Weight Loss Predicts Inferior Outcome in Polycythemia Vera Patients

Background: Conventional risk factors for inferior outcomes in polycythemia vera (PV) include elevated hematocrit, white blood cell (WBC) count, age, and abnormal karyotype. Weight loss adversely impacts survival in cancer patients. JAK2 myeloproliferative neoplasms (MPN) upregulate tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8 and induce decreased leptin levels leading to weight loss. The impact of weight loss in PV patients receiving best supportive care (i.e. frontline hydroxyurea [HU] therapy, phlebotomy) on overall survival (OS) is largely unknown. In this study, we seek to investigate: (1) differential effect on survival for weight loss, and (2) variables with predictive value for weight loss among JAK2 inhibitor-naïve PV patients. Methods: After IRB approval, 46 patients at the Michael E. DeBakey VA Medical Center diagnosed with PV between 2000 and 2016 were selected for analysis. Our outcome of interest was OS among PV patients exhibiting weight loss versus patients who maintained, gained weight or had minor weight loss. To objectively estimate weight changes overtime, the difference between baseline BMI [BMI-B] at the time of diagnosis and BMI at last follow-up (BMI-L) was obtained for each patient. Survival analysis was performed for PV patients exhibiting more than 10% weight loss (>10%) versus all other patients (less than 10% loss, stable and increased weight) (<10%) over time. Kaplan-Meier (KM) method was used to determine OS. Cox regression model was performed to assess independent role of different variables including age, blood cell counts and ferritin level Statistical analysis was performed using SAS software. Results: Median BMI loss was 10% (0.03-36.72%); 33/46 (71.7%) and 13/46 (28.2%) patients developed <10% and >10% BMI loss, respectively. Baseline characteristics are summarized in Table 1. Median BMI at last follow up was 21 for PV patients exhibiting >10% BMI loss and 27.7 for PV patients exhibiting <10% BMI loss (p<0.01). Median age was higher among patients exhibiting >10% BMI loss (68 vs 56 y, respectively, p=0.006). A non-significant clinical trend for higher WBC was observed among patients losing >10% BMI (10.9 vs 7.6 K/uL, p=0.08). Median Hemoglobin (Hb), hematocrit (Hct) and ferritin were intriguingly lower in the >10% loss group at 16 vs 18.3 g/dL (p=0.01), 49.3 vs 54.2% (p=0.04) and 29.8 vs 50.6 ng/mL (p=0.09) respectively, while median RDW was higher at 18 vs 15.1% (p=0.01). OS was 9125 days vs 5364 days, in patients with <10% and >10% BMI loss, respectively (p=0.02, HR=0.20; CI 95% 0.04-0.84) (Figure 1). On multivariate analysis, age (hazard ratio [HR], 1.34; p<0.02) and WBC count (HR, 1.57; p<0.01), were predictive of OS. Conclusions: A subgroup of PV patients exhibit progressive weight loss. Over 10% BMI reduction is associated with decreased survival, suggesting that "early weight loss" is an independent clinical variable that predicts high risk PV. While a larger study is needed to validate this observation, this small study highlights the role of leukocytosis, advanced age and weight loss in PV. Confirmation of the observations reported here could unveil an important role for pharmacologic and/or dietary interventions to improve survival among high-risk PV patients. Disclosures Rivero: agios: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

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.

Download Full-text

Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽

10.1182/blood-2019-122393 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2898-2898

Author(s):

Vania Phuoc ◽

Leidy Isenalumhe ◽

Hayder Saeed ◽

Celeste Bello ◽

Bijal Shah ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Fdg Pet ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Effectiveness of Reduced Toxicity Conditioning Regimen with Intravenous Busulfan Plus Pentostatin (BUPENT) in Patients Older Than 50 Years with Advanced Hematologic Malignancies.

Blood ◽

10.1182/blood.v114.22.3331.3331 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3331-3331

Author(s):

Tulio E. Rodriguez ◽

Mala Parthasarathy ◽

Scott E. Smith ◽

David H. Vesole ◽

Zachary M. Earley ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Graft Failure ◽

Conditioning Regimen ◽

Advisory Committees ◽

Reduced Toxicity

Abstract Abstract 3331 Poster Board III-219 Introduction Current data suggests that recipient age above 50 is associated with an inferior outcome after myeloablative allogeneic stem cell transplantation (SCT). Overall survival (OS) of 31%, and transplant related mortality (TRM) of 17% at 100 days have been reported in this population (Ditchkowski, et al 2005; Yanada, et al. 2004). Encouraging results are observed with non-myeloablative conditioning regimens. However, for patients with a high relapse risk, this approach may not be sufficient to achieve long term disease control. In these cases, a reduced toxicity, yet ablative stem cell transplantation (RT-SCT) may give adequate time to the transplanted cells to mature and mount an immune-mediated antitumor response. This study evaluated the outcome after RT-SCT using a conditioning regimen consisting of intravenous busulfan (Bu) and pentostatin (Pent). Methods Consented adult patients up to 70 years with a fully-matched related (MRD) or unrelated donor (MUD) were screened for enrollment. Conditioning consisted of Bu 1.6 mg/kg every 12 hours days -7 to -4, and Pent 4 mg/m2 on day -3 and -2 prior to stem cell infusion on day 0. GVHD prophylaxis was methotrexate 10 mg/m2 on day 1, and 5 mg/m2 on days 3, and 6. Tacrolimus was started on day -2, and then tapered over 1 month after day +100. Characteristics Twenty six patients were analyzed. Male to female ratio was 1:1. Stem cell source was from MRD in 15 patients and MUD in 11. Median age was 62, with 92% of patients being older than 50 years. Indications for treatment were AML (35%), MDS (42%), Refractory CLL (23%), Relapsed NHL (12%), and Philadelphia (+) ALL (4%). All AML patients were high risk either due to poor cytogenetic, transformation, or relapse and only two of them were transplanted in first complete remission. MDS patients were RAEB (36%), secondary MDS (36%), or multilineage dysplasia (18%). Two patients had prior autologous transplants. Results No graft failure was observed. All patients achieved neutrophil (NEU) engraftment. Two patients expired prior to platelet (PLT) engraftment. Median engraftment days for NEU and PLT were 13 days. At a median follow up of 25 months, the OS and progression free survival for the entire group was 40% and 38% respectively. The OS in the MRD group was 58%. TRM at 100 days was seen in one patient (4%) due to veno-occlusive disease (VOD). Limited chronic GVHD was the most common observed toxicity (54%), followed by diarrhea (30%) and mucositis (23%). Mucositis was mainly grade 1 (8%) and grade 2 (8%). No grade 3 mucositis was observed. There was only one case of VOD and one case of acute GVHD. Conclusion To our knowledge, this is the first report of a RT-SCT using BuPent. This study demonstrates the efficacy of the regimen in patients older than 50 years. No graft failure was observed and the regimen related toxicity was acceptable in this high-risk population. The overall survival of 40% at a median follow up of 25 months compares favorably with prior reports of myeloablative allogeneic stem cell transplatation in patients older than 50 years. This regimen provides an exciting opportunity to extend the benefits of allogenic transplant to an older population, and warrants replication with larger controlled trials. Disclosures Rodriguez: Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vesole:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Millenium: Speakers Bureau; Centocor Ortho Biotech: Speakers Bureau.

Download Full-text

Final Analysis of a Randomized Comparison of ABVD Chemotherapy with a Strategy That Includes Radiation Therapy (RT) in Patients with Limited-Stage Hodgkin Lymphoma (HL): NCIC CTG/ECOG HD.6

Blood ◽

10.1182/blood.v118.21.590.590 ◽

2011 ◽

Vol 118 (21) ◽

pp. 590-590 ◽

Cited By ~ 1

Author(s):

Ralph M. Meyer ◽

Mary Gospodarowicz ◽

Joseph M. Connors ◽

Robert G Pearcey ◽

Woodrow A Wells ◽

...

Keyword(s):

High Risk ◽

Disease Progression ◽

Board Of Directors ◽

Final Analysis ◽

Primary Analysis ◽

Advisory Committees ◽

Limited Stage ◽

Risk Patients ◽

Single Modality

Abstract Abstract 590FN2 Background: The NCIC CTG / ECOG HD.6 trial is based on the hypothesis that for patients with limited-stage HL, treatment with single-modality ABVD provides comparable disease control, is associated with a reduced incidence of deaths due to late treatment effects and thus might improve long-term survival in comparison with treatment that includes extended-field RT. In this randomized controlled phase III trial, our primary objective was to compare the 12-yr overall survivals (OS) of limited-stage HL patients treated with ABVD alone with those receiving therapy that includes RT. Secondary outcomes include freedom from disease progression (FFDP), in which those dying prior to disease progression are censored, and event-free survival (EFS), in which the first of disease progression or death is considered an event. In 2005, we published 5-yr outcomes (median follow-up 4.2 yrs [Meyer, J Clin Oncol]). We now report results of the final analysis. Methods: Eligible patients had non-bulky clinical stage I-IIA HL; patients with subdiaphragmatic disease were eligible if disease was confined to the iliac, inguinal and/or femoral regions. Prior to randomization, patients were stratified into low and high-risk categories; low-risk patients had all of lymphocyte predominant or nodular sclerosis histology, age < 40 yrs, ESR < 50, and involvement of 3 or fewer disease-site regions; all others were high-risk. Patients randomized to therapy that includes RT received single-modality subtotal nodal irradiation (STNI) if low-risk and combined-modality ABVD (2 cycles) plus STNI if high-risk. All patients randomized to the experimental arm received single-modality ABVD (4 cycles); those not demonstrating a complete remission with restaging after 2 cycles received 6 cycles. Between March 1994 and April 2002, 405 patients were entered; 399 were eligible and included in the primary analysis (modified intent–to-treat [ITT]). The clinical cut-off date for follow-up was 2010/DEC/31 and the database was locked on 2011/JUL/15. All P-values are 2-sided. Results: The median duration of follow-up is 11.3 yrs. The OS was superior in patients randomized to ABVD (P=.04; HR=0.5; 12-yr estimates 94% vs. 87%). In comparison with patients randomized to therapy that includes RT, FFDP trended to being inferior in patients randomized to ABVD (P=.07; HR=1.82; 12-yr estimates 88% vs. 92%); no differences in EFS were detected (P=.5; HR=0.87; 12-yr estimates 86% vs. 80%). Sensitivity analyses included a true ITT evaluating all randomized patients and adding data obtained between the clinical cut-off and data-lock dates; results were robust and yielded similar findings. Causes of death in ABVD vs. RT-arm patients (N = 12 vs. 24) included HL or early treatment complication (6 vs. 4), second cancers (4 vs. 9), and other (2 vs. 11). Analysis of high-risk patients allocated to ABVD (N=137) vs. ABVD+STNI (N=139) showed similar respective results to the primary analysis: in comparison with those randomized to RT, OS was superior in the ABVD arm (12-yr estimates 92% vs. 81%; HR=.47; P=.04), FFDP was inferior (12-yr estimates 87% vs. 94%; HR=3.03; P=.01) and no differences in EFS were detected (12-yr estimates 84% vs. 78%; HR=.87; P=.6). Late-effects trended to being less frequent in ABVD patients, including second cancers (6.1% vs. 10.8%) and cardiac events (9.7% vs. 14.8%). Conclusions: We conclude that in patients with limited-stage HL, ABVD improves OS as compared with treatment that includes STNI, including combined modality therapy, because it is associated with fewer deaths from causes other than HL. The HD.6 trial hypothesis was thus confirmed. With respect to modern RT approaches, the implications of our results are: i) at 12 years, 88% of patients are disease-free and more than 90% are alive when initially treated with ABVD alone; ii) limitations exist in using FFDP as a proxy measure for OS when late treatment effects may occur; and, iii) when treatment strategies have competing risks, long-term follow-up provides crucial insights into the interpretations of best therapy. Disclosures: Connors: Seattle Genetics: Consultancy, Research Funding. Horning:Genentech: Employment, Equity Ownership. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Persistent Improvement In Clinical Outcomes With Bortezomib-Thalidomide-Dexamethasone Vs Thalidomide-Dexamethasone Incorporated Into Double Autologous Transplantation For Multiple Myeloma: An Updated Analysis Of Phase 3 Gimema-MMY-3006 Study

Blood ◽

10.1182/blood.v122.21.2090.2090 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2090-2090 ◽

Cited By ~ 4

Author(s):

Michele Cavo ◽

Monica Galli ◽

Annalisa Pezzi ◽

Francesco Di Raimondo ◽

Claudia Crippa ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Low Risk ◽

Standards Of Care ◽

Consolidation Therapy ◽

Phase 3 ◽

Advisory Committees ◽

Cox Regression Analysis

Abstract Over the last years, incorporation of novel agents into autologous stem cell transplantation (ASCT) has improved markedly the outcomes of younger patients with newly diagnosed multiple myeloma (MM). Superior results with experimental treatments vs previous standards of care have been frequently reported after preliminary analyses and need to be confirmed with longer follow up. The randomized phase 3 GIMEMA-MMY-3006 study was designed to compare bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double ASCT. Data from the initial analysis, with a median follow up of 36 months, demonstrated that patients randomized to the VTD arm enjoyed superior complete/near complete response (CR/nCR) rates after both induction and consolidation therapy, and had a significantly longer PFS compared to those prospectively assigned to the TD arm. We performed an updated analysis of the study after a median follow up of 59 months and results are herein reported. A persistent TTP and PFS benefit with incorporation of VTD into ASCT was confirmed. On an intention-to-treat analysis of 236 patients randomized to the VTD arm, median TTP was 62 months and median PFS was 57 months. The median values for 238 patients randomly assigned to the TD arm were 45 months for TTP (HR=0.64, p=0.001) and 42 months for PFS (HR=0.66, p=0.001) (Fig. 1). With the longer follow up of this analysis, an initial divergence between OS curves could be appreciated after 4 years, although the difference was not yet statistically significant at 6 years (75% for VTD vs 69% for TD). Superiority of VTD over TD for TTP and PFS was retained across prespecified subgroups of patients with high risk and low risk disease. In particular, PFS benefit with VTD was seen for patients age >60 years (HR=0.62, p=0.013) and younger than 60 years (HR=0.70, p=0.026), with ISS stage 1 (HR=0.59, p=0.009) and ISS stage 2-3 (HR=0.69, p=0.018), and for those with t(4;14) and/or del(17p) (HR=0.43, p<0.001) and with t(4;14) alone [t(4;14) positivity but lack of del(17p)] (HR=0.41, p=0.001). In comparison with patients with t(4;14) positivity who were randomized to TD, those assigned to the VTD arm had significantly longer PFS (median: 24 vs 53 months, HR=0.41, p=0.0007) (Fig. 2) and a trend towards longer OS (4-year estimates: 66% vs 81%, p=0.052). By the opposite, similar PFS curves were seen for patients in the VTD group regardless of the presence or absence of t(4;14) (Fig. 3). On multivariate Cox regression analysis, randomization to the VTD arm was an independent factor predicting for prolonged PFS (HR=0.64, P=0.001). Additional disease- and treatment-related variables independently affecting PFS included attainment of CR/nCR after both induction (HR=0.64, p=0.010) and consolidation therapy (HR=0.57, p<0.001), β2-m >3.5 mg/L (HR=1.7, p<0.001) and presence of t(4;14) and/or del(17p) (HR=2.0, p<0.001). On multivariate analysis, β2-m, cytogenetic abnormalities and attainment of CR/nCR after consolidation therapy were independently associated with OS. With an updated median follow-up of 49 months from the landmark of starting consolidation therapy, median PFS was 50 months for patients receiving VTD consolidation and 38 months for those treated with TD (HR= 0.69, P=0.015) (Fig. 4). Superior PFS with VTD vs TD consolidation therapy was observed for patients who failed CR/nCR after the second ASCT (HR=0.48, P=0.003) and was retained in both low risk and high risk subgroups. Finally, duration of OS from relapse or progression was similar between the two treatment groups (median, 42 for VTD vs 35 months for TD, p=0.47), even when bortezomib was incorporated into salvage therapy. In conclusion, this updated analysis of the GIMEMA-MMY-3006 study demonstrated: 1) a persistent PFS benefit with VTD vs TD in the overall population, as well as in subgroups of patients with high risk and low risk MM; 2) the ability of VTD, but not of TD, incorporated into double ASCT to overcome the adverse prognosis related to t(4;14); 3) the significant contribution of VTD consolidation to improved outcomes seen for patients randomized to the VTD arm; 4) the lack of more resistant relapse after exposure to VTD as induction and consolidation therapy compared to TD. A longer follow up is required to assess the OS benefit, if any, with VTD plus double ASCT. Disclosures: Cavo: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: 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; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Tacchetti:Janssen and Celgene: Honoraria. Zamagni:Celgene: Honoraria; Janssen-Cilag: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Brioli:Celgene: Honoraria.

Download Full-text

Car-Bird [Carfilzomib, Clarithromycin(Biaxin®), Lenalidomide/(Revlimid®), Dexamethasone) for Newly-Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.4761.4761 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4761-4761 ◽

Cited By ~ 1

Author(s):

Tomer M Mark ◽

Abbe Schickner ◽

John N. Allan ◽

Adriana C Rossi ◽

Roger Pearse ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Maximum Response ◽

First Line ◽

Advisory Committees ◽

Cell Harvest ◽

Grade Iii

Abstract Background: Carfilzomib (Cfz), lenalidomide, and dexamethasone synergize to provide an impressive overall response rate (ORR) in upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The ORR to Cfz+dexamethasone (Cfz-Dex) as first-line therapy is unknown. We hypothesized that sequential treatment with Cfz-dex and BiRD would improve provide similar ORR and improve tolerability. A protocol of Cfz-Dex, consolidation with BiRd (Clarithromycin(Biaxin¨), Lenalidomide/(Revlimid¨), dexamethasone), and lenalidomide maintenance (Len) was conducted to evaluate ORR and safety as induction therapy for MM. Methods: Forty patients (pts) with symptomatic untreated MM were enrolled in a phase 2 study of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 min on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each dose thereafter and dex 40mg on D1, 8, 15, 22. After the first 26 pts were enrolled, the protocol was amended to increase the Cfz from 45 to 56mg/m2. Echocardiography and spirometry were performed prior to study entry and serum brain natriuretic peptide (BNP) was followed monthly to evaluate for heart or lung toxicity. Cfz-dex was continued until plateau in disease response, defined as unchanged M-protein for 2 cycles. Elective stem cell collection was then performed in transplant eligible pts and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg on D1, 8, 15, 22 of 28-day cycle. BiRd was continued until a 2nd response plateau after which lenalidomide maintenance (Len) at 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results: 36 pts completed at least 1 cycle and were evaluable for response. 58% of pts were ISS II/III. High-risk cytogenetics and unfavorable MyPRS score were found in 62% and 21% of pts, respectively. Median study follow-up was 66.2 weeks (range 3.7-114.7). Maximum response to the Cfz-dex, BiRd, and Len is shown in Table 1. Median time to PR was 1 cycle. Median time to maximum response with Cfz-dex, BiRD, and Len was 2, 2, and 4 cycles respectively. At last audit, 8 (22%) pts remain on Cfz-Dex; 21 (58%) reached plateau and received BiRd. Of the pts that received BiRd, 9 (43%) improved categorical response and 19 (90.5%) received Len. Two (11%) pts deepened response to CR while on Len. 97.5% of pts are alive and 82.5% without progression at last follow-up. One pt died after coming off study (withdrew consent) from sepsis during elective autologous stem cell transplant. Pts with high risk cytogenetics had a trend towards a shorter progression free survival (PFS), with median 71.7 weeks vs not reached (NR) (P = 0.058). Similar results were seen with unfavorable MyPRS score with a shorter median PFS at 71.7 weeks vs NR (P = 0.094). 17 pts had stem cell harvest following Cfz-dex. All collected stem cells to support at least two transplants, with median 14.5 x 10^6 (range 7.06-27) CD34/kg in a median of 1 (range 1-2) apheresis session. 18 pts (46.2%) have come off study, 6 (15%) for disease progression (2 during CfzDex , 1 during BiRD, 3 during Len) and 5 pts (12.5%) due to toxicity: 3 pts for renal failure [2 Grade 2, I grade 3, all with renal recovery after discontinuation, all attributable to Cfz]; 1 pt due to Grade III CHF [attributable to Cfz with recovery]; 1 pt with Grade III Thromboembolic [attributable Len]. There was no correlation between pre-study cardiac and lung function, or serial BNP, with toxicities. Seven (17.9%) pts came off study for noncompliance, lost to follow up, investigator discretion, or withdrew consent (Cfz-dex: 4, BiRD: 1, Len: 2). Discussion: This is the first prospective study evaluating induction response to Cfz/Dex in MM. Cfz/Dex is safe and active, with ORR of 91.7% and rate of >=VGPR of 55.6%, despite the majority with a high-risk cytogenetics. Cfz-dex did not hinder stem cell harvest. ORR improved with lenalidomide-based consolidation and maintenance, with CR rate > 50%. Baseline heart/lung function or serial BNP change did not predict emerging toxicities. Table 1: Maximum Response For Car-BiRD Phase: Response Category Car-Dex BiRD Lenalidomide N = 36 N = 21 N = 19 PD 0 1 (4.8) 0 SD 3 (8.3) 0 0 PR 13 (36.1) 1 (4.8) 1 (5.3) VGPR 17 (47.2) 12 (57.1) 8 (42.1) CR 1 (2.8) 0 0 SCR 1 (2.8) 5 (23.8) 8 (42.1) ICR 1 (2.8) 2 (9.5) 2 (10.5) >=PR 91.7 95.2 100 >=VGPR 55.6 90.4 94.7 >=CR 8.4 33.3 52.6 Disclosures Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for first-line treatment of myeloma. . Rossi:Celgene: Speakers Bureau. Pekle:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Onyx: Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Download Full-text

Curing Multiple Myeloma (MM) with Total Therapy (TT)

Blood ◽

10.1182/blood.v124.21.195.195 ◽

2014 ◽

Vol 124 (21) ◽

pp. 195-195 ◽

Cited By ~ 2

Author(s):

Bart Barlogie ◽

Alan Mitchell ◽

Frits van Rhee ◽

Joshua Epstein ◽

Shmuel Yaccoby ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Board Of Directors ◽

Phase 2 ◽

Advisory Committees ◽

Cure Fraction ◽

Metronomic Therapy ◽

Age And Sex

Abstract Intra-tumoral heterogeneity is a hindrance to curing malignant disease. By employing all MM-active drugs upfront, TT was designed to overcome such obstacle by targeting all potential MM sub-clones broadly. We are reporting on long-term results of phase-2 TT1, phase-3 TT2 and phase-2 TT3a trials, with median follow-up times of 21yr, 12yr and 9yr, respectively. Five year estimates of OS, PFS and CR duration (CRD) increased from 58%, 28% and 40% with TT1 to 65%, 42% and 50% with TT2’s control arm (TT2-), to 68%, 56% and 58% with TT2’s thalidomide arm (TT2+), and to 74%, 65% and 74% with TT3a (all p<0.0001). The 5-yr estimates of time to progression (TTP)/time to relapse (TTR) from CR decreased from 59%/58% in TT1 to 43%/42% in TT2-, to 28%/34% in TT2+, and to 22%/18% in TT3a (all p<0.0001). When examined in the era of gene expression profiling (GEP) of purified plasma cells, 5-yr estimates of TTP/TTR in GEP70 low-risk MM were 47%/46% with TT2-, 26%%/36% with TT2+, and 18%/16% with TT3a (all p<0.0001); the corresponding data for the 15% with high-risk MM were 60%/50% with TT2-, 62%/64% in TT2+, and 48%/35% in TT3a (NS). Relative survival (RS) was computed per year in relationship to age- and sex-matched controls. RS ratios approached 1 at 10–15 years for TT1 and TT2-, but earlier, at 5-10 years, for TT2+ and TT3a. A parametric mixture cure model was used to estimate PFS and CR duration for each protocol, from baseline and from a 5-year landmark. The cure model fits the data well and provides cure-fraction estimates that increase with later protocols (Figure 1). Importantly, when comparing data from GEP-defined low-risk and high-risk MM, plateaus for both PFS- and CRD-based cure fractions emerged at 10 years in the former and earlier, at 5 years, in the latter (data not shown). PFS-based cure-fraction estimates increasedsignificantly with successive TT trials: 9% in TT1, 16% in TT2-, 25% in TT2+, and 33% in TT3a (p=0.04). CRD-based cure-fraction estimates were 18%, 28%, 36%, and 49%, respectively (p=0.17) (Table 1). When a 5-year landmark was applied to exclude early myeloma-related events, PFS-based cure fraction estimates were 28% in TT1, 39% in TT2-, 51% in TT2+, and 70% in TT3a (p<0.001); in this setting, CRD-based cure fraction estimates were 32%, 47%, 56%, and 75%, respectively (p=0.007). MRD flow cytometry was available in 83 of 175 TT2 PFS patients, of whom 78% were MRD-. Our TT results are consistent with curability of MM. Solely novel agent-based trials without transplant lack the long-term follow-up to determine their cure potential. As MM usurps the bone marrow micro-environment (ME) for its growth and survival, we reasoned that ME alterations reflecting an angiogenic switch may persist beyond the state of clinical CR and even MRD. We therefore performed GEP analyses of bone marrow biopsies in CR and compared findings with age- and sex-matched controls. Indeed, biopsy “normalization” was linked to superior CR duration and is being developed as an early “cure surrogate” marker to help define the length of maintenance therapy in future trials. Although about 50% of CR patients treated with TT3a can be considered cured, the median PFS in high-risk MM of 2yr has not improved with successive TT trials. Reasoning that cytokine storms emanating after myelosuppressive therapies to restore normal hematopoiesis may be growth-stimulatory to MM cells, we applied non-myelotoxic metronomic therapy (Papanikolaou, Haematologica, 2014). Six newly diagnosed transplant-ineligible high-risk patients were offered an extended 28-day course of low-dose metronomic therapy with bortezomib, thalidomide, dexamethasone and continuous infusions of doxorubicin and cisplatin, to which were added arsenic trioxide and vincristine infusions. Remarkably, 5 of 6 achieved CR status after a single course and remain disease-free without further therapy 6-8 months later. Our results attest to the curability of MM with TT and, given the short PFS of 2yr in high-risk MM, such patients should be the focus of future novel interventions that yield information in a timely manner. Table 1 Cure fraction estimates Protocol PFS CR duration N Cure Fraction N Cure Fraction From start of therapy TT1 231 8.8% 79 17.9% TT2 -Thal 345 15.5% 146 28.2% TT2 +Thal 323 25.1% 200 35.6% TT3a 303 32.9% 189 48.8% From 5-yr landmark TT1 65 28.4% 33 32.3% TT2 -Thal 145 39.2% 84 47.4% TT2 +Thal 150 51.1% 134 55.9% TT3a 197 69.8% 148 74.7% PFS CR duration Figure 1 Cure fraction estimates from baseline Figure 1. Cure fraction estimates from baseline Disclosures van Rhee: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Heuck:Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽

10.1182/blood-2019-131887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4569-4569 ◽

Cited By ~ 1

Author(s):

Frits van Rhee ◽

Sharmilan Thanendrarajan ◽

Carolina D. Schinke ◽

Jeffery R. Sawyer ◽

Adam Rosenthal ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Early Results ◽

Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

Download Full-text