Prognostic Value of Dynamic Monoclonal Protein Pattern on Probability of Myeloma Progression from the Precursor State

Abstract Multiple Myeloma (MM) is a cancer of terminally differentiated plasma cell resides in bone marrow, which is always preceded by clinically asymptomatic precursor states. The process of malignant transformation however is not fully understood. Analyses of cells from precursor state have provided evidence that it is a genetically advanced lesion, wherein tumor cells carry many of the genetic changes found in MM cells. Furthermore, mice xenografts from patient (pt) with precursor disease showed progressive growth on its own suggesting progression potential is counteracted by active extrinsic restraints that prevent its progression to MM (Das R et al. Nature Medicine, 2016). Hence, precursor progression to MM can be viewed as a dynamic process in which the clonal mass is the net result of pro-growth, pro-survival replicative capacity of the myeloma clones vs. anti-tumor immunity. The change in the net clonal mass sometimes is large enough to be detected by measurable fluctuations in serum monoclonal protein spike (M-spike) levels and reflects a highly dynamic battle between plasma cell clone and cell-mediated anti-myeloma immunity among those pts. The prognostic value of this highly dynamic state on risk of progression to MM is largely unknown. In this study we sought to assess the association between the dynamic M-spike pattern and the risk of progression from a precursor clone to MM. Methods: All pts with positive serum electrophoresis (SPEP) values measured from January 2011 to January 2021 for our institution were included for this study. All pts that had <3 M-spike readings before requiring anti-myeloma regimen, received active treatment for MM within 90 days of the first positive SPEP, had M-spike values >3g/l or had clear evidence of progression by serial increasing M-spike values were excluded.. We assigned the pattern of M-spike values over time into two groups according to stability. To eliminate the test-to-test variability, we defined stable disease as lack of more than 20% difference from lowest M-spike, and fluctuating disease if the difference exceeds 20%. The time-to-treatment (TTT) was then measured from the first positive SPEP to the time of treatment and was censored at the date of last follow-up for pts who did not have anti-myeloma treatment with death as competing risk. The effect of M-spike pattern on TTT, treating as binary outcome, was also evaluated using logistic regression analysis. Univariate analysis of TTT was performed using Gray's method. All tests were two-sided and p-value ≤ 0.05 were considered statistically significant. Results: A total of 565 pts were studied, 193 with a fluctuating pattern and 372 with a stable pattern. Median age at first positive SPEP was 76 years old (range: 38-101), 271 (48%) of them were male; 427 (75%) were Caucasian and 123 (22%) African American. Baseline creatinine was 1.17 mg/dl (range 0.5-11.2 SD 0.94). Baseline albumin was 3.97 g/dl (range 1.6-5.2 SD 0.47), 336 pts (59%) were IgG, 75 (13%) IgA, and 142 (25%) had IgM M-spike; 326 (58%) pts had Kappa light chain and 239 (42%) had Lambda. Autoimmune diseases were more common in the stable disease pattern (17% vs. 10% p=0.028), the most frequent one was Rheumatoid arthritis in 33 pts (6%). Furthermore, baseline albumin was statistically higher in pts in the stable cohort (4.04 vs. 3.85g/dl, p=<0.0001). Median follow up was 46.9 months (range: 3.2-120.9). Logistic regression: the odds ratio (OR) of having progression to treatment for fluctuation group was 4.5 (95% CI: 1.37-14.18, p= 0.013) in comparison to stable group. Time-to-event analysis: pts with fluctuating M-spike had higher chance of needing therapy (Hazard Ratio: 3.73, 95% CI: 1.19-11.66, p=0.024) than stable group. Cumulative incidence of needing treatment is shown in Figure-1. Conclusion: The dynamic pattern of M-spike seen here with fluctuating values over time (over time is two words) was significantly predictive of progression to MM in pts with a precursor disease state. These findings may reflect a different nature of tumor vs. immune system balance and possible impaired immunity in these pts which may have implications for future clinical trials that evaluate the efficacy of anti-myeloma immunotherapeutics. Furthermore, our finding suggest that fluctuations in M-spike levels may be factored into risk models that predict the progression to MM among pts with precursor clones. Larger studies are warranted to further study this concept. Figure 1 Figure 1. Disclosures Malek: Medpacto Inc.: Research Funding; Janssen: Other: Advisory board ; Takeda: Honoraria; Cumberland Inc.: Research Funding; Amgen: Honoraria; BMS: Honoraria, Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board.

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Characterization of the Severe Phenotype of Pyruvate Kinase Deficiency

Blood ◽

10.1182/blood-2019-125352 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 949-949

Author(s):

Hanny Al-Samkari ◽

Eduard J. van Beers ◽

D Holmes Morton ◽

Wilma Barcellini ◽

Stefan W. Eber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Extramedullary Hematopoiesis ◽

Advisory Board ◽

Missense Mutations ◽

Severe Phenotype ◽

Advisory Committees ◽

Transfusion Requirements ◽

Over Time

Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p<0.0001), have received chelation therapy (90% vs. 42%, p<0.0001), and had more lifetime transfusions (median: 77 versus 15, p<0.0001). Rates of other PKD complications including pulmonary hypertension, extramedullary hematopoiesis, liver cirrhosis, endocrinopathy, and bone fracture appear similar between the two groups. Laboratory values, including hemoglobin, total bilirubin, normalized PK enzyme activity, and median absolute reticulocyte count appear similar between the two groups. The underlying genetic mutation patterns (missense mutations versus non-missense mutations) were also similar between the groups. Phenotype stability over time was highly variable: of the patients with a severe phenotype at enrollment, 62% had a severe phenotype during the first follow-up year and 39% had a severe phenotype at the second follow-up year. Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers:RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini:Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic:Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek:Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Prognostic Value of the Hevylite Chain in MGUS Patients in a Population Study

Blood ◽

10.1182/blood-2018-99-110329 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4506-4506

Author(s):

Aránzazu García Mateo ◽

Maria-Victoria Mateos ◽

Alberto Orfao ◽

Teresa Contreras Sanfeliciano ◽

Luzalba del Carmen Contreras Sanfeliciano ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Plasma Cells ◽

Risk Group ◽

Clonal Expansion ◽

Low Risk ◽

Advisory Committees ◽

Risk Of Progression

Abstract Introduction: Studies have shown that a large monoclonal protein (MP) and immunoparesis in MGUS/SMM have predictive value of progression since they may be indirectly related to the degree of clonal expansion of bone marrow plasma cells (BMPC). A recently available assay, the Hevylite® (HLC), has allowed a more precise determination of MP and the quantification of isotype-matched immunosuppression (i.e. suppression of the monoclonal isotype but of the alternative light chain) which has shown prognostic value in some studies. In this study, we aim to evaluate the association between the alteration of the HLC parameters in MGUS patients with already known prognostic factors, but also, with less studied biomarkers such as circulating clonal plasma cells (cCPC) by Next Generation Flow (NGF) (Flores-Montero et al., Leukemia, 2017). Methods: A total of 175 MGUS patients diagnosed between October 2008 and September 2015 were included in the study. The median follow-up was 64 months (range: 1-100 months). MGUS and MGUS progression were defined according to the International Myeloma Working Group (IMWG) criteria. Clinical records were retrieved for all patients. HLC determinations were carried on a SPA+ turbidimeter analyzer and using specific reagents (Binding Site®, UK). The 6 HLCs pairs (IgGk, IgGl, IgAk, IgAl, IgMk and IgMl) were analyzed in all samples. HLC normal ranges were defined by the laboratory based on normal sera. Statistical analysis was done using IBM-SPSS-22. Results: HLC ratio was altered in 56.3% of the 111 patients with available sera (47.5% for IgG MGUS and 73.9% and 87.5% for IgA and IgM), respectively (p = 0.026). Patients with altered HLC ratio presented an MP significantly higher (Table 1) than those with normal ratio (0.62 g/dL vs 0.33 g/dL, p<0.0001; HR: 53.23 with 95% CI (2.82 / 1005.54), p=0.008); 100% of the patients had MP>1.5 g/dL (p = 0.044)). Interestingly, it also correlated with a greater frequency and a greater amount of cCPC by NGF (68.29%, p=0.001; 0.2864 /mL vs 0.0139 /mL p=0.0001). Regarding BMPC infiltration, there was a correlation between altered HLC ratios and greater percentages of infiltration of BMPC (3.72% vs. 2.43%, p = 0.001) and higher percentage of BMPC measured by multiparameter flow cytometry (MFC) (54.42% vs 24.42%, p <0.001; HR: 1.02 with 95% CI (1.01 / 1.03), p = 0.007). Patients with altered HLC ratio presented MP> 1.5 mg/dL (100%, p = 0.044), non-IgG (78,12%, p = 0.003) and ratio of altered CLL (77,77%, p = 0.011). Patients with normal HLC ratios correlated with other low risk of progression to MM parameters, such as a MP <1 g/dL (100%, p=0.0001) or <0,5 g/dL (87.8%, p=0.0001) or less than 5% of BMPC (91.3%, p=0.007).Considering the IMWG risk stratification model, 100% of the patients classified as intermediate risk (p = 0.0001) had an altered HLC ratio, while in the low risk group, ratios were evenly distributed. When considering the Spanish (GEM) model, 92% of the patients in the low risk group had normal HLC ratios (p = 0.010). Uninvolved HLC suppression >25% was observed in 15.2% of the patients. These patients presented significantly higher MP (0.91 g/dL vs 0.42 g/dL, p<0.0001; HR: 7.22 with 95% CI (1.11 / 46.83), p=0.038), greater infiltration of BMPC by MFC (70.54% vs 35.52%, p<0.0001; HR: 1.02 with 95% CI (1 / 1.04), p=0.040) and a greater amount of cCPC (0.8905 /mL vs 0.0256 /mL, p=0.030) compared to those without HLC suppression. Patients with moderate (<25%) or no suppression correlated with less aggressive parameters, such as the lower MP, <1 g/dL (95.8%, p = 0.0001) or < 0.5 g/dL (70.5%, p = 0.005). However, no significant correlation was found between the IMWG or the Spanish risk stratification models, and the frequency of HLC suppression. Conclusions: HLC abnormalities have been associated with negative prognostic factors previously established, reinforcing the idea that the HLC parameters are directly related to a greater propensity of clonal expansion, or a greater tumor load. However, the short follow-up time did not allow the confirmation of the prognostic value of HLC alterations regarding greater risk of progression to MM. A re-evaluation of the results at 10 years is foreseen. We expect to be able to access whether an evolving pattern exists for the HLC parameters mainly to investigate if the immune suppression by HLC progressively intensifies in patients closest to progressing to MM. Disclosures García Mateo: Celgene: Honoraria; Amgen: Honoraria; Binding Site: Research Funding. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Puig:Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Queizan:Janssen: Consultancy. Olivier:Celgene: Honoraria; Jassen: Honoraria.

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Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT): A Phase 2 Trial of Induction, Consolidation and Maintenance in Subjects with High Risk Smoldering Multiple Myeloma (SMM): Initial Analysis of Safety Data

Blood ◽

10.1182/blood-2020-142584 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Shaji K. Kumar ◽

Al-Ola Abdallah ◽

Ashraf Z. Badros ◽

Betsy Laplant ◽

Binod Dhakal ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

High Risk ◽

Research Funding ◽

Advisory Board ◽

Phase 2 ◽

Phase 3 ◽

Phase 2 Trial ◽

Risk Of Progression ◽

M Spike

Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike > 2 gm/dL OR an involved to uninvolved FLC ratio > 20 OR bone marrow PC% > 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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Baseline Hypoalbuminemia Does Not Appear to be an Adverse Prognostic Factor in Patients with Relapse/Refractory B-Cell Lymphomas Treated with Axicabtagene Ciloleucel (axi-cel)

Blood ◽

10.1182/blood-2019-126594 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5343-5343

Author(s):

Megan Melody ◽

Sangeetha Gandhi ◽

Zaid Abdel Rahman ◽

Paula A Lengerke Diaz ◽

Nicole Gannon ◽

...

Keyword(s):

Serum Albumin ◽

B Cell ◽

Mayo Clinic ◽

Research Funding ◽

Response Rate ◽

Normal Serum ◽

Advisory Board ◽

Genetics Research ◽

Significant Difference

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

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The Role of Serum Immunoglobulin Free Light Chain In Response and Progression In Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood.v116.21.3095.3095 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3095-3095

Author(s):

Xavier Leleu ◽

Wanling Xie ◽

Meghan Rourke ◽

Ranjit Banwait ◽

Renee Leduc ◽

...

Keyword(s):

Median Time ◽

Research Funding ◽

Response Rate ◽

Early Response ◽

Response To Therapy ◽

Time To Progression ◽

Therapy Initiation ◽

M Spike

Abstract Abstract 3095 Introduction: Waldenstrom macroglobulinemia (WM) is a low grade B cell lymphoma characterized by the secretion of IgM protein in the serum. The IgM level lacks sensitivity due to its prolonged half-life. The serum free light chain (sFLC) assay has shown significant clinical application in plasma cell dyscrasias, specifically in multiple myeloma, and is used to monitor response to therapy. In this study, we sought to examine the role of sFLC in the response and progression of patients with WM. Methods: This study was performed using serum collected from a homogeneous cohort of patients diagnosed with WM and uniformly treated on a phase 2 trial using the combination of bortezomib with rituximab, previously untreated (N=26) or relapsed and or refractory to prior therapy (N=37). Patients eligible for this analysis must have measurable sFLC levels at baseline. A total of 48 patients were included. FLC response is defined as achievement of normal iFLC value or 50% decrease from baseline in the iFLC level during therapy and follow-up. Concordance between FLC and IgM response rate was evaluated using Kappa statistics. Correlation was evaluated using Spearman correlation coefficient. Time to progression was estimated using Kaplan-Meier methodology. We also did landmark analysis to compare overall response rate and time to progression by FLC or IgM response status at 2 months after therapy initiation; Fisher Exact test or Log-rank test were used. Results: The median iFLC value was 103.50mg/L (range 22.5–3540), the median kappa over lambda ratio was 13.45 (0.01-665), and the median serum IgM value by nephlometry was 3995 mg/dL (537-10,800). Overall, as per M spike response criteria, 29 (60%, 90% CI: 48%, 72%) patients responded, e.g. had partial response or better, and 19 patients failed to obtain response. Using serum IgM protein measurement by nephlometry during therapy and follow up post-therapy, 35 (73%, 90% CI: 60%, 83%) patients responded with a PR or better (>50% decrease), with 3 (6%) having normalization of their serum IgM. In comparison, iFLC response during treatment and follow up occurred in 38 (79%, 90% CI: 67%, 88%): with 2(4%) having normalization of value, 21(44%) having 50% reduction and 15(31%) having both. The time to iFLC response and IgM response among patients who achieved response by both criteria was calculated (N=33). The median time to iFLC response was 2.1 months (range 0.9–28.7months), while the median time to IgM response was 3.0 months (0.9-14.7) (p=0.07). The median time to progression per the protocol was 18.9 months (95% CI:10.5-NR). The Kappa concordance between iFLC 25% increase and M spike progression was 0.63 (95% CI: 0.41–0.84). This showed a better concordance compared to using the iFLC >50% definition (kappa=0.58, 95% CI: 0.35, 0.81), indicating that progression using iFLC>25% would be a better definition for patients with WM. The median time to progression by iFLC>25% increase was 13.7 months (95% CI:10.9-19.4) and the median time to IgM >25% increase was 14.6 months (95% CI: 9.5–19.1), showing a more rapid detection of progression by iFLC compared to M spike and IgM measurements. We next examined whether attaining a response using iFLC can be a predictor of overall response to therapy. Seventeen patients (35%) achieved an iFLC response at 2 months after therapy initiation. Patients with early iFLC response were more likely to have intermediate/high ISS-WM stage, elevated B2M or low Hemoglobin<11.5 gm/dL (p<0.05). Early iFLC response was related to overall IgM response during therapy and follow up (p=0.02). In multivariable models when adjusting for ISS stage, B2M or Hgb, there was no significant association between FLC early response and TTP either by protocol, FLC or IgM criteria. However, there was trend that early response was related to prolonged TTP especially when adjusting for hgb risk factors (HRs ranges from 0.63∼0.80, p>0.3 for various TTP endpoints. Conclusion: iFLC may be a useful marker of tumor measurement that correlates well with IgM and M spike measurements. The time to iFLC response was shorter by 1 month compared to IgM or M spike measurement. The median time to progression by iFLC was shorter by 1 month compared to IgM. There was a trend that early response was related to prolonged TTP when adjusting for other risk factors. Disclosures: Leleu: Celgene: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Chugai: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; LeoPharma: Consultancy, Honoraria.

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Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽

10.1182/blood.v120.21.801.801 ◽

2012 ◽

Vol 120 (21) ◽

pp. 801-801 ◽

Cited By ~ 21

Author(s):

Francisco Cervantes ◽

Jean-Jacques Kiladjian ◽

Dietger Niederwieser ◽

Andres Sirulnik ◽

Viktoriya Stalbovskaya ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Extension Phase ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

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Healthcare Resource Utilization Trends over Time with Continuous Lenalidomide Treatment (Tx) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM)

Blood ◽

10.1182/blood.v124.21.1326.1326 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1326-1326

Author(s):

Katja Weisel ◽

Dan T. Vogl ◽

Michel Delforge ◽

Kevin Song ◽

Meletios Dimopoulos ◽

...

Keyword(s):

Multiple Myeloma ◽

Resource Utilization ◽

Research Funding ◽

Healthcare Resource ◽

Healthcare Resource Utilization ◽

Medical Utilization ◽

Fixed Duration ◽

Advisory Committees ◽

Over Time

Abstract Introduction: Multiple myeloma (MM) is an incurable hematologic condition that is associated with high Tx costs. Resource consumption is driven by hospitalization and medical utilization, which is highest during periods of uncontrolled disease, such as after diagnosis and during relapses (De Portu 2013). In the pivotal phase 3 FIRST trial, continuous Tx with lenalidomide plus low-dose dexamethasone (Rd) was compared with fixed-duration Rd (Rd18) or fixed-duration combination Tx with melphalan, prednisone, and thalidomide (MPT), each for 18 months (mos), in NDMM pts who were ineligible for stem cell transplantation. Continuous Rd extended progression-free survival (PFS) and overall survival (interim analysis) vs. MPT. However, it is still unclear whether extending Tx duration with Rd adversely affects healthcare resource utilization. This analysis quantifies the rates of hospitalizations and medical utilization with continuous Rd over time based on data collected in the FIRST trial. Methods: The FIRST trial (N = 1,623) was a pivotal multinational, randomized, open-label study with a median follow up of 37 mos. Non-protocol-driven resource-use data was collected until subjects discontinued study Tx. To assess whether continuous Rd increases healthcare resource utilization over time, the rates of resource utilization for subjects treated with continuous Rd (N = 535) were plotted for up to 48 mos. In addition, hospitalization and medical utilization rates during the Tx period (18 mos) were estimated and compared between the 2 fixed-duration Tx arms. Results: Resource utilization amongst pts treated with continuous Rd declined over time (Figure). The annualized hospitalization rate in the first 3 mos was 3.2 times higher than the average rate for the remaining 45 mos of follow-up (2.02 vs. 0.62), and 4.2 times higher for medical utilization (5.66 vs. 1.34). After 4 years (yrs) of continuous Rd Tx, hospitalization and medical utilization rates were estimated to be 83% and 84% lower than those observed in the first 3 mos of Tx, reflecting the long-term disease control observed with continuous Rd in the FIRST trial. The highest hospitalization rates were associated with infections (0.20 per patient year), cardiovascular disorders (0.06), and respiratory and thoracic disorders (0.05). The mean (standard deviation) length of stay per admission was 14.08 (21.19) days. The highest medical utilization rates were associated with blood transfusions (0.76 interventions per patient year), general imaging procedures (0.21), respiratory and thoracic imaging procedures (0.20), and therapeutic interventions (0.09).The hospitalization rates for the fixed dose Tx arms were 0.91 (Rd18) and 0.79 (MPT) per patient year of follow-up during the Tx period of 18 mos, resulting in a rate ratio (RR) of 1.15 (1.01–1.30). The equivalent rates for medical utilization were 3.00 (Rd18) and 2.86 (MPT) medical interventions per patient year (RR = 1.05 [0.98–1.12]). Conclusions: The rates of resource utilization among pts treated with continuous Rd dropped substantially after the first 3 mos of Tx, and then gradually declined as Tx duration increased. The findings suggest that continuous Tx with Rd does not further increase resource utilization in hospitalizations and medical utilization compared to fixed-duration Tx. A comparison between the 2 fixed arms showed a 15% increase in hospitalization with Rd18 vs. MPT, and no differences in medical utilization between the 2 arms. A limitation of this analysis is that the resources were collected only while pts were receiving their respective Txs. Future analysis should include all costs generated by healthcare resources throughout pts Tx, including Tx-free intervals, and the costs associated with relapses. Figure 1: Hospitalization and medical utilization rates per patient year for patients treated with continuous Rd Figure 1:. Hospitalization and medical utilization rates per patient year for patients treated with continuous Rd Disclosures Weisel: BMS: Consultancy; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Noxxon: Consultancy. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Vogl:Amgen: Consultancy; Millennium/Takeda: Research Funding; GSK: Research Funding; Acetylon: Research Funding; Celgene Corporation: Consultancy. Delforge:Janssen: Honoraria; Celgene Corporation: Honoraria. Song:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Celgene Corporation: Consultancy, Honoraria. Cavenagh:Celgene Corporation: Honoraria. Hulin:Celgene Corporation: Honoraria. Foá:Celgene Corporation: Consultancy. Oriol:Janssen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Guo:Celgene Corporation: Consultancy. Monzini:Celgene Corporation: Employment, Equity Ownership. Van Oostendorp:Celgene: Employment. Ervin-Haynes:Celgene: Employment. Facon:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Prognostic Relevance of Monocytopenia and Lymphocyte-to-Monocyte Ratio in Primary Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v128.22.1996.1996 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1996-1996

Author(s):

Lyla Saeed ◽

Mrinal M Patnaik ◽

Kebede H. Begna ◽

Aref Al-Kali ◽

Mark R Litzow ◽

...

Keyword(s):

Risk Stratification ◽

Lymphocyte Count ◽

Research Funding ◽

Prognostic Value ◽

Leukocyte Count ◽

Multivariable Analysis ◽

Absolute Lymphocyte Count ◽

Monocyte Count ◽

Lymphocyte To Monocyte Ratio

Abstract Background We have previously shown an independent adverse prognostic effect of lymphopenia (absolute lymphocyte count <1.2 x 10(9)/L) for survival in MDS (Jacobs et al. Am J Hematol 2010;85:160) whereas others have suggested a similar value from lymphocyte-to-monocyte ratio (LMR); patients with LMR ≥5 experienced shorter survival with median 67 vs. 126 months (Mushtaq et al. JCO May 20 Supp. 2016:7062). Whether or not "monocytopenia" also carries a prognostic value in MDS is currently unknown and was the main objective for the current study, which also addresses the prognostic value of LMR. Methods We retrospectively recruited 889 consecutive patients with primary MDS who were untreated at the time of referral to our institution and in whom absolute monocyte count (AMC) and absolute lymphocyte count (ALC) at time of referral were documented. The diagnosis of MDS and leukemic transformation (LT) was made according to WHO criteria (Blood. 2009;114:937). Complete follow-up information was updated in January 2015. For the purposes of the current study, monocytopenia was defined as AMC below the lower limit of the institutional normal range, which was 0.3 to 0.9 x 10(9)/L. Comparisons of survival and other clinical parameters were performed between i) patients with and without monocytopenia and ii) patients with and without LMR ≥5. Conventional methods were used for statistical analysis. Results Patient characteristics: Median (range) values for the 889 study patients (69% males) included: age 72 (18-98), hemoglobin 9.6 g/dL (5.4-15.7), leukocyte count 3.4 x 10(9)/L (0.4-35), platelet count 106 x 10(9)/L (2-1804), circulating blasts 0% (0-18), bone marrow blasts 3% (0-19) and absolute lymphocyte count (ALC) 1.2 x 10(9)/L (.02-8.9). Transfusion need was documented in 33% of patients and abnormal cytogenetics in 49%. Risk stratification by the revised international prognostic scoring system (IPSS-R) was very high in 11%, high in 16%, intermediate in 21%, low in 36% and very low in 16%. The median (range) AMC for the entire study population of 889 patients was 0.22 x 10(9)/L (0.0-1.8).The number of patients with subnormal AMC was 539 (61%). After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformations were documented. Comparison of patients stratified by absolute monocyte count and LMR Compared to patients with AMC >0.3 x 10(9)/L, MDS patients with monocytopenia displayed younger age (p<0.0001), lower hemoglobin (p=0.005), higher red blood cell transfusion need (p=0.03), lower leukocyte count (p<0.0001), lower platelet count (p<0.0001), lower absolute neutrophil count (p<0.0001), higher circulating (p=0.03) and bone marrow (p<0.0001) blasts, higher incidence of abnormal karyotype (p=0.03), and higher risk distribution in terms of both IPSS-R (p<0.0001) and cytogenetic risk stratification by IPSS-R (p=0.03). In univariate analysis, lower AMC was associated with inferior survival (p=0.002); significance was even more apparent when comparing patients with and without monocytopenia (p=0.0003; HR 1.3, 95% CI 1.1-1.5). Similarly, there was significant association between LMR and survival (p<0.0001) with patients with LMR ≥5 experiencing inferior survival (p=0.03; HR 1.2; 95% CI 1.02-1.4). In multivariable analysis, the adverse effect of monocytopenia was shown to be independent of age (p<0.0001), gender (p=0.0001), anemia (Hemoglobin <10 g/dL; p=0.002), thrombocytopenia (platelets <100 x 10(9)/L; p=0.01), neutropenia (absolute neutrophil count <0.8 x 10 (9)/L; p=0.005), subnormal ALC (p=0.0008), circulating blast percentage (p=0.002), cytogenetic risk stratification by IPSS-R (p=0.006) and LMR (p=0.02) or LMR ≥5 (p=0.002); however, significance was lost when risk stratification by IPSS-R was added to the multivariable analysis (p=0.7). In regards to LMR, it retained its significance (p=0.009) during multivariable analysis that included monocytopenia or subnormal ALC, as covariates; however, significance was lost in the context of IPSS-R (p=0.24 for LMR and 0.8 for LMR ≥5) Conclusions Monocytopenia in MDS clusters with adverse disease features and both monocytopenia and higher LMR were associated with poor survival. Despite the display of prognostic independence from each other and other risk factors considered individually, the survival impact of neither monocytopenia nor LMR was found to be independent of IPSS-R. Disclosures Al-Kali: Novartis: Research Funding; Celgene: Research Funding.

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Phase II Study of the Salvage Mini-Hyper-CVD in Combination with Inotuzumab Ozogamicin (INO) for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v128.22.1606.1606 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1606-1606 ◽

Cited By ~ 2

Author(s):

Koji Sasaki ◽

Elias J. Jabbour ◽

Susan M. O'Brien ◽

Farhad Ravandi ◽

Deborah A Thomas ◽

...

Keyword(s):

Dose Reduction ◽

Research Funding ◽

Response Rate ◽

Single Agent ◽

Conditioning Regimen ◽

Advisory Board ◽

Historical Cohort ◽

Platelet Recovery ◽

Low Intensity

Abstract Background: Outcome of patients with R/R ALL is poor. INO is a CD22 monoclonal antibody bound to a calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of targeted therapy to effective low-intensity chemotherapy might further improve clinical outcome. The aims of this study are to evaluate response rate, progression-free survival (PFS), overall survival (OS), and to assess the safety of this regimen. Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. INO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. After the occurrence of veno-occlusive disease (VOD), the dose of INO was modified to 1.3 mg/m2 for Cycle 1 followed by 1.0 mg/m2 for subsequent cycles starting at the Patient #48. Results: Fifty-seven patients (29 men, 28 women) have been enrolled. Patient characteristics and outcome are summarized in Table 1. Median age is 34 years (range 9-87). Median follow-up is 15 months (range, 2-34). The overall response rate was 45 (79%): 31 (53%) CR, 13 (23%) CR without platelet recovery (CRp), and 1 (2%) CR with incomplete count recovery (CRi). Grade 3/4 toxicities included infections during induction (52%), infections during consolidation (73%), prolonged thrombocytopenia (79%), hyperglycemia (50%), hypokalemia (35%), hyperbilirubinemia (24%), elevated AST/ALT (21%), hemorrhage (18%), and VOD (11%; n=6). Of 6 patients who developed VOD, all 6 had allogeneic stem cell transplantation (allo-SCT) prior to or post INO therapy; three had prior allo-SCT (conditioning regimen; 2 fludarabine/clofarabine; 1 cyclophosphamide/total body irradiation); 4 had allo-SCT after INO therapy (conditioning regimen; 2 fludarabine/busulfan/clofarabine; 1 fludarabine/melphalan; 1 fludarabine/busulfan); 1 had chimeric antigen receptor T-cell therapy. Twenty-seven (47%) patients proceeded to receive allo-SCT. At the last follow-up, 25 (44%) patients are alive. Thirty-two (56%) patients died: 7 early death; 5 refractory disease; 7 post relapse after subsequent salvage, 3 in CR/CRp (1 sepsis; 2 unknown), 10 post allo-SCT (1 VOD; 3 transplant complications; 5 relapse; and 1 unknown). The 2-year PFS and OS rates were 52% and 34%, respectively (Figure 1). Median OS for patients with S1 was not reached with 2-year OS of 53%; patients with S2, 6 months with 2-year OS of 0%; patients with ≥S3, 5.6 months with 2-year OS of 0% (p=0.005). Patients who were treated with mini-hyper-CVD plus INO plus/minus rituximab had a tendency of higher PFS rates, and improved OS compared to a historical cohort with single-agent INO in R/R ALL (2-year PFS; 52% vs. 36%; p=0.20: 2-year OS; 44% vs. 25%; p=0.01). Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Burger:Pharmacyclics: Research Funding. Jain:Pharmacyclics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Servier: Consultancy, Honoraria; Infinity: Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Celgene: Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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