IgM-Gammopathies Transformed into Aggressive Lymphoma: Incidence, Basal Clinical Features and Outcome of a Registry Based, Spanish Retrospective Series

Background Transformation into aggressive lymphoma (AL) is a rare complication of indolent lymphoproliferative disorders (LPDs) and is characterized by poor outcome. Immunoglobulin M (IgM) gammopathies are a spectrum of conditions, from monoclonal gammopathy of undetermined significance (MGUS) to Asymptomatic Waldenstroem Macroglobulinemia (AWM) and Symptomatic WM (SWM) that can eventually evolve to transformed WM (tWM). Actually, tWM represents a clinical challenge, mainly because of its poor characterization. Aims This registry study aims to better characterize tWM, focusing on prognostic factors heralding transformation to AL. Methods Two registries of IgM-MGUS, AWM and SWM [Owen, Semin Oncol 2003] based in Salamanca and in the region of Castilla and Leon (Spain) were investigated to identify cases with histological transformation. IgM-secreting patients with other LPDs (e.g. chronic lymphocytic leukemia, marginal zone lymphoma, IgM-multiple myeloma) were excluded from the analysis. All patients provided written informed consent in accordance to Helsinki's declaration. Statistical analysis was carried out using R v 3.3.3. tool; survival analyses were performed with Log-Rank method, while group comparison was performed with t-student for continuous variables and Chi-square tests for categorical variables. Results Data from 903 patients with IgM-secreting disorders diagnosed between 1976 and 2019 were analyzed; 587 cases with confirmed diagnosis of IgM-MGUS, AWM or SWM were selected. Out of 587 IgM-gammopathies, 22 cases with histological transformation to AL were identified. Cumulative incidence of tWM was: 1.4% at 5, 3.4% at 10 and 5.3% at 12 years, respectively (figure 1). Clinical features at first diagnosis of patients subsequently developing tWM where then analyzed: 3/22 tWM evolved from previous IgM-MGUS, while the remaining patients originally presented with AWM (6/22) or SWM (13/22). IPSS-WM prognostic score was LR for 5, IR for 12 and HR for 3/20 patients, respectively [Morel, Blood 2009]. Glancing on distributions between groups according to the outcome, tWM differed from not transformed (NT) cases for: lower median age at diagnosis (66 vs 72 years, p=0.018), lower platelets levels (median 188 vs 235 x 10^9/mmc, p=0.017), higher LDH ratio (0.8 vs 0.67, p=0.015), higher incidence of chromosome 6q deletion by FISH (40 vs 14%, p=0.021) and higher clonal B lymphocytes infiltration on marrow aspirate by flow cytometry (15 vs 4.5%, p= 0.022). Moreover, 13/22 patients received anti-WM treatment within 3 months from initial diagnosis, mainly chlorambucil-based; 5/22 patients received rituximab in first line and 13 in second line. From the whole series, after a median follow-up of 80 months, median transformation-free survival was 61 months from initial diagnosis (range: 0-228). Among these, Only 1/22 of tWM patient is still alive; 19/21 deaths were thus related to AL/WM, with a median survival after transformation of 12 months (0-53). In the whole series (n=587), median OS from initial diagnosis of IgM gammopathy was 76 months for the tWM group (6-225), that is shorter than the NT group (128 months, p=0.012, figure 2). Focusing only on patients treated at initial diagnosis, median survival after first treatment (SAFTI) was 62 vs 90 months for tWM vs NT (p=0.011, figure 3), and median time to next treatment was 28 vs 46 months, respectively (p=0.13). Overall, 10/22 tWM patients received ≥3 treatment lines, and median number of lines prior to transformation was 2 (0-3). Finally, in the whole series IPSS-WM score at diagnosis confirmed to impact on survival (median OS=151, 119 and 56 months for LR, IR and HR groups, respectively, p <0.001). However, this was not the case for tWM cases only, where OS was no longer different between groups. Conclusions In this retrospective study, we confirmed dismal outcome for tWM patients; incidence of transformation was comparable to expectations at 5 years, but higher at subsequent follow-up. At initial diagnosis of IgM gammopathy, younger age, low platelets level, high LDH ratio, high B lymphocytes infiltration by flow cytometry and presence of 6q deletion were significantly enriched among patients subsequently developing tWM. IPSS-WM score looked less predictive among tWM patients probably given to the limited numbers of tWM series. Novel prognostic tools are eagerly awaited for tWM patients. Figure Disclosures Cavallo: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Puig:The Binding Site: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria. Ferrero:Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding.

Download Full-text

Decreased Expression of CD62L and CD54 Correlates with Poor Cytogenetic Risk Group In Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v116.21.2915.2915 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2915-2915

Author(s):

Canan Alhan ◽

Theresia M. Westers ◽

Claudia Cali ◽

Floortje L. Kessler ◽

Monique Terwijn ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Healthy Volunteers ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Risk Category ◽

Advisory Committees ◽

Cd34 Cells

Abstract Abstract 2915 Interactions in the bone marrow (BM) between haematopoietic progenitor cells (HPC) and the BM micro environment are important for the regulation of cell adhesion, proliferation, differentiation and survival. Expression of both CD62L (L-selectin) and CD54 (ICAM-1) on HPC demonstrated to play a role in signal transduction routes for proliferation and growth regulation. Especially CD54 is involved in uncontrolled proliferation and block of apoptosis. Previously, it was described that decreased expression of CD62L in acute myeloid leukemia (AML) was associated with a poor cytogenetic risk profile and an adverse clinical outcome (Graf M et al, Eur J Haematol 2003) Myelodysplastic syndromes are a group of clonal HPC disorders characterized by ineffective hematopoiesis and a propensity to evolve into AML. The International Prognostic Scoring System (IPSS) provides information on both survival and risk of development of an AML. The purpose of our study was to evaluate CD62L and CD54 expression on CD34+ cells in MDS patients by flow cytometry and to assess the value of a CD62L/CD54 ratio for prognostication. Bone marrow samples of 30 newly diagnosed MDS patients (3 RA(RS)/18 RCMD(RS), the <5% blasts group; 5 RAEB-1, 4 RAEB-2, the >5% blasts group), 16 AML patients with prior MDS and 26 healthy volunteers were analyzed for CD62L and CD54 expression on CD34+ cells by using flow cytometry. An adhesion index was calculated as a ratio of the percentage and MFI of CD62L and CD54 positive cells (as was reported by Buccisano et al, Eur J Haematol 2007). The CD62L/CD54 ratio was significantly decreased in MDS with <5% blasts (median 79.09 p<0.0001) as compared to healthy volunteers (median 480.4) and even more decreased in high risk MDS (median 14.67 p<0.0001 and p=0.001 as compared to healthy volunteers and MDS with <5% blasts, respectively) and AML with prior MDS (median 12.54, p<0.0001 and p=0.009 as compared to healthy volunteers and MDS with <5% blasts, respectively). The MDS patients were assigned to the good, intermediate or poor IPSS cytogenetic risk category. Cytogenetics was available for 22 MDS patients. The CD62L/CD54 ratio was significantly lower in the cytogenetic poor risk category compared with the good risk category (median 5.4 and median 70.79 respectively, p=0.018). Moreover, a low CD62L/CD54 ratio correlated significantly with poor cytogenetics, p=0.006. In the group of MDS patients with <5% blasts, 4 developed a refractory anemia with excess of blasts or AML within a follow up period of 12 months. There was a trend for a lower CD62L/CD54 ratio for MDS patients who developed an AML compared with patients who did not. In conclusion, the CD62L/CD54 ratio is significantly decreased in MDS compared with healthy volunteers and even more decreased in AML with prior MDS. Both CD62L and CD54 are involved in regulation of proliferation and apoptosis of the HPC. A decreased adhesion ratio in low risk MDS patients might reflect HPC damage at an early stage of the disease with an increased proliferative capacity and a decreased apoptotic profile. Interestingly, a low CD62L/CD54 ratio showed a significant inverse correlation with the IPSS cytogenetic risk category. Due to an absence of metaphases in a proportion of MDS patients, cytogenetics is not always available. The CD62L/CD54 ratio might serve as a surrogate marker for poor prognosis cytogenetics in case no karyotype is available. Low risk MDS patients who developed an AML within 12 months tended to have a lower CD62L/CD54 ratio. Although these results are promising, sample size and follow up period needs to be extended. The CD62L/CD54 ratio might add to prognostication of MDS patients and might identify MDS patients with <5% blasts who are at risk for development of an AML. Disclosures: Ossenkoppele: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van de Loosdrecht:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Prognostic Factors, Outcomes and Clinical Characteristics in Patients with Transformed Follicular Lymphoma (t-FL): Cohort Study of 172 Patients

Blood ◽

10.1182/blood-2018-99-118489 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1600-1600

Author(s):

Preetesh Jain ◽

Loretta J. Nastoupil ◽

Rashmi Kanagal-Shamanna ◽

Graciela M. Nogueras González ◽

Mansoor Noorani ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

Recursive Partitioning ◽

B Cell Lymphoma ◽

Initial Diagnosis ◽

Low Grade ◽

Advisory Committees ◽

Ecog Ps

Abstract Introduction: Patients (pts) with transformed follicular lymphoma (t-FL) exhibit an aggressive clinical course and high risk of relapse. In this study we have analysed the clinical characteristics, prognostic factors, treatments and survival outcome of pts with pathologically confirmed t-FL. Methods: We reviewed pts with low grade lymphoma who developed a subsequent aggressive B-cell lymphoma at MDACC from 7/1998 to 07/2017. Transformation was defined as development of an aggressive lymphoma in the setting of a prior diagnosis of low grade NHL. Pts with composite histology or grade IIIb FL at dx were excluded. We identified a total of 273 pts who transformed from a low grade lymphoma, including 172 with an initial diagnosis of FL (63%), MZL (18%), and SLL (19%).Pts with t-FL were analyzed for clinical characteristics, treatments and outcome. Overall survival (OS) was defined from the time of initial diagnosis of t-FL to death/last follow up while failure free survival (FFS) was calculated from time of starting first line treatment after transformation to treatment failure/discontinuation/switch or death. Optimal cut off values for various prognostic markers associated with survival were identified using recursive partitioning. Results: Among the 172 pts with t-FL, 164 (95%) were diffuse large B cell lymphoma (DLBCL) and 8 (5%) with other histology. The median follow up time after transformation was 21.3 months (0.6-215 months). The median age at transformation was 63 (33 to 88) and 59% were males. The median time from initial diagnosis of FL to t-FL was 41 months (2 to 379 months). In the 122 pts where initial grading was available; 47, 43, and 32 were I, II, IIIa, respectively. Median lines of treatment received prior to transformation were 1 (range 0-11) and 124 pts (72%) had prior treatment with rituximab. Thirty one pts (18%) were in observation for FL prior to transformation. B symptoms in 13% pts, 12% has ECOG PS (3-4), CNS involvement was noted in 1% and median number of sites involved at transformation were 1 (range 1-6). 52 pts (30%) had transformation at a site distant from the initial site of FL. Twenty eight of 32 pts (87%) who had MYC testing (by IHC) were positive. Other characteristics included, 41% pts with lambda monoclonal light chain expression, median Ki-67 was 75% (8-100%), LDH > ULN in 47%, MUM-1 + in 56%. Median β2M was 2.3 mg/dL. Overall, the median OS from transformation was 106.7 mo (36.8-Not Estimable) and the median FFS = 8.77 mo (5.6-10.5). There was no survival difference between pts with DLBCL and HD. At the time of last follow up, 107 pts were alive and 65 died, including 45 due to progression. . Overall, 161 pts received treatment for t-FL, 58 with R-CHOP (Rx1), 52 with R-non-CHOP (Rx2), 27 with R-EPOCH based (Rx3), and 24 with miscellaneous treatments (Rx4). In univariate analysis, we identified factors significantly associated with inferior OS, (lower hemoglobin, low platelet counts, lower absolute lymphocyte counts, higher LDH, and higher β2M). Advanced ECOG-PS and presence of B symptoms also correlated with inferior OS. Using recursive partitioning, age ≥ 81 years, Hb < 12 gm/dL, WBC < 5K/uL, LDH ≥1184, β2M ≥ 4 mg/dL were associated with significantly increased risk of death (Figure-1 A-E). In multivariate analysis, age ≥ 81 years (HR=3.95, 95% CI 1.82-8.60; p=0.001), presence of double hit lymphoma (DHL) (HR=4.15, 95% CI 1.74-9.91; p=0.001) and Rx2 treatment (R-non-CHOP based regimen, compared to Rx1, Rx3 and Rx4) (HR=2.36, 95% CI 1.27-4.38; p=0.001) had inferior OS. We also analysed FFS in pts with information available on their initial therapy for t-FL (n=161). Presence of DHL and treatments other than R-CHOP were predictive of inferior FFS in MVA. Pts who received non-CHOP based regimens had inferior FFS (Figure-1F; p=0.007). Conclusions: Patients with t-FL have a heterogeneous disease course and most pts can be salvaged with subsequent therapies. R-CHOP based regimens appear to have most benefit following transformation. Common laboratory tests hemoglobin, WBC, platelet count, LDH and beta2 microglobin help in predicting the survival of t-FL pts. In pts where MYC was tested, most were positive. Comprehensive cytogenetic and molecular analyses are needed to recognize various pathogenic mechanisms and identify novel therapeutic targets in t-FL. Disclosures Nastoupil: Janssen: Research Funding; Karus: Research Funding; Gilead: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Juno: Honoraria; Celgene: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Spectrum: Honoraria; TG Therappeutics: Research Funding. Samaniego:ADC Therapeutics: Research Funding. Westin:Celgen: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Wang:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding; Dava Oncology: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Download Full-text

Impact of sFLC Ratio on Outcome in Patients with MM: Validating the Utility of sFLC in Response Definition

Blood ◽

10.1182/blood-2019-131835 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3080-3080

Author(s):

Nadine Abdallah ◽

S. Vincent Rajkumar ◽

Dragan Jevremovic ◽

Prashant Kapoor ◽

Angela Dispenzieri ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Complete Response ◽

Light Chains ◽

Advisory Committees ◽

Normal Ratio ◽

Abnormal Ratio

Background: The treatment of Multiple Myeloma (MM) has evolved significantly in the past decade with the introduction of novel agents and drug combinations, thus enhancing treatment efficacy and allowing more patients to achieve complete response (CR). This has created a need to identify surrogates for depth of treatment response. Serum free light chain (sFLC) ratio normalization has been shown to be prognostic for progression free survival as well as overall survival in patients achieving a complete response to therapy. Consequently, it has been incorporated as a defining feature for stringent CR, along with lack of clonal plasma cells by immunohistochemistry (IHC) or low sensitivity flow cytometry. The routine use of multiparametric flow cytometry with higher sensitivity to detect residual disease than IHC or the older 4-color flow cytometry, has raised the question as to whether sFLC ratio is still a valid indicator of response depth. Moreover, in nearly half of the patients with an abnormal sFLC ratio after treatment, the abnormality is secondary to suppression of one or both serum light chains. Therefore, we designed a retrospective study to address these issues. Patients and Methods: This is a retrospective study using the Multiple Myeloma Database at Mayo Clinic, Rochester. We included patients who, after any line of therapy, had negative serum and urine immunofixation and absence of clonal bone marrow plasma cells by flow cytometry (PC-PRO), which has a sensitivity of >10-4. Simultaneous sFLC data was also extracted. Patients were grouped into three categories based on their sFLC ratios: 1) normal ratio (normal), 2) abnormal ratio due to suppression of the uninvolved light chain (LC), involved LC, or both (Abn-suppressed) and 3) abnormal ratio due to elevation of the involved LC (Abn-inv elevated). The primary endpoint was the median time to next treatment (TTNT), defined as the time from sample collection to the time of initiation of the subsequent therapy or time of last follow up if a subsequent line of treatment was not initiated. Results: The cohort consisted of 510 patients. 285 (56%) were males and 225 (44%) females. Median age was 61 years (IQR: 55-67). Median Follow-up was 41 months. The last treatments administered prior to data collection included stem cell transplant (SCT) (with or without maintenance) in 290 (57%) patients, and non-SCT regimens in the others. The sFLC ratio was normal in 337 (66%) and abnormal in 173 (34%) patients. Among the patients with abnormal sFLC ratios, 81 had elevated involved LC, 25 had suppression of the involved LC, 45 had suppression of the uninvolved LC and 22 had suppression of both LCs. We first examined the TTNT for the three groups and found that the TTNT was identical for those with a normal ratio and those with an abnormal ratio due to suppression of one or both light chains (Figure 1). So, we combined these two groups (Normal-Abn suppressed) and compared their outcomes to the patients with abnormal sFLC ratio due to elevated involved LC. The Abn-inv elevated group had a shorter TTNT as shown in Figure 2 (log-rank 0.06, Wilcoxon <0.01). The Abn-inv elevated group also had decreased overall survival compared to the other group (log-rank: 0.05, Wilcoxon: 0.01) (Figure 3). Conclusion: This study provides 2 important observations. First, patients with an abnormal ratio due to suppression of one or both LCs have outcomes similar to those with a normal ratio, suggesting a need to clarify the current definition of stringent CR. Second, the study suggests an important prognostic value for an abnormal sFLC ratio due to elevated involved LC, suggesting this as an important surrogate for depth of response. Disclosures Kapoor: Janssen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Download Full-text

Identification of Prognostic Immunophenotypes at First Diagnosis in Patients with Acute Myeloid Leukemia (AML) By a Standardized Multicolor Flow Cytometry (MFC) Panel Originally Designed to Detect Measurable Residual Disease (MRD) at Follow-up

Blood ◽

10.1182/blood-2020-138683 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-35

Author(s):

Maximilian Alexander A Rohnert ◽

Malte von Bonin ◽

Michael Kramer ◽

Philipp Ensel ◽

Nadja Holtschke ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Statistical Significance ◽

The Other ◽

Advisory Committees ◽

Prognostic Relevance ◽

Aberrant Phenotype

Aims In AML, several risk factors obtained at first diagnosis (FD) have been reported to be associated with shorter RFS and OS. The primary prognostic relevance of multicolour flow cytometry (MFC) has been a matter of debate for years. During follow-up (FU), the prognostic relevance of MRD as detected by MFC is less controversial and MFC is recommended in particular (but not exclusive) for those patients (pts) with no reliable genetic marker. We thought to evaluate the prognostic value at FD of a recently established antigen panel and a corresponding analysis strategy, which had been originally developed for MRD-detection. Methods Based on an 8-colour antibody panel (CD45, CD34, CD117, HLA-DR, CD13, CD33, CD7, CD56), we have developed a hierarchical gating strategy with mainly fixed gates. That allows to detect MRD with a high level of standardization and inter-observer reliability (Röhnert M., et al. 25th EHA 2020). Four distinct categories of aberrations (deficiency of CD13 or CD33, cross-lineage expression of CD7 or CD56) detectable on at least 10% of the myeloid blast population were used to define aberrant phenotypes termed leukemia associated immunophenotypes (LAIP) at FD. These categories were also chosen to define MRD during FU. MRDpos by LAIP was defined as the (re-)occurrence of an aberrant category already detectable at FD, while MRDpos by DfN (different from normal) was defined by the de-novo detection of an aberrant category at FU. The prognostic value of the aberrant phenotypes at FD was examined in a cohort of 528 pts. In 122 pts, we further analysed MRD (LAIP/DfN) after completion of intensive induction chemotherapy (IT). Consolidation therapy consisted of allogeneic hematopoietic stem cell transplantation (n=77) or chemotherapy (n=45). The bone marrow samples were measured centrally and analysed independently by three different investigators. Results The probability to achieve a complete remission (CR) varied between the different aberrant phenotypes (LAIP) at FD. Compared to pts without aberrant phenotype (CR rate=68%, n/N=100/148), pts with CD56only (the sole aberrant category was a cross-lineage expression of CD56=only) had a significantly lower CR rate (46%, n/N=15/33, p=0.019). The other exclusive aberrant categories did not significantly influence CR rates compared to pts without LAIP: CD13only (75%, n/N=53/71, p=0.286), CD33only (64%, n/N=59/97, p=0.28) and CD7only (62%, n/N=31/50, p=0.472). In pts with possibly co-occurring aberrant categories (compound aberrant phenotype=comp), the CR rate was significantly higher in CD13comp compared to all other patients (75% vs. 64%, 107/143 vs. 246/385, p=0.018). The other compound aberrancies did not significantly influence CR rates: CD33comp (63% vs. 68%, 90/143 vs. 263/385, p=0.244), CD7comp (66% vs. 67%, 72/109 vs. 281/419, p=0.842) and CD56comp (68% vs. 66%, 84/123 vs. 269/405, p=0.699). Regarding overall survival (OS), just CD56only retained its statistical significance (HR 2.5, CI 1.4-4.7, p=0.004). CD13comp was associated with favourable outcome but without reaching statistical significance (HR 0.7, CI 0.4-1.0, p=0.059). In the cohort of pts with MRD assessment at the end of IT, 67% were classified as responders (CR n=62, CRi n=19) and 33% as non-responders (PR n=14, refractory n=26) by cytomorphology. By MFC, 71% of these pts were classified as MRDpos (n=51/36 responders/non-responders) and 29% as MRDneg (n=30/4). MRDpos was defined by LAIP only (23%), DfN only (44%) or concordantly by LAIP+DfN (33%). OS of MRDneg pts was significantly longer compared to MRDpos patients (HR 4.3, CI 1.0-18.1, p=0.033). Conclusions Using our analysis approach originally developed for MRD monitoring, MFC could provide additional information for initial risk stratification. The presence of an isolated cross-lineage expression of CD56 (CD56only) was associated with a lower CR rate and significant shorter OS. In contrast, CD13comp (CD13 deficiency ± other aberrant categories) was associated with a higher CR rate and prolonged OS. Furthermore, MRDpos as defined by the combined LAIP/DfN strategy provided significant prognostic information. The presented results are currently refined and validated using genetically defined subcategories. The approach has to be confirmed in an independent cohort of pts. Disclosures Rollig: Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy; Abbvie, Novartis, Pfizer: Consultancy, Research Funding. Buecklein:Pfizer: Consultancy; Novartis: Research Funding; Celgene: Research Funding; Amgen: Consultancy; Gilead: Consultancy, Research Funding. Subklewe:Novartis: Consultancy, Research Funding; Janssen: Consultancy; Roche AG: Consultancy, Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Morphosys: Research Funding; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding. Krause:Pfizer: Honoraria; MSD: Honoraria; Takeda: Honoraria; Gilead: Other: Travel Support; Celgene: Other: Travel Support; Siemens: Research Funding. Schlenk:Roche: Research Funding; AstraZeneca: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; PharmaMar: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

Download Full-text

Clinical and Genomic Characteristics in De Novo Blastoid/Pleomorphic (dnMCL) and Transformed Blastoid/Pleomorphic (t-MCL) Mantle Cell Lymphoma (MCL) in the Ibrutinib Era: Comprehensive Analysis of 168 Patients

Blood ◽

10.1182/blood-2018-99-115360 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1599-1599 ◽

Cited By ~ 1

Author(s):

Preetesh Jain ◽

Rashmi Kanagal-Shamanna ◽

Shaojun Zhang ◽

Chi Young Ok ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

De Novo ◽

Initial Diagnosis ◽

Cns Involvement ◽

First Line ◽

Advisory Committees ◽

Ki 67 ◽

Ecog Ps

Abstract Introduction: Patients (pts) with histologically aggressive MCL (HA-MCL; blastoid or pleomorphic) including [de novo (dnMCL) or those transformed from classic morphology (t-MCL)], exhibit a poor prognosis. This analysis provides a comprehensive assessment of so far the largest patient cohort with HA-MCL treated with various modalities. Methods: We included all HA-MCL pts [blastoid (n=142) or pleomorphic morphology (n=26)] at MD Anderson Cancer Center from 12/1997 to 07/2018. Among the 168 pts, 99 were dn-MCL and 69 were t-MCL. Pt characteristics were collected at the time of initial diagnosis in dnMCL and at transformation in t-MCL. Overall survival (OS) was defined from the time of initial diagnosis of HA-MCL to death/last follow-up and failure free survival (FFS) - time of starting first-line treatment after diagnosis of HA-MCL to treatment failure. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on specimens from 100 pts (among them, 27 tumor-normal pairs and 73 tumors without matched germline), this included CNT (classic never transformed=52), dnMCL=27, t-MCL=21. Two t-MCL pts had tumors sequenced at both classic and HA-MCL phase. Results: Median age for all 168 pts was 65 years (range, 39 to 95). Median time from initial diagnosis of classic t-MCL to HA t-MCL was 39 months (5 to 240 months). The median follow up after the diagnosis of HA-MCL was 19 months (0.1-168). Main clinical features of HA-MCL were - 72% pts had stage IV disease, 67% with marrow involvement, 27% leukemic phase, 20% with B symptoms, 6% had ECOG PS (3-4) and central nervous system involvement in 9% pts. Other features were, median Ki-67% 70% (10-100%), complex karyotype 11%, LDH > upper limit of normal 44%, Sox-11 positive in 82%, median β2M of 2.9 mg/dL. In pt subsets, t-MCL were distinct from dnMCL in having significantly higher median age, higher Ki-67% and lower proportion of marrow involvement at diagnosis. All pts with t-MCL had prior treatment for MCL before transformation. Overall, the median OS after diagnosis of HA-MCL was 32.5 months (45 and 13 months for dnMCL and t-MCL respectively; p=0.001) and the median FFS was 12.5 months (22 and 5 months for dnMCL and t-MCL respectively; p=0.001). In univariate analysis, factors significantly associated with inferior OS in HA-MCL were older age, high Ki-67%, higher LDH, elevated WBC count, higher β2M, lower hemoglobin, lower platelet counts and advanced ECOG-PS, presence of B symptoms, CNS involvement, complex karyotype and t-MCL. Recursive partitioning analysis revealed that Ki-67% ≥50%, LDH ≥1282, β2M ≥ 4, hemoglobin <12 and platelet count <58,000 were associated with significantly increased risk of death. In multivariate analysis (MVA), adjusting for the above variables, higher age (yrs), t-MCL category, Ki-67% ≥50%, ECOG-PS (1-4 compared to 0) and CNS involvement were significantly associated with inferior OS in HA-MCL. (Figure-1 A-D) For FFS, presence of t-MCL, poor ECOG-PS, LDH ≥ 663, CNS involvement were predictive of inferior FFS by MVA. Pts who received ibrutinib based therapies as their first line treatment for HA-MCL had longer FFS compared to intensive chemoimmunotherapy such as R-HCVAD; HR 0.40 (95%CI 0.16-0.99; p=0.04). Frequently mutated genes in HA-MCL were NF1 (34%), SDHA (34%), TP53 (31%), NOTCH1/2 (31%), ATM (26%), and KMT2D (23%). Tumors with different histology subtypes exhibited distinct mutation profiles. TP53 mutations were frequently seen in dnMCL than in t-MCL (39% vs. 20%) and rare in CNT (5%, p=0.0015, compared to dnMCL). SDHA was frequently mutated in dnMCL than in t-MCL or CNT (48% vs. 10% vs. 3%, p<0.01). Deleterious ATM and FAT2 mutation were frequent in HA t-MCL than in classic phase of t-MCL (30% vs. 0%, p=0.2 and 40% vs. 0% respectively, p=0.2). Copy number analysis revealed similar pattern between CNT and classic phase t-MCL (except 19p gain which is 2x higher frequency in classic phase t-MCL than CNT), but distinct copy number gains were noted in HA t-MCL and dnMCL (Fig. 1E). Striking difference between dnMCL and HA t-MCL was observed on chromosome 17, with much higher levels of 17p loss and 17q gain in dnMCL than in HA t-MCL. Conclusions: Histologically aggressive MCL (dn or t-MCL) is a therapeutic challenge. Pts with t-MCL, Ki-67% ≥ 50%, poor PS and CNS involvement had the worst outcomes. Ibrutinib based treatments improve the outcomes of HA-MCL. Further comprehensive molecular analyses will be reported by our group. Disclosures Nastoupil: Spectrum: Honoraria; Janssen: Research Funding; Novartis: Honoraria; Merck: Honoraria, Research Funding; Juno: Honoraria; Gilead: Honoraria; Karus: Research Funding; TG Therappeutics: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Neelapu:Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Acerta: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karus: Research Funding; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Wang:MoreHealth: Consultancy; Kite Pharma: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; Acerta Pharma: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Dava Oncology: Honoraria; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding.

Download Full-text

Large Granular Lymphocytosis and Its Impact on Long Term Clinical Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation: 14-Year Follow-up Data

Blood ◽

10.1182/blood-2019-128750 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2019-2019

Author(s):

Guldane Cengiz Seval ◽

Atilla Uslu ◽

Ekin Kircali ◽

Sinem Civriz Bozdag ◽

Klara Dalva ◽

...

Keyword(s):

Flow Cytometry ◽

Stem Cell ◽

T Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Support Research

Introduction: Several studies have attempted to describe the characteristics associated with large granular lymphocytosis (LGL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its clinical significance. However the clinical features of LGL lymphocytosis in the allo-HSCT setting is still sparse. The current study represents a detailed review of 667 patients transplanted in a single center with the objective to define the incidence of LGL lymphocytosis, to identify associations with transplant-related clinical parameters and to assess the impact on transplant related outcomes. Patients and Methods: During a 14-year follow up period (2005-2017) in this unicentric cohort study, we identified 19 patients (2.8%) with a significant LGL lymphocytosis, among 667 consecutive adult patients who underwent allo-HSCT. LGL lymphocytosis was defined as the presence of at least two of the following criteria: (1) sustained lymphocytosis above 3.0x109/L observed in at least three consecutive determinations over a time frame of 2-3 months, (2) predominance (that is, >30%) of LGLs in the peripheral blood, (3) confirmation of clonality by T-cell receptor analysis using PCR. Flow cytometry analyses were performed using the flow cytometry system FACSCalibur (BD Biosciences, San Jose, CA). The immunophenotyping of the lymphocytes included the following antibody panel: CD2, CD3, CD4, CD5, CD7, CD8, CD16, CD25, CD30, CD56, CD57, HLA-DR, TCRab, and TCRgd. T-LGL expansion was defined as an abnormal T cell population type CD31, CD81, or CD41, with expression of at least 1 of the NK markers (CD16, CD57, or CD56), and with presence of LGLs in peripheral blood films. Results: A total of 19 (Female/ male: 10 [52.6 %]/ 9 [47.4 %]) patients included into the study met the morphological criteria for LGL lymphocytosis. The median age of the patients was 46 years (range, 18- 62 years). The majority of the patients (64.7 %) had the diagnosis of acute myeloid leukemia. The stem cell source was peripheral blood stem cells (PBSC) in 15 patients (88.2 %) and most of the patients underwent an allo-HSCT with a MAC (n= 13) regimen at a median of 25.1 months from allo-HSCT. The median onset of LGL lymphocytosis was 11.5 (2.1- 55.7) months and median lymphocyte count at the time of diagnosis of LGL lymphocytosis was 5400/ mL (5170- 8700/ mL). None of the patient showed cytopenia, palpable splenomegaly, and none of them had typical signs or symptoms of an autoimmune disease. In addition; GvHD, viral infections, disease relapse and loss of donor chimerism were excluded during lymphocytosis. Samples from 19 patients were phenotyped by flow cytometry. These studies confirmed a T cell phenotype of LGLs in the majority of patients (n=12). Two patients presented with LGLs consistent with NK cells and seven showed properties of a mixed NK/T-cell lineage. A monoclonal LGL population of T-cell origin was identified in eight (42.1%) of these patients. With a median follow-up of 12.2 months none of the patients demonstrating increased LGL values has progressed to LGL leukemia or any other lymphoproliferative disorder. Four patients experienced cutaneous acute GVHD followed by a progressive chronic GVHD. Two patient developed a grade II acute cutaneous GVHD which rapidly responded to steroids in addition to cyclosporin A. Five patients had de novo chronic GVHD. In subgroup analysis, we compared the OS of monoclonal and oligoclonal LGL lymphocytosis and 1-year-OS was longer but non-significantly in monoclonal LGL lymphocytosis group; 75% ± 1.6% vs. 44.4% ± 2.2%, respectively (p= 0.21) (Figure). Median PFS was 28.8 months in oligoclonal LGL lymphocytosis group and 8.3 months in monoclonal LGL lymphocytosis group but the number of patients in this group does not provide enough statistical power to confirm whether the differences in PFS were statistically significant (p= 0.3). At the time of this report, three patients have died. The primary cause of death was relapse of the primary disease in one of the patients, whereas 2 patients died of TRM (10.5%). Discussion: In conclusion, we observed LGL lymphocytosis in 2.8 % of a large cohort of post allo-HSCT survivors. Our data indicate that, even if monoclonal, post-transplantation LGL expansion may be considered as an expression of chronic stimulation triggered by allo-HSCT rather than the result of a malignant transformation. Disclosures Özcan: Amgen: Honoraria, Other: Travel support; BMS: Other: Travel support; Jazz: Other: Travel support; Sanofi: Other: Travel support; Bayer: Research Funding; Novartis: Research Funding; Roche: Other: Travel support, Research Funding; Archigen: Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; Abdi Ibrahim: Other: Travel support; MSD: Research Funding; AbbVie: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding; Celgene Corporation: Research Funding, Travel support. Ilhan:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Beksac:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text

Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab: Clinical Activity Including Survival in Patients with Recurrent/Refractory Follicular or ‘Aggressive' Lymphoma.

Blood ◽

10.1182/blood.v114.22.584.584 ◽

2009 ◽

Vol 114 (22) ◽

pp. 584-584 ◽

Cited By ~ 14

Author(s):

Nam H. Dang ◽

Mitchell R Smith ◽

Fritz Offner ◽

Gregor Verhoef ◽

Peter Johnson ◽

...

Keyword(s):

B Cell ◽

Tumor Progression ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Aggressive Lymphoma ◽

Clinical Activity ◽

Advisory Committees ◽

Time To Tumor Progression

Abstract Abstract 584 Background: CMC-544 is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The maximum tolerated dose (MTD) for single agent CMC-544 was previously determined to be 1.8 mg/m2administered IV every 28 days, and clinical activity was shown in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Preliminary safety and efficacy data without long-term follow-up on patients with FL and non-refractory DLBCL treated with CMC-544 given in combination with rituximab was previously reported. Objectives: To assess clinical activity of CMC-544 in combination with rituximab in refractory ‘aggressive' NHL and to present long-term follow-up, including progression free survival (PFS) and overall survival (OS) of pts with relapsed FL and DLBCL. Patients and Methods: Patients were eligible if they had CD20+/CD22+ B cell NHL, which had not responded to or progressed after 1 or 2 therapies of probable clinical benefit, including at least 1 regimen containing rituximab. In patients with FL and DLBCL, subjects could have had no more than 2 prior therapies and could not be refractory to rituximab or a rituximab-containing therapy. Patients in the latter part of the study could have DLBCL, mantle cell lymphoma, transformed FL with no limit on number of prior therapies and must have had no response to, or relapse within 6 months of, the first dose of the previous rituximab-containing therapy (refractory ‘aggressive' lymphoma). After a limited dose-escalation to determine the MTD of CMC-544 in combination with rituximab, an expanded cohort at the MTD was conducted. Patients received 375 mg/m2 of rituximab IV on day 1 followed by CMC-544 on day 2 of each 28-day cycle for up to 8 cycles, provided that there was no disease progression. Results: The MTD of CMC-544 given with rituximab was confirmed as the single agent dose of 1.8 mg/m2. Enrollment is complete at 119 patients, with 110 treated with CMC-544 at the MTD of 1.8 mg/m2. Based on 112 patients, median age was 66 y (range: 20-85), 60% were male; 36% had 1 prior chemo/immunotherapy regimen, 46% had 2, and 13% had ≥3; 71% had stage III/IV disease, 38% elevated LDH, and 17% bulky disease (>7.5 cm). Patients with recurrent DLBCL were generally older, with a median age of 72 y and were thus deemed inappropriate for high-dose therapy. The most common treatment-emergent adverse events (AEs), all grades, were nausea (48%), thrombocytopenia (46%), fatigue (44%), and increased aspartate aminotransferase (AST) (34%). AEs resulting in discontinuation from treatment were most commonly hematologic AEs or elevation of ≥1 liver function test. Median follow-up is approximately 14.5 months, 10.3 months, and 2.5 months for patients with FL, recurrent DLBCL, and refractory ‘aggressive' lymphoma, respectively. The 1-year OS rate was 97% for FL and 77% for patients with recurrent DLBCL. Patients with FL (n=38) had an objective response rate (ORR) of 87%, with a median PFS of 23.6 months. Patients with relapsed DLBCL (n=40) had an ORR of 80%, with a median PFS of 15.1 months while in the rituximab-refractory pt arm (n=25) the response rate was much lower at 20%, with a median PFS of only 2 months. One year PFS was 84% for FL and 53% for recurrent DLBCL. The lower response rates and PFS in the refractory subgroup are consistent with the poor prognosis of patients with refractory 'aggressive' lymphoma. PFS in DLBCL (either de novo or from transformed follicular) with 1-2 prior therapies based on time-to-tumor progression was also analyzed. DLBCL patients with a prior time to tumor progression of less than 1 year (n=19) had an ORR of 47% (21% CR/CRu), with a median PFS of 4.3 months while DLBCL patients with a prior time to tumor progression of greater than 1 year (n=28) had an ORR of 79% (50% CR/CRu) and a median PFS of 15.1 months. Conclusion: The combination of inotuzumab ozogamicin (CMC-544) plus rituximab has a safety profile similar to that previously reported for CMC-544 alone, with hematologic, gastrointestinal, and hepatic AEs being the main toxicities. The response rates and PFS results indicate promising efficacy in patients with recurrent/refractory FL and DLBCL, These results, particularly in patients with follicular lymphoma and recurrent DLBCL, support continued clinical development of this regimen. Disclosures: Dang: Wyeth Research: Consultancy; Genentech: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Speakers Bureau. Smith:Millennium: Research Funding; Genentech: Research Funding; Wyeth Research: Consultancy, Research Funding. Johnson:Wyeth Research: Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding. Coiffier:Wyeth Research: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Wyeth Research: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Foran:Wyeth Research: Research Funding. Hua:Wyeth Research: Employment. Vandendries:Wyeth Research: Employment, Equity Ownership. Fayad:Wyeth Research: Consultancy, Research Funding.

Download Full-text

Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Download Full-text

Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

Download Full-text

Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-116496 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2149-2149

Author(s):

Romil Patel ◽

Neeraj Y Saini ◽

Ankur Varma ◽

Omar Hasan ◽

Qaiser Bashir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Advisory Committees ◽

First Remission ◽

Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

Download Full-text