patients who responded (6/21) and in those with cytogenetic evolution (4/11). Clonal hematopoiesis without an identifiable driver mutation was common. In post-EPAG samples, additional myeloid candidate gene somatic mutations were detected in 2 cytogenetic evolvers and in 4 responding patients, all at low variant allele frequencies (VAF) that were close to the 2.5% detection threshold. There was no significant change in VAF in either candidate or in non-candidate genes in responders and in cytogenetic evolvers. Only one early cytogenetic evolver (UPN 01) showed an expansion of mutated clones (SETBP1 and RUNX1), from VAF of 5% to 40%, when 80% of bone marrow metaphases showed chromosome 7q deletion. In summary, extended administration of EPAG at a fixed dose of 150 mg daily for 6 instead of 3 months induces additional responses in a subgroup of patients with rSAA. After EPAG was discontinued, most patients maintained durable robust responses. The temporal relationship between clonal evolution and drug exposure suggests that in a subgroup of patients, EPAG may promote expansion of dormant pre-existing clones with an aberrant karyotype. No clinical or laboratory findings prior to therapy, including WES, predicted response or risk of clonal evolution. Careful monitoring of refSAA patients treated with EPAG is indicated, particularly in the first 6 months of treatment. Table 1 Table 1. Disclosures Winkler: Novartis/GSK to institute: Research Funding. Cooper: Novartis/GSK to institute: Research Funding. Townsley: Novartis/GSK to institute: Research Funding. Grasmeder: Novartis/GSK to institute: Research Funding. Young: Novartis/GSK to institute: Research Funding. Dunbar: Novartis/GSK to institute: Research Funding.

Download Full-text

Myeloid Neoplasm Gene Somatic Mutations in Patients with Severe Aplastic Anemia Treated with Eltrombopag and Standard Immunosuppression

Blood ◽

10.1182/blood.v128.22.727.727 ◽

2016 ◽

Vol 128 (22) ◽

pp. 727-727 ◽

Cited By ~ 1

Author(s):

Danielle M. Townsley ◽

James N. Cooper ◽

Thomas Winkler ◽

Phillip Scheinberg ◽

Olga Rios ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Research Funding ◽

Somatic Mutations ◽

Clonal Evolution ◽

Response Rates ◽

Complete Response ◽

Hematologic Response ◽

Treatment Naïve ◽

Cytogenetic Evolution

Abstract The major complication of severe aplastic anemia is clonal evolution, defined as any new cytogenetic abnormality or progression to MDS/AML, which occurs in about 15% of SAA patients, usually many months to years after the diagnosis. Eltrombopag, a thrombopoietin receptor agonist, appears capable of stimulating hematopoietic stem cell proliferation in patients with bone marrow failure. Addition of eltrombopag to standard immunosuppressive treatment (IST) with horse antithymocyte globulin (hATG) and cyclosporine (CsA) markedly increases hematologic response rates in treatment-naive SAA, with overall response rates up to 90% and complete response rates approaching 60% (Townsley DM et al, ASH 2015, clinicaltrials.gov NCT01623167). In comparison, IST alone achieves 60% overall response rates, of which 10% are complete (Scheinberg Blood 2012). Somatic mutations in myeloid cancer candidate genes are present in one-third of patients after IST alone (Yoshizato T et al, NEJM 2015). Specific subsets of mutations were associated with clinical outcomes: a group including ASXL1 and DNMT3A with a poor response to IST, inferior survival, and clonal evolution, while BCOR and PIGA were associated with good response and favorable outcomes. Monosomy 7, the most prevalent cytogenetic abnormality defining clonal evolution, can develop in the absence of gene mutations, underscoring the non-determinative and complex role mutations play in clonal evolution (Dumitriu B et al, Blood 2015). Of patients with disease refractory to IST who were subsequently treated with single-agent eltrombopag, 19% (8/43) developed cytogenetic abnormalities, usually within the first year of treatment, but only rarely with morphologic changes consistent with MDS/AML (Desmond R et al, Blood 2014). The frequency of somatic mutations following treatment with eltrombopag added to IST in treatment-naïve SAA patients is unknown. We used amplicon-based next-generation sequencing to assess mutations in 54 candidate genes recurrently mutated in myeloid neoplasms. Bone marrow cells of 90 subjects who had been treated with IST/eltrombopag were obtained at 6 months following treatment initiation, or at the time of clonal evolution. At least one detectable mutation was identified in 21 (23%) subjects. All 21 patients had exhibited a hematologic response to treatment by 6 months; of those patients with somatic mutations, 14 of 19 (74%) had a complete hematologic response. In comparison, of the 69 patients who lacked mutations, 20 (29%) had a complete response. Nine different genes were mutated in total, with the most frequent genes being ASXL1 and BCOR. BCOR was associated with more robust responses (6 of 7 had a complete response) and younger age (range 12 - 49 years; Table). One subject with a longstanding history of JAK2-positive essential thrombocytosis and myelofibrosis at baseline had two additional mutations detectable following treatment, TET2 and ASXL1. With a median follow up of 21 months, clonal cytogenetic evolution occurred in 7/90 (8%) subjects. Three of seven patients also had a mutation in a myeloid cancer gene (two with DNMT3A and one with ASXL1/RUNX1); in the other four, no somatic mutation was detected, either at the 6-month time point or at time of cytogenetic evolution. Four patients had monosomy or partial deletion of chromosome 7: one patient had complex (t(3;3)(q21;q26), -7), one patient had deletion 13q that later disappeared, and one patient had trisomy 6 and trisomy 15 in 2 metaphases. The patient with complex cytogenetics did not have somatic mutations detected at evolution, and she later died due to relapsed AML following transplant. The rates of somatic mutations in myeloid cancer genes and of cytogenetic evolution in patients treated with IST/eltrombopag do not appear to be higher than we and others have reported in aplastic anemia treated with standard IST, without eltrombopag (Kulasekararaj AG et al, Blood 2014). The distribution of genes mutated and the allelic frequency of these mutations also were similar to patients treated with standard IST. These results suggest that the benefits of a higher response rate and quality of response associated with the addition of eltrombopag to IST for the initial treatment of SAA are not associated with a higher risk of clonal progression. Disclosures Townsley: GSK/Novartis: Research Funding. Cooper:GSK/Novartis: Research Funding. Winkler:GSK/Novartis: Research Funding. Scheinberg:Novartis: Consultancy, Speakers Bureau. Rios:GSK/Novartis: Research Funding. Weinstein:GSK/Novartis: Research Funding. Desierto:GSK/Novartis: Research Funding. Fernandez Ibanez:GSK/Novartis: Research Funding. Dunbar:GSK/Novartis: Research Funding. Ma:Neogenomics Laboratories: Employment. Albitar:Neogenomics Laboratories: Employment, Equity Ownership. Young:GSK/Novartis: Research Funding.

Download Full-text

Eltrombopag for Moderate Aplastic Anemia and Unilineage Cytopenias: Dosing, Long-Term Follow-up, Clonal Evolution and Somatic Mutation Profiling

Blood ◽

10.1182/blood-2018-99-112994 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 538-538

Author(s):

Xing Fan ◽

Thomas Winkler ◽

Ronan Desmond ◽

Bogdan Dumitriu ◽

Danielle M. Townsley ◽

...

Keyword(s):

Aplastic Anemia ◽

Median Duration ◽

Primary Endpoint ◽

Health Research ◽

Research Funding ◽

Somatic Mutations ◽

Clonal Evolution ◽

Severe Thrombocytopenia ◽

Severe Anemia

Abstract Eltrombopag (EPAG) received FDA approval for treatment of refractory severe aplastic anemia (rSAA) in 2014, based on our phase I/II dose escalation trial of single agent EPAG for patients failing one or more treatment cycles with ATG/cyclosporine (Olnes NEJM 2012; Desmond Blood 2014). There is no standard treatment for patients with moderate aplastic anemia (MAA) or hypo-productive uni-lineage cytopenias (MAA/UC), conditions that can also impact on morbidity, mortality and quality of life. To explore the safety and effectiveness of EPAG in MAA/UC, we conducted a phase II study of EPAG given at escalating doses from 50-300mg/day (25-150mg/day for East Asians) through a primary hematologic response endpoint at 16-20 weeks (NCT 01328587). 34 patients enrolled between February 2012 and March 2017. 27 had never been treated with ATG/CSA IST. Responding patients could continue EPAG treatment on an extension arm. The drug was well-tolerated in 33/34 patients, with 1 patient coming off study at 10 weeks for nausea and vomiting. 25 patients reached the maximal dose. The median duration of follow-up in all patients was 16 months, and 27 months in responding patients. 17 of 34 (50%) of patients met criteria for response at the primary endpoint in at least one initially protocol-qualifying lineage (Hb <8.5 or RBC transfusion-dependence and/or platelets < 30,000 or platelet transfusion-dependence). 12 of 23 with severe anemia had an erythroid response (> 1.5 gr/dL increase in Hb or > 50% reduction in transfusions), including a patient with RSP19-mutated Diamond-Blackfan anemia. 7/24 with severe thrombocytopenia had a platelet response (>20,000/ul or transfusion-independence). 2/13 with both severe anemia and thrombocytopenia had bi-lineage responses at the primary endpoint, and an additional 5 went on to bi-lineage responses during the extension period. 3 patients without a response to EPAG were later treated with ATG/CSA and responded. EPAG was discontinued in 11/17 (65%) responding patients upon achievement of robust blood counts (Hb > 10mg/dL, platelets > 50,000/uL, and ANC > 1000) or stable blood counts for 6 months in 1 patient (6%) after a median duration of drug administration of 8 months (2-14 months) (Fig 1). In contrast to our prior experience in rSAA, the majority of patients still being followed on study after drug discontinuation (8/10) needed to have EPAG re-initiated for declining counts at a median of 6 months (2-38) later. All 8 responded again, with 4/8 able to discontinue EPAG after a second robust or stable response. 2/34 patients (6%) developed marrow cytogenetic abnormalities while on drug in contrast to 16/83 (16%) rSAA patients treated with EPAG in our prior studies. Both MAA patients were responders and neither had dysplastic changes or increased blasts. Patient # 5 had +8 in 7/20 metaphases at 22m, went off drug and relapsed, and EPAG was restarted off protocol. Repeat cytogenetics on EPAG were normal. Patient #20 had del13q in 5/20 metaphases at 9.5m, EPAG was stopped, and repeat cytogenetics off drug were normal. Of note, patient #12 had a robust response and had been off drug for 25m when counts declined and BM revealed dysplastic changes with no increase in blasts and normal cytogenetics. The acquisition and selection of somatic mutations, particularly in myeloid candidate genes (MCG) recurrently mutated in MDS/AMLhas been proposed to be an initiating step in clonal evolution. We performed targeted next generation exome sequencing (NGS) of 66 MCG and additional genes previously found to be somatically-mutated in SAA (Yoshizato, NEJM, 2015) pre-EPAG treatment and at the primary response endpoint of 16-20 weeks. Only 5 patients showed somatic mutations in these genes at baseline (SETBP1, CBL, SF3B1, PPMID, EP300). There were no significant changes in VAF. 2 mutations became detectable on EPAG (BCOR, and DNMT3A transiently), and 1 disappeared (SF3B1). In summary, administration of EPAG at escalating doses up to of 300mg/day was well-tolerated and 50% of patients with MAA/UC had clinically-meaningful responses, including those not previously treated with IST. The responses were durable, often robust, although frequently required ongoing EPAG treatment, in contrast to the experience in rSAA. Clonal cytogenetic evolution was rare, with no instances of chromosome 7 abnormalities, and there was no consistent expansion of MCG somatically-mutated clone size in patients during EPAG treatment. Figure. Figure. Disclosures Winkler: National Institute of Health: Research Funding. Young:CRADA with Novartis: Research Funding; GlaxoSmithKline: Research Funding; National Institute of Health: Research Funding. Dunbar:National Institute of Health: Research Funding.

Download Full-text

Incidence and Outcomes of Chronic Myeloid Leukemia (CML) Patients (pts) with Other Chromosomal Abnormalities (OCA) Treated with Second Generation Tyrosine Kinase Inhibitors (TKI)

Blood ◽

10.1182/blood.v120.21.4311.4311 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4311-4311

Author(s):

Naveen Pemmaraju ◽

Hagop M. Kantarjian ◽

Elias J. Jabbour ◽

Alfonso Quintás-Cardama ◽

Gautam Borthakur ◽

...

Keyword(s):

Research Funding ◽

Chromosomal Abnormalities ◽

Clonal Evolution ◽

Philadelphia Chromosome ◽

Group Versus ◽

Chronic Phase ◽

Initial Therapy ◽

Chromosome 7 ◽

2Nd Generation

Abstract Abstract 4311 Background: Development of OCA (i.e., chromosomal abnormalities in the Philadelphia chromosome negative metaphases) has been reported among patients receiving imatinib as initial therapy for CML. Little is known about incidence and outcomes of OCA in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Objectives: We describe incidence of OCAs in CML pts treated with frontline 2nd generation TKI and determine the outcomes of pts who develop OCA events. Methods: We reviewed pts treated with frontline 2nd generation TKI, dasatinib (n=99) or nilotinib (n=117), treated on 2 parallel ongoing prospective single-arm Phase II protocols at our institution. An OCA was defined as a cytogenetic abnormality in one or more non-Philadelphia chromosome positive clones (different than clonal evolution). Pts were followed with cytogenetic analysis at 3 month (mo) intervals for the first year, then every 6–12 mo. 30 pts with OCA were identified. Pts in chronic (n=25) or accelerated phase (n=5) at diagnosis were included in the analysis. Results: With a median follow-up of 30 mo (range 0–71), 11 (11%) pts treated with dasatinib and 19 (16%) pts treated with nilotinib developed OCA. The difference in incidence of OCA with dasatinib and nilotinib was not statistically significant (p=0.280). At start of therapy, median age of pts developing OCA was 53 (41–71) with dasatinib and 52 (37–82) with nilotinib, compared to those pts without OCA: 48 (18–83 yrs) with dasatinib and 49 (17–87) with nilotinib. The most common OCA event overall was abnormality of chromosome 7 found in 5 pts (one pt with both inv(7) and +7) for total of 6 occurrences (including inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1) involving chromosome 7). The most common translocation event was t(6;13) in 2 pts. No pts developed trisomy 8 (historically most common OCA among imatinib treated pts). Median time to first appearance of OCA was 9 mo (range 3–58) for all 2nd generation TKI pts (12 mo (range 3–58) for dasatinib group and 9 mo (3–48) for nilotinib group). 9 pts had OCA on more than one occasion. OCA disappeared in 25 pts during course of follow-up. Outcomes for OCA group versus non-OCA group are shown in Table 1, and outcomes with focus on chronic phase pts only in Table 2. For pts in accelerated phase, 3/6 pts (50%) in dasatinib group and 2/17 pts (12%) in nilotinib group developed an OCA. None of the pts who developed OCA has developed AML or MDS. Conclusions: OCA are observed in 10–15% of pts receiving initial therapy with 2nd generation TKI. At median follow up of 30 mo, occurrence of OCA confers no statistically significant adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders. Disclosures: Off Label Use: Dasatinib and Nilotinib originally used in investigational setting when trials were begun. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cortes:Novartis, BMS, ARIAD, Pfizer: Consultancy, Research Funding.

Download Full-text

Could Chronic Gvhd Overcome the Poor Prognosis of Patients with MDS and TP53 Undergoing Allogeneic HSCT?

Blood ◽

10.1182/blood.v126.23.2890.2890 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2890-2890

Author(s):

Juan Carlos Caballero ◽

Mercedes Sánchez-Barba ◽

Mónica Del Rey ◽

Kamila Janusz ◽

Eva Lumbreras ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Somatic Mutations ◽

Advisory Committees ◽

Poor Outcome

Abstract Background and Aim Although new agents have been approved for the treatment of MDS, the only curative approach for these patients is allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, in these patients this approach has only obtained 40-60% of overall survival. Somatic mutations in MDS have recently been analyzed in order to confirm clonally and also prognostic impact in MDS patients. In this regard, TP 53 mutated gene is present in MDS in less than 10% of patients and is associated with advanced disease and high-risk features. Recent studies confirms poor outcomes in patients with TP 53 mutated receiving allogeneic stem cell transplantation1,2. The present study try to analyze if the development of chronic graft versus host disease (cGVHD) could modify, due to graft versus leukemia effect, the adverse prognosis of these high-risk patients (TP53 mutated patients). Design and Methods <>Results of HSCT in 92 MDS patients from 5 centers in Spain were retrospectively studied. Samples were collected 1 month prior to transplant. 280ng of the genomic DNA from BM cells was screened for somatic mutations in TP53 gene. The study was done by NGS on a GS Junior Instrument (Roche) according to an amplicon sequencing design. For each sample, eight exons (4-11) were amplified with preconfigured primer plates provided within the IRON II study network. Data analysis, were carried out using the Sequence Pilot software version 3.5.2 (JSI Medical Systems) and GS Amplicon Variant Analyzer software, versions 2.7 and 2.9 (Roche Applied Science). Minimum coverage of sequenced exons was 100 reads and the sensitivity of variant detection was set to a lower limit of >2% for bidirectional reads. Only those variants that resulted in amino acid change in the protein sequence were considered. OS and RFS were calculated using the Kaplan-Meier method. The log-rank test was used for comparisons. All calculations were done using SPSS 18.0. Cumulative incidence of relapse was also calculated by xlstat version 2014 program. <>Results Median age was 54 years (17-69), 71.7% were "de novo" MDS and regarding IPSS, 53% were in the int-2/high-risk category. Other characteristics were in Table 1. In the pre-transplant evaluation, 15 patients out of 92 (16,3%) were TP 53 mutated. The mutations were located in exons 5, 6, 7, 8 and 10. These variations were present in a variable percentageof the cell population (3 to 84%). All mutations were specific nucleotide changes except for two cases. At the time of the last update, 16 patients had relapsed (17.4%) and 40 had died (43.5%). After a median follow up of 15.5 months, OS was 56.5%. Median OS for patients with mutated TP53 trend a toward to be shorter than survival for patients without mutated TP53 (median of 7 mo vs median not reached, respectively, p=0.156). Multivariate analysis for OS confirmed complex karyotype (HR 5,588, 95CI 1,794-17,407, p=0.003) and no developement of cGVHD (HR 3,531, 95IC 1,634-7,632, p=0.001) as predictors for poor outcome. Cumulative incidence of relapse was 20.3% (+/-4.3%) at 1 years. Mutational status of TP53 significantly influenced on relapse (53.3% +/-12.9% vs 13.7% +/-4% at 1 year for patients with vs without TP 53 mutation (Gray test=0.001, Figure 2). Regarding Relapse Free Survival (RFS), after a median of follow up of 17 months, RFS was 67.9% and as previously suggested, the presence of TP 53 mutation had an impact on RFS (41.7% for mutated (median RFS of 6 months) and 75% for non mutated patients (median RFS not reached), p=0.009). Multivariate analysis for RFS confirmed age (HR 1.054, 95CI 1.005-1.106, p=0.032) and TP 53 mutated (HR 3.054, 95IC 1.145-8.149, p=0.026) as predictors for lower RFS. Regarding 15 patients with mutated TP 53, 7 did relapsed and 9 had died. Developement of cGVHD showed a trend toward to improve outcome among TP 53 mutated patients, with a better OS and RFS for those developing cGVHD as compared to those who did not (OS of 55% vs 17% for patients with and without cGVHD, p=0.039, Figure 2 and RFS of 71% vs 50%, respectively, p=0.3). <>Conclusions Mutated TP53 pre-allo patients presents poor outcome as compared to not mutated, as previously described Bejar1 and Kim2. Nevertheless, the developement of cGVHD could overcome the adverse impact of this factor due to the developement of graft versus tumor efect, improving survival curves (OS and RFS) as compared to previous published results. Study supported by GRS-1033/A/14 P53. 1.-BŽjar, JCO 2014, 32(25). 2.-Kim, BBMT 2015, Epub ahead of print. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sanz: JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Valcarcel:AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Díez-Campelo:CELGENE: Research Funding, Speakers Bureau; JANSSEN: Research Funding; NOVARTIS: Research Funding, Speakers Bureau.

Download Full-text

Cytogenetic Progression in Patients with Multiple Myeloma As Assessed By Serial Bone Marrow Biopsy Is Associated with Worse Outcome

Blood ◽

10.1182/blood.v126.23.4209.4209 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4209-4209

Author(s):

Catherine Randall Paschal ◽

Jens C Eickhoff ◽

Aric C Hall ◽

Jennifer Laffin ◽

Natalie Scott Callander ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

High Risk ◽

Risk Group ◽

Clonal Evolution ◽

Intermediate Risk ◽

Disease Course ◽

Cytogenetic Abnormalities ◽

Standard Risk

Abstract Background:Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal, mutated plasma cells, which ultimately leads to multi-organ damage and in most cases death. Despite improved treatments, clinical heterogeneity remains, with some patients succumbing to disease within 1-2 years. Certain cytogenetic and FISH abnormalities at diagnosis confer a higher likelihood of poor outcomes (Mikhael et al., 2013). Still, the utility of repeated cytogenetic assessment over the course of disease is unknown. Methods: We performed a retrospective review to identify MM patients with cytogenetics (CG) performed at diagnosis who had two or more bone marrow (BM) examinations performed during follow up over a five year period at UW Carbone Cancer Center. We reviewed the pathology and CG results from each BM sample. CG data was categorized into risk groups using the mSMART stratification criteria: High risk - deletion 17p13, t(14;16), t(14;20); intermediate risk - t(4;14), hypodiploid, deletion 13, gain of 1q21; standard risk - hyperdiploidy and all other abnormalities, and normal CG. CG progression over disease course was categorized based on stability or change in CG risk group. We measured survival from date of diagnosis to death or last follow up. Results: 130 patients with CG at diagnosis were identified over the five year period of the study. These patients had 365 follow-up bone marrow (BM) aspirates, 341 with repeat CG study. Initial cytogenetics were as follows: 90 (69%) of 130 patients had normal CG at diagnosis, 13 (10%) standard risk CG, 16 (13%) intermediate risk CG, and 11 (8%) high risk CG. Serial CG studies showed both development of new CG abnormalities in patients with previously normal studies, and clonal evolution with CG abnormal patients acquiring additional abnormalities on repeat testing. 24 (27%) of 90 patients with normal CG at diagnosis developed abnormal CG during disease course: 12 had intermediate risk CG and 9 high risk CG, the latter all due to p53 deletion. Clonal evolution and drift among initially CG abnormal patients were also common. Of the 34 patients with abnormal CG results on diagnosis and subsequent bone marrow samples, clonal evolution was identified in 19 patients (56%) and 4 (12%) patients developed new CG abnormalities unrelated to the prior clone, while 11 (32%) showed stable CG. Despite this high rate of change, only two patients with abnormal CG at diagnosis moved from a lower to a higher cytogenetic risk group. When we correlated CG at diagnosis with survival, we found that patients with high risk CG at diagnosis appeared to have shorter median overall survival at 3.8 yrs (range 1-12 yrs) compared with 7.4 yrs (range 2-12 yrs) for intermediate risk, 8.5 yrs (range 2-9 yrs) for standard risk, and 8.2 yrs (range 1-12 yrs) for normal CG. Comparison among all four groups was not statistically significant however, possibly due to the small proportion of high risk CG patients. When we examined the effect of acquiring CG abnormalities, we found that development of abnormal CG in patients with normal CG at diagnosis was associated with shorter median OS (4.0 yrs) compared to either persistent normal CG (11.3 yrs) or any CG abnormality at diagnosis (7.4 yrs), overall comparison p = 0.0048. Conclusion: Our longitudinal study of 130 unselected patients with MM revealed a cohort who showed cytogenetic progression. In patients with normal CG at diagnosis, the presence of cytogenetic abnormalities in follow-up BM specimens was associated with inferior overall survival. This finding indicates that serial testing may facilitate the detection of a higher risk patient cohort. Further analysis is underway to identify clinical parameters that underlie a higher risk of clonal evolution or development of new cytogenetic abnormalities. The results of our study will help elucidate the optimal prognostic utility of cytogenetic analysis in patient care. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Clofarabine (Clo) and Busulfan (Bu) as a Novel Reduced Toxicity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation (HCT) In Patients (pts) with Acute Lymphoblastic Leukemia (ALL).

Blood ◽

10.1182/blood.v116.21.3484.3484 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3484-3484

Author(s):

Partow Kebriaei ◽

Celina Ledesma ◽

Kirk Culotta ◽

Elizabeth J. Shpall ◽

Stefan O. Ciurea ◽

...

Keyword(s):

High Risk ◽

Disease Control ◽

Research Funding ◽

Hematopoietic Cell ◽

Mixed Chimerism ◽

Fixed Dose ◽

Unrelated Donor ◽

Allogeneic Hct ◽

Grade Ii

Abstract Abstract 3484 Allogeneic HCT improves long-term disease control in pts with ALL, but the treatment-related mortality (TRM) associated with most myeloablative transplant conditioning regimens limits the benefits of HCT. Therefore, we investigated a novel regimen consisting of Clo combined with intravenous (i.v.) Bu in patients with ALL undergoing allogeneic HCT. Methods: Clo 40 mg/m2 followed by Bu 130 mg/m2 were infused daily for 4 days followed by hematopoietic cell infusion 2 days later. Bu was infused either as a fixed dose per BSA, or to target an average daily AUC of 5,500 microMol-min for pts up to 60 years of age or 4000 microMol-min for pts greater than 60 years, determined by a test dose of Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. Dilantin was given for seizure prophylaxis. GVHD prophylaxis was based on tacrolimus and mini-MTX, with the addition of rabbit anti-thymocyte globulin (4 mg/kg total dose) for unrelated donor transplants. The presence of minimal residual disease (MRD) was determined by multiparameter flow cytometry. Results: 14 pts (12 B-lineage, 2 T-lineage) with median age 29 years (range 21–64) received an allogeneic matched sibling (n=8) or matched unrelated donor (n=6) HCT in CR1 (n=7, 3 MRD positive), CR2 (n=6, 3 MRD positive), or refractory relapse (n=1). Nine pts had high-risk cytogenetic profiles as defined by the presence of t(9;22), t(4;11), or complex cytogenetics. The median time from diagnosis to HCT was 8.5 months (range 2–115) with a median 2 lines of chemotherapy received (range 1–3). Median days to ANC > 0.5 × 109/L and platelet count > 20 × 109/L were 12 (range 10–14) and 16 (13-23), respectively. The most common toxicity was mucositis (8 grade II, 2 grade III). Grade 3 reversible elevation of liver function tests was noted in 3 pts. No VOD or renal toxicity was noted. One pt with a prior history of stenotrophomas and fungal pneumonia died of pneumonia complications 18 days after HCT. Eleven pts are evaluable for response. All evaluable pts achieved CR clearing MRD by day +30 after HCT. Five pts achieved full donor chimerism at 30 days following HCT, 4 pts remain with mixed chimerism at 60 day assessment following HCT, and 1 pt progressed early. The incidence of grades II-IV acute GVHD is 40% (n=3 grade II GI, n=1 steroid refractory liver); chronic GVHD was not assessed due to short follow-up. With a median follow-up of 3 months among surviving patients (0.4-8), overall and disease-free survival is 92% at 3 months. Two pts in CR2 with persistent MRD at time of HCT progressed at a median 5 months following HCT. Two pts older than 60 years were treated on the reduced Bu dose arm, and both remain in continued remission. Conclusion: The CloBu combination is well-tolerated in this small cohort of patients with high-risk ALL who received a median of 8.5 months of intensive (mainly HCVAD-based) chemotherapy prior to receiving transplant. The clearing of MRD encourages further investigation of this regimen. Longer follow-up is needed to more completely assess disease control. Disclosures: Kebriaei: Otsuka Pharmaceuticals: Research Funding. Off Label Use: Busulfan and Clofarabine for trasplant conditioning. De Lima:Otsuka: Membership on an entity's Board of Directors or advisory committees. Champlin:Otsuka: Research Funding; Genzyme: Consultancy. Andersson:Otsuka: Consultancy.

Download Full-text

Prognostic Correlates and Outcomes of Relapsed T-Cell Acute Lymphoblastic Leukemia/Lymphoma: An Analysis of 41 Consecutive Patients

Blood ◽

10.1182/blood.v126.23.3730.3730 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3730-3730

Author(s):

Tasha Lin ◽

Hassan B Alkhateeb ◽

Aref Al-Kali ◽

Michelle Ann Elliott ◽

Naseema Gangat ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Complete Remission ◽

Treatment Outcomes ◽

Median Time ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Relapsed Disease

Abstract Background: Acute T-cell lymphoblastic leukemia (T-ALL)/ lymphoma (T-LBL) are immature T-cell malignancies with very poor outcomes. In patients with relapsed disease, survival is often < 12 months (Marks et al, Blood, 2009). Prognostic correlates and treatment outcomes after relapse remain largely unknown. Aims: To evaluate prognostic correlates and treatment outcomes in patients with relapsed T-ALL/LBL. Methods: After IRB approval, 92 consecutive patients with T-cell ALL/LBL were identified. 41 patients with relapsed disease after achieving a first complete remission (CR1) were included in the study group. Features at the time of relapse were retrospectively abstracted and analyzed. Survival time after relapse was calculated from the time of relapse until death or last follow-up. Conventional methods were used for statistical analysis. Results: A. Baseline characteristics of all patients 92 patients were identified [41 LBL, 51 ALL]. Median age was 33 years (range; 18-88) and 66 (72%) were males. Median follow-up was 25 months (range 0.9-260). 13(14%) received palliative care or were lost to follow-up before treatment initiation. At last follow-up, there were 41 (52%, n = 79) relapses and 42 (46%, n = 92) deaths. Of 79 patients, 71 (90%) achieved a CR1 and 8 (10%) had primary refractory disease. Comparisons between ALL and LBL revealed expected differences in presenting features such as frequency of primary mediastinal mass at presentation in LBL and high leukocyte count in ALL. Significant differences in treatment were seen. Asparaginase-based and ALL-directed therapy were more common in the ALL group (71% vs. 45%, p = 0.009; 88% vs. 71%, p = 0.04). 13 (81%) LBL and 14 (27%) ALL underwent allogeneic SCT. The remaining three in each group underwent autologous SCT in CR1. B. Characteristics of relapsed patients 41 relapsed after achieving CR1 [23 LBL, 18 ALL]. Median time to relapse was 8.0 months (range 2.3-130), with no difference between ALL and LBL groups. Median age was 34 years (range 19-71) and 29 (71%) were males. Median follow-up after relapse was 7.2 months (range 0.3-207). At time of last follow-up, there were 30 (73%) deaths, 25 (61%) achieved a second complete remission (CR2) and 14 (34%) had persistent disease. 12 (48%) had relapse following CR2. 34 (83%) relapsed following CR1 after induction chemotherapy alone. 6 (15%) and 1 (2%) relapsed following allogeneic and autologous SCT respectively. 27 (66%) had BM involvement, 5 (12%) had CNS involvement, 13 (32%) had mediastinal involvement, and 3 (7%) had isolated extramedullary relapse. Ten (43%) patients with LBL relapsed with ALL. Of 27 patients with available data, 9 (33%) had high-risk cytogenetics at relapse, defined as ≥ 5 chromosomal abnormalities and/or markers known to confer an unfavorable prognosis. 16 of these 27 patients had follow-up cytogenetic studies performed, of which 8 (50%) had evidence of clonal evolution. Patients were treated with up to five regimens. 12 (31%) received asparaginase-based therapy and 13 (33%) received nelarabine with CR2 rates of 75% and 25% respectively. Median number of regimens needed to achieve CR2 was one. 18 (46%) went onto SCT following CR2: 14 (allogeneic), 3 (autologous), and 1 (donor lymphocyte infusion). The majority received myeloablative conditioning (92%). C. Outcomes and prognostic correlates for survival after relapse Median survival following relapse was 8.2 months (IQR 4.1-21.3) and did not differ between LBL and ALL. Nine (36%) who achieved CR2 are alive at time of last follow-up. 25 (61%) achieved CR2, but 12 (48%) relapsed following CR2, with median time to second relapse of 7.6 months (IQR 4.7-14). Nine of 18 who underwent SCT following CR2 had disease relapse (8 allogeneic, 1 autologous). Only BM involvement at relapse significantly correlated with post-relapse survival (HR 2.4 [1.1, 5.1], p = 0.03). Clonal evolution, high-risk cytogenetics, nelarabine therapy, achieving CR2, and SCT were not independent predictors of survival in our small subset of patients. Conclusion: Patients with relapsed T-ALL/LBL have dismal outcomes, in spite of advances in therapy with newer agents such as nelarabine and the use of allogeneic SCT. Regardless of T-ALL/LBL subtype, BM involvement at relapse appears to be a significant factor negatively impacting post-relapse survival. Further studies are needed to validate these findings. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding.

Download Full-text

Lenalidomide Induction and Maintenance Maximizes Outcome for Newly Diagnosed Transplant Eligible Myeloma Patients Irrespective of Risk Status: Long-Term Follow-up of the Myeloma XI Trial

Blood ◽

10.1182/blood-2019-126160 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1910-1910 ◽

Cited By ~ 1

Author(s):

Graham Jackson ◽

Charlotte Pawlyn ◽

David Cairns ◽

John R Jones ◽

Bhuvan Kishore ◽

...

Keyword(s):

High Risk ◽

Financial Support ◽

Research Funding ◽

Risk Groups ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Long Term Follow Up

Background: Immunomodulatory (IMiD) compounds are effective therapies for multiple myeloma (MM) acting via modulation of the CUL4 E3-ubiquitin ligase cereblon. Based on their structure individual IMiD compounds have different substrate specificities altering both their efficacy and side effect profile. These mechanistic differences impact the optimum sequencing of these agents as induction and maintenance. Within the UK NCRI Myeloma XI trial we compared triplet induction regimens containing Lenalidomide (Len) or Thalidomide (Thal) and maintenance treatment with Len or observation. With extensive long term follow up data we have explored the interaction of the induction and maintenance use of Thal and Len before and after ASCT. Methods: Myeloma XI is a multicenter, randomized controlled trial for newly diagnosed MM, with pathways for transplant eligible (TE) and non-eligible patients. TE patients were randomized between Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to max. response. For patients with a suboptimal response there was a subsequent randomization to intensification with a proteasome inhibitor containing triplet or no further therapy prior to ASCT. A maintenance randomization at 3 months post ASCT compared Len till disease progression vs observation (Obs). Analyses by molecular risk strata were pre-specified in the protocol. Adverse cytogenetic abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), or del(17p): standard risk (SR, no adverse cytogenetic abnormalities), high risk (HiR, one adverse cytogenetic abnormality), or ultra-high risk (UHiR, two or more adverse cytogenetic abnormalities). Results: 2042 TE patients were randomized to CRD n=1021 and CTD n=1021. After a median follow up of 68 months (interquartile range 49-83) for the induction randomization, 1378 PFS and 728 OS primary endpoint events had occurred. Patients received a median (range) of 5 (1-18) cycles of CRD and 5 (1-13) cycles of CTD induction therapy. There were higher rates of haematological toxicity with CRD and peripheral neuropathy with CTD. CRD induction was associated with a significantly improved median PFS (hazard ratio (HR) 0.86, 95%CI 0.77, 0.96, CRD 36 months vs CTD 33 months, P=0.005, Figure 1A) and median OS (HR 0.81, 95%CI 0.70, 0.93, CRD 96 months vs CTD 85 months, P=0.004, Figure 1B). Responses were deeper with CRD (>=VGPR 65.3%, PR 24.5%) than CTD (>=VGPR 52.8%, PR 33.2%) and depth of response was associated with outcome. Significant heterogeneity in PFS outcome was identified between molecular risk groups with HiR and UHiR benefiting most from induction with CRD rather than CTD (SR HR 0.99 [95%CI 0.79, 1.24], HiR HR 0.58 [0.44, 0.78], UHiR HR 0.60 [0.38, 0.94], P.het 0.01). 897 TE patients were randomized to Len (n=496) and Obs (n=401). After a median follow up of 68 months (interquartile range 51-84) for the maintenance randomization, 527 PFS primary endpoint events had occurred. Lenalidomide was associated with a significant improvement in PFS compared to observation (median PFS Len 64 [54,76] vs Obs 32 [28,36], HR 0.52 [0.45,0.61], P<0.001). This was consistent across all risk subgroups (SR HR 0.44 [95%CI 0.34, 0.56], HiR HR 0.50 [0.37, 0.67], UHiR HR 0.52 [0.31, 0.87], P. het 0.87). Optimum outcomes were seen in those receiving Len as both induction and maintenance therapy (Figure 1C). Patients receiving CRD induction followed by Len maintenance (CRD-R) had a median PFS of 77 months [56, 86] compared to CTD-R 64 [49, 74], CRD-Obs 37 [33, 42] and CTD-Obs 44 [38, 51]. Conclusions: In this study the use of Len as both induction and maintenance was associated with the best outcomes irrespective of cytogenetic risk group. With long term follow up CRD induction for newly diagnosed transplant eligible myeloma patients was associated with both a PFS and OS benefit compared to CTD and was better tolerated. The PFS impact of CRD was particularly notable in patients with high and ultra-high risk disease. Lenalidomide maintenance was associated with significantly longer PFS than observation across all risk groups. on behalf of the NCRI Haematological Oncology Clinical Studies Group Disclosures Jackson: Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jones:Celgene: Honoraria, Research Funding. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria; Novartis, Janssen: Research Funding. Lindsay:Celgene: Other: personal fees and non-financial support ; Takeda: Other: personal fees and non-financial support ; Amgen: Other: non-financial support. Russell:Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding. Gregory:Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding; Amgen, Merck: Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. OffLabel Disclosure: CTD/CRD induction therapy and Lenalidomide maintenance 10mg 21/28 days

Download Full-text

Randomized Trial of Two Dosages of Rabbit Antithymocyte Globulin in Patients with Aplastic Anemia

Blood ◽

10.1182/blood-2018-99-111323 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3873-3873

Author(s):

Atsushi Narita ◽

Xiaofan Zhu ◽

Hideki Muramatsu ◽

Xiaojuan Chen ◽

Ye Guo ◽

...

Keyword(s):

Logistic Regression ◽

Regression Analysis ◽

Aplastic Anemia ◽

Research Funding ◽

Antithymocyte Globulin ◽

Clonal Evolution ◽

Multivariate Logistic Regression Analysis ◽

Multivariate Logistic Regression ◽

Free Survival

Abstract Introduction: In patients with severe aplastic anemia (SAA) who are not candidates for stem cell transplantation (SCT), immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CyA) is the treatment of choice. A randomized controlled trial demonstrated the inferiority of rabbit ATG compared with horse ATG for first-line treatment of SAA (Scheinberg et al. N Engl J Med 365:430-438, 2011). However, horse ATG remains unavailable in many countries outside the USA. In Asian countries, the recommended dose of rabbit ATG ranges from 2.5 to 3.5 mg/kg/day. Here we report the first prospective randomized multicenter study comparing two dosages of rabbit ATG in patients with SAA (www.umin.ac.jp UMIN000011134). Methods: Patients with SAA who required initial IST in Japan (n = 89), China (n = 85), and Korea (n= 48) were enrolled between May 2012 and October 2017. Randomization was 1:1 in blocks between the two dosages of rabbit ATGs. The IST regimen comprised rabbit ATG (thymoglobulin®, 2.5 or 3.5 mg/kg/day for 5 days), CyA (6 mg/kg/day for minimum 6 months), and methylprednisolone (2 mg/kg/day for 5 days) with subsequent tapering of the dose for 28 days. The dose of CyA was adjusted to maintain whole blood trough concentrations between 150 and 250 ng/mL. The primary endpoint was hematologic response at day 180. Secondary endpoints included frequency of Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD), hematologic response at day 360, relapse, and overall survival (OS). Results: In total, 222 patients (age 0.5-71.0 years) were randomized, with 112 patients receiving 2.5 mg/kg and 110 receiving 3.5 mg/kg of rabbit ATG. Patient characteristics were well matched between the two groups. Median follow-up duration for all patients was 742 days from first ATG infusion (range, 16-2165) and 887 days for those surviving till the end of the study (range, 32-1757). After 3 months, in the 2.5mg/kg of rabbit ATG group, 4 (4%) patients achieved a complete response (CR) and 35 (31%) a partial response (PR), for an overall response rate (ORR) of 35%. In the 3.5mg/kg of rabbit ATG group, 1 (1%) patient achieved a CR and 43 (39%) a PR, for an ORR of 40%. After 6 months, in the 2.5mg/kg of rabbit ATG group, 55 patients (49%) achieved an ORR including 7 (6%) who achieved a CR and 48 (43%) PR. In the 3.5mg/kg of rabbit ATG group, 53 patients (48%) achieved a response including CR in 9 patients (8%) and PR in 44 (40%). The response rates did not differ significantly between the two groups at 3 (P = 0.488) or 6 (P = 0.894) months. Multivariate logistic regression analysis identified disease severity [odds ratio (OR), 2.09; 95% confidence interval (CI), 1.18−3.67; P = 0·011] and interval between diagnosis and treatment (OR, 1.86; 95% CI, 1.07−3.22; P = 0.027) as independent predictors of response to IST at 6 months. Despite relatively short follow-up, relapse and clonal evolution occurred with similar frequencies between the two groups, with 4 relapse (among 55 responders) and 1 clonal evolution in the 2.5 mg/kg group and 4 relapse (among 53 responders) and no evolutions in the 3.5 mg/kg group. One patient in the 3.5 mg/kg group developed EBV-LPD at day 109 after IST. During follow-up, 22 (10%) patients died, all of whom showed no response to IST. The causes of death were infections (n = 13), hemorrhage (n = 4), SCT-related complications (n = 2), clonal evolution (n = 1), and unknown (n = 2). Transplantation free survival (TFS), failure free survival (FFS), and OS at three-year were similar between the two groups [TFS, 73% (95% CI, 63%−81%) vs. 71% (95% CI, 60%−80%); P = 0.991; FFS, 45% (95% CI, 35%−54%) vs. 45% (95% CI, 61%−84%); P = 0.909; OS, 85% (95% CI, 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0.107]. Multivariate logistic regression analysis revealed that lack of response to IST was an independent predictor of OS (OR, 6.95; 95% CI, 1.76%−27.46%; P = 0.006). Conclusions: The current study revealed no differences in the efficacy and safety between 2.5 mg/kg and 3.5 mg/kg dose of rabbit ATG for patients with SAA. However, as the follow-up period was relatively short, longer surveillance is warranted to compare long-term complications and survival rates between the two groups in the follow up study. Disclosures Usuki: Daiichi Sankyo: Research Funding; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Novartis: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; SymBio Pharmaceuticals Limited.: Research Funding; Shire Japan: Research Funding; Sanofi K.K.: Research Funding; Pfizer Japan: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; GlaxoSmithKline K.K.: Research Funding; Celgene Corporation: Research Funding, Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Nakao:Novartis: Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Download Full-text

Occurrence and Prognostic Significance of Cytogenetic Evolution in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.4176.4176 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4176-4176

Author(s):

Moritz Binder ◽

S. Vincent Rajkumar ◽

Rhett P. Ketterling ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Risk Stratification ◽

Research Funding ◽

Prognostic Significance ◽

Parameter Estimates ◽

Nested Models ◽

Cytogenetic Evolution

Abstract Background: Cytogenetic evaluation, especially using fluorescence in situ hybridization (FISH), at the time of diagnosis is essential for initial risk stratification and the employment of risk-adapted treatment strategies in multiple myeloma. Little is known about the occurrence and prognostic significance of cytogenetic evolution during follow up. Methods: We studied 433 patients who were diagnosed with multiple myeloma between January 2000 and December 2011 and had at least two FISH evaluations at Mayo Clinic Rochester, including the diagnostic specimen. Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Cytogenetic evolution was defined as a new deletion, monosomy, trisomy, tetrasomy, or translocation during follow up. Multivariable-adjusted logistic regression models were used to assess the associations between the parameters of interest and the presence of cytogenetic evolution in follow-up specimens. Multivariable-adjusted Cox proportional hazards models were used to assess the effect of cytogenetic evolution on overall survival. All models were adjusted for sex, age, the presence of high-risk FISH abnormalities, and the number of abnormalities at the time of diagnosis. Likelihood ratio tests were used to assess the goodness of fit of nested models. The χ2 or Fisher's exact test was used to assess the distribution of cytogenetic abnormalities in subgroups. Results: The median age at diagnosis was 60 years (32 - 82), 264 (61%) of the patients were male. The median overall survival for the entire cohort was 7.0 years (6.2 - 7.8). At the time of diagnosis, 150 (35%) and 57 (13%) of the 433 patients presented with a hyperdiploid karyotype and cytogenetic high-risk abnormalities, respectively. Independent of each other, the presence of a translocation at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow up (OR 0.39, 95% CI 0.24 - 0.63, p < 0.001) while the presence of at least one trisomy or tetrasomy at the time of diagnosis was associated with increased odds (OR 2.53, 95% CI 1.37 - 4.70, p = 0.003). A greater proportion of patients presenting with a hyperdiploid karyotype experienced cytogenetic evolution during follow up. Those patients more frequently evolved additional trisomies and tetrasomies, while translocations were more common in those presenting with a non-hyperdiploid karyotype (Table 1). The development of additional abnormalities during the three years following diagnosis (compared to no new abnormalities) was associated with increased subsequent mortality in those who survived at least three years (HR 3.22, 95% CI 1.82 - 5.68, p < 0.001). Including the time between first and last cytogenetic evaluation as a covariate did not significantly change the parameter estimates or improve model fit (p = 0.727). Conclusions: Demographics, risk profile, and overall survival of this cohort reflect the fact that patients had to survive long enough to undergo repeated cytogenetic evaluation. Hyperdiploid and non-hyperdiploid genotypes were associated with distinct behavior regarding cytogenetic evolution during follow up. The identification of cytogenetic evolution was an adverse prognostic factor in those who survived at least three years after diagnosis. These findings emphasize the importance of the dynamics of the underlying clonal disease process for accurate risk assessment and suggest that selected subgroups of patients may benefit from risk stratification during follow up. Table 1. Cytogenetic evolution during follow up in 433 patients with multiple myeloma stratified by karyotype at the time of diagnosis Hyperdiploid (n = 150) Non-hyperdiploid (n = 283) p New abnormality 76 (51%) 108 (38%) 0.012 New monosomy 8 (5%) 24 (8%) 0.243 New trisomy 48 (32%) 55 (19%) 0.004 New tetrasomy 37 (25%) 27 (10%) < 0.001 New deletion 17 (11%) 27 (10%) 0.557 New translocation 1 (1%) 11 (4%) 0.065 Most common new abnormality [type (percent of type in each group)] Monosomy mono(13) (75%) mono(13) (62%) Trisomy tri(11) (22%) tri(3) (22%) Tetrasomy tetra(15) (48%) tetra(15) (30%) Deletion del(17p) (79%) del(17p) (63%) Translocation t(11;14) (100%) t(11;14) (36%) Data are given as count (percent) unless denoted otherwise. Disclosures Binder: American Society of Hematology: Research Funding. Kumar:AbbVie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Download Full-text