Long-Term Remissions Of Patients With Follicular Lymphoma Grade 3 Treated With Rituximab, Cyclophospamide, Doxorubicine, Vincristine and Prednisone (R-CHOP)

Abstract Background Follicular lymphoma grade 3 (FLG3) are recognized as a distinct entity in the World Health Organization classification of lymphoma. FLG3 are defined as > 15 centroblasts per high power field and are further subdivided into A or B on the basis of the presence of centrocytes. Their natural history is similar to that of diffuse large B cell lymphomas (DLBCL) and there is still debate about their optimal management. Methods We conducted a retroprospective analysis of 156 patients with FLG3 receiving frontline treatment at MD Anderson Cancer Center between 06/1973 and 11/2004. Multivariate analysis (MVA) was performed using Hazard Ratio (HR) Cox regression with backward stepwise selection. Logistic regression with odds ratio (OR) was used for MVA of categorical variable. Results Patient baseline characteristics are shown in the Table. Forty-five (29%) patients received R-CHOP, of which 12 (27%) received more than 6 cycles and 9 (20%) and radiation therapy as consolidation. In particular, patients with stage I/II disease (9) all received 5-6 cycles, with additional radiation therapy consolidation in 4 patients. The overall response rate was 100% and 43 (96%) patients achieved complete remission (CR). After a median follow-up of 9 (2-12) years, median PFS has not been reached with 14 (31%) patients relapsing. Nearly all relapses occurred within 3 years, except for 1 patient who relapsed after 8 years and achieved a second durable CR with single agent Rituximab (Figure). On MVA, the only characteristic associated with a shorter PFS was the presence of > 4 nodal sites (HR 4.2, p=0.03). Among relapsed patients, 3 (21%) transformed to DLBCL (1 at first relapse) and died. Six (43%) relapsed patients received stem cell transplant (1 allogeneic) and 5 (36%) received more than 2 salvage regimens. Median OS has not been reached for all R-CHOP treated and relapsed patients. On univariate analysis, the only factor associated with a shorter OS after relapse was transformation (p=0.01). Baseline characteristics associated with transformation on MVA were IPI score 3-4 (OR 1.1, p=0.004) and elevated LDH (OR 2.4, p=0.01). Nine patients died, 2 (22%) of lymphoma progression, 4 (44%) of therapy-related acute myeloid leukemia (AML) and 3 (32%) of cancer-unrelated causes On MVA, factors associated with shorter OS after R-CHOP were age > 60 years (HR 11, p=0.02) and LDH > 618 IU/L (HR 5.9, p=0.01). On univariate analysis, age > 60 years was the only factor associated with AML onset (p=0.04). Conclusions R-CHOP is an effective treatment for patients with FLG3 and small number of nodal sites, with rare late progressions. The incidence of transformation is low but is fatal. Onset of second myeloid malignancies is the main cause of death and warrants caution in elderly patients. Disclosures: No relevant conflicts of interest to declare.

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5-Azacytidine (AZA) in Combination with Ruxolitinib (RUX) As Therapy for Patients (pts) with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs)

Blood ◽

10.1182/blood.v126.23.823.823 ◽

2015 ◽

Vol 126 (23) ◽

pp. 823-823 ◽

Cited By ~ 2

Author(s):

Naval Daver ◽

Guillermo Garcia-Manero ◽

Jorge E. Cortes ◽

Lingsha Zhou ◽

Sherry Pierce ◽

...

Keyword(s):

Research Funding ◽

Myeloproliferative Neoplasms ◽

Single Agent ◽

Myeloproliferative Neoplasm ◽

Hematological Toxicity ◽

Cell Transplant ◽

Bone Marrow Biopsies ◽

Baseline Characteristics ◽

Grade 3

Abstract Background: Clinical trials exclusively focusing on pts with MDS/MPN are lacking. AZA is a DNA methyltransferase (DNMT) inhibitor approved for the therapy of MDS while RUX is a JAK inhibitor approved as therapy for primary myelofibrosis and polycythemia vera. RUX and AZA may target distinct clinical and pathological manifestations of MDS/MPNs. Aim: To determine the efficacy and safety of RUX + AZA in pts with MDS/MPN requiring therapy including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia BCR-ABL1 negative (aCML), and myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)(ClinicalTrials.gov Identifier: NCT01787487). Methods: A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets >200) continuously (pts with platelets below 50 were not eligible) in 28-day cycles for the first 3 cycles followed by the addition of AZA 25 mg/m2 on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m2. The AZA could be started earlier than cycle 4 and/or at a higher dose in pts with proliferative disease or elevated blasts. Results: 24 pts were enrolled between March 1, 2013 and April 1, 2015. Baseline characteristics are summarized in table 1. 17 pts remain alive after a median (med) follow-up of 6.0 (3.7 - 21.3+) months. Responses were evaluated by the MDS/MPN IWG response criteria (Savona et al., Blood 2015, 125(12):1857-65). Responses were noted in 12 (50%) pts. Details of responses are shown in table 2. Med time to responses was 1.8 mos (0.7 - 5.5+) and the med duration of response is 7.0 mos (1.8 - 17.6+). Additionally, 9 pts had >5% pretreatment BM blasts: 6 of these pts had follow-up BM evaluations and 3 achieved a reduction in blasts to <5% with a med time to blast reduction of 5.5 mos (5.5 - 11.2+). Serial evaluation of bone marrow biopsies documented reduction in EUMNET fibrosis score in 3 of 11 (27%) evaluable pts after a med of 5.5 mos (2.1 - 5.6+) on therapy. The reduction was by one grade in all 3 pts (MF-2 to MF-1 in 2 pts, MF-1 to MF-0 in 1 pt) and was confirmed on a subsequent BM biopsy in 2 pts. No pts experienced grade 3/4 non-hematological toxicity. New onset grade 3/4 anemia and thrombocytopenia were seen in 12 (50%; of which 5 had a 2+ grade change) and 8 (31%) pts, respectively. The med overall survival is 15.1+ mos. 7 pts have died: pneumonia (n=3), sepsis (n=2), progression to AML (n=1), and transition to hospice (n=1). The AZA was started in cycle 4 in 12 pts (50%). The AZA was started earlier due to leukocytosis or increased blasts in 11 pts (46%), in cycle 1 (n=6), cycle 2 (n=4), and cycle 3 (n=1). 13 pts have discontinued protocol therapy due to leukocytosis (n=6), progression to AML (n=1), lack of response (n=3), pneumothorax (n=1), stem cell transplant (n=1), and loss of insurance (n=1), respectively. Conclusion: Concomitant administration of RUX with AZA was feasible and effective in pts with MDS/MPNs, with expected myelosuppression as the only significant toxicity. This combination warrants further evaluation. Table 1. Baseline characteristics (N = 24) Characteristic N (%) / [range] Med age, years 71 [55 - 79] Prior treatment 9 (38) Diagnosis MDS/MPN-U CMML aCML 11 (46) 10 (42) 3 (12) MF - DIPSS Int-1/ Int-2/ High 4(17)/ 11(46) / 9(37) MDS - IPSS Low/ Int-1/ Int-2/ High 9(38) /12(50) / 2(8) / 1(4) Splenomegaly 12 (50) Med WBC x 109/L 26.3 [3 - 123.2] Peripheral blood blasts >/= 1% 17 (71%) LDH 1040 [409 - 3567] EUMNET fibrosis grade MF-1/ MF-2/ MF-3 10(42)/ 6(26)/ 1(4) JAK2 + 6 (25) Med JAK2 allele burden 42.2 [3 - 90] Karyotype Diploid Abnormal 18 (75) 6 (25) 28-gene molecular panel in 23 pts*, (1 pt not done) ASXL1 DNMT3A TET2 KRAS/NRAS PTPN11 IDH 2 4 (17) 4 (17) 3 (13) 2(8) / 2(8) 2(8) 2 (8) *Mutations identified in only 1 pt included EZH2, GATA2, RUNX1, MPL, KIT. Table 2. Response evaluation by the MDS/MPN IWG 2015 criteria Response category Evaluable pts Responders/Evaluable (%) *All responses, some pts have > 1 response All 12/24 (50) Clinical improvement (CI) spleen Pts with palpable spleen > 5 cm 8/11 (73) CI total symptom score Pts with baseline TSS > 20 3/12 (25) CI Hemoglobin (HGB) Baseline HGB < 10 g/dL 1/7 (15) CI Transfusion independence History of transfusion dependence 1/5 (20) Partial marrow response Baseline and follow-up BMs 5/11 (45) Optimal marrow response Baseline and follow-up BMs 1/11 (9) *No CR or PR documented Disclosures Daver: ImmunoGen: Other: clinical trial, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

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Serious Pulmonary Toxicity with SGN-30 and Gemcitabine, Vinorelbine, and Liposomal Doxorubicin in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL): Cancer and Leukemia Group B (CALGB) 50502

Blood ◽

10.1182/blood.v112.11.232.232 ◽

2008 ◽

Vol 112 (11) ◽

pp. 232-232 ◽

Cited By ~ 5

Author(s):

Kristie A. Blum ◽

Jeffrey L Johnson ◽

Sin-Ho Jung ◽

Bruce D. Cheson ◽

Nancy L. Bartlett

Keyword(s):

Phase Ii ◽

Liposomal Doxorubicin ◽

Interstitial Fibrosis ◽

Univariate Analysis ◽

Single Agent ◽

Cell Transplant ◽

Open Label ◽

Synergistic Cytotoxicity ◽

Grade 3

Abstract Background: SGN-30 is a chimeric anti-CD30 antibody that is well-tolerated but has modest single agent activity in classical HL. Synergistic cytotoxicity is observed in vitro when SGN-30 is combined with gemcitabine. In CALGB 59804, a phase II study of gemcitabine, vinorelbine, and liposomal doxorubicin (GVD), 70% of patients (pts) with HL responded (Bartlett, et al. Ann Onc18:1071–1079, 2007). Based on these results and the potential synergy between gemcitabine and SGN-30, the CALGB conducted a doubleblind randomized, phase II trial of SGN-30/placebo + GVD to determine overall response rate (ORR) and event-free survival (EFS). Methods: 30 pts with CD30-positive classical HL relapsed/refractory after „□ 1 therapy were treated with GVD + 12 mg/kg SGN-30 or placebo. Pts were permitted to come off study after „□ 2 cycles for stem cell transplant (SCT). To assess the safety of the combination, 16 pts in part 1 of the trial received open label SGN-30 + GVD, without unexpected grade 3–4 toxicity during cycle 1. In part 2, 14 pts were randomized to SGN-30 + GVD (n=7) or placebo + GVD (n=7). After 2 pts developed late pulmonary events in part 1, part 2 was amended to stop the trial if the risk of grade 2–5 pulmonary events with SGN-30 + GVD compared to placebo + GVD exceeded 20%. Results: In 30 pts, median age was 35 years (range, 19–78 years), median prior therapies 2 (range 1–4), 11 pts had undergone a previous autologous SCT, 12 pts had received radiation, and 12 pts were refractory to their last regimen. After a median of 3 cycles of therapy, ORR was 63% (32% complete response (CR)) in 30 pts, 65% (35% CR) in 23 pts receiving SGN-30 + GVD, and 58% (29% CR) in 7 pts receiving placebo + GVD. Median EFS was 9 months (7.8 months for those pts with prior SCT and not yet reached for pts without prior SCT), with no statistically significant differences in EFS with the addition of SGN-30. Grade 2–5 pneumonitis occurred in 5 pts, all receiving SGN-30 + GVD, leading to closure of the trial. In part 1, 1 pt (prior ABVD, ICE) developed grade 4 pneumonitis after 3 cycles with fevers, hypoxia, and ground glass infiltrates requiring mechanical ventilation. A 2nd pt (prior ABVD, spine XRT) died from pneumonitis after 2 cycles despite intubation, antibiotics, and steroids. In part 2, 2 pts (prior ABVD and prior ABVD, ICE, SCT, mediastinal XRT) developed grade 3 pneumonitis after 4 and 2 cycles, respectively, that improved with steroids, and 1 pt (prior ABVD) developed grade 5 pneumonitis after 5 cycles. Autopsy in this pt demonstrated mild interstitial fibrosis and Pseudomonas and Enterococcal lobar pneumonia without evidence of HL. In the 4 other pts, bronchoalveolar lavage (n=4) and transbronchial lung biopsy (n=2) demonstrated no evidence of infection or progressive HL. In univariate analysis, age, gender, number of prior therapies, time from last treatment, prior autologous SCT, prior XRT, use of GCSF, and the number of GVD cycles were not significantly associated with the development of grade 2–5 pneumonitis (p-values=0.34–1.00). Conclusion: With grade 2–5 pneumonitis in 5/23 pts receiving SGN-30 + GVD, no events in the placebo arm (n=7), and historical results from CALGB 59804 demonstrating a 2% incidence of pulmonary events with GVD, the data from CALGB 50502 suggest that SGN-30 cannot safely be administered concurrently with GVD. Compared with historical GVD outcomes, the addition of SGN-30 to GVD does not appear to improve ORR or EFS.

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C-MOPP: Results of a Forgotten Regimen for Follicular Lymphoma in the Era of Rituximab and PET.

Blood ◽

10.1182/blood.v114.22.4755.4755 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4755-4755

Author(s):

Mark J. Fesler ◽

Medhat Osman ◽

James Glauber ◽

Paul J. Petruska

Keyword(s):

Follicular Lymphoma ◽

Progressive Disease ◽

Overall Response Rate ◽

De Novo ◽

Conflicts Of Interest ◽

Cell Phenotype ◽

Grade Ii ◽

Baseline Characteristics ◽

Grade 3 ◽

Center Cell

Abstract Abstract 4755 Review Category: 623 Keywords: Follicular Lymphoma/ Chemotherapy/ Rituximab/ C-MOPP/Therapy Introduction A variety of options are available in first and second-line treatment of advanced follicular lymphoma. We report the efficacy and toxicity of an immunochemotherapy regimen, C-MOPP-R, in both upfront and salvage settings. Patients and Methods We retrospectively reviewed all thirty-five cases of follicular lymphoma treated with C-MOPP-R at our institution from 2000 through 2008. Excisional lymph node biopsies demonstrating follicle center cell phenotype with any follicular component were required. Patients received six planned 28-day cycles of rituximab 375mg/m2 IV day 1 & 8, cyclophosphamide 650mg/m2 IV day 1 & 8, uncapped vincristine 1.4mg/m2 IV day 1 & 8, procarbazine 100mg/m2 PO day 1-14, and prednisone 60mg/m2 PO day 1-14. All patients received pegylated filgrastim day 9 and prophylactic antimicrobials. Remission was assessed with PET, bone marrow biopsy/aspirate, and clinical assessment using the Revised Response Criteria for Lymphoma in all but one patient, who had computed tomography instead of PET. Most patients received consolidation therapy on a phase II pilot study, and progression-free and overall survival will be reported in the future. Results See table for baseline characteristics, response, and grade 3 & 4 toxicities. The overall response rate for de novo and relapsed patients was 100% and 76%, respectively. Seven patients did not complete six cycles of therapy, two patients due to progressive disease and five due to various toxicities at the judgment of treating physicians. Eight patients required cessation of vincristine during therapy for grade II neuropathy. Conclusions C-MOPP-R is an efficacious, tolerable immunochemotherapy regimen in de novo and relapsed follicular lymphoma. Response rates in an upfront setting are particularly high, and it represents a feasible regimen that should be considered in this disease. Disclosures: No relevant conflicts of interest to declare.

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Single Agent Bendamustine Is An Effective Pre-Vaccine Treatment for Patients with Relapsed Follicular Lymphoma Undergoing Idiotypic Vaccination

Blood ◽

10.1182/blood.v118.21.2691.2691 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2691-2691 ◽

Cited By ~ 1

Author(s):

Maurizio Bendandi ◽

Carlos Becerra ◽

Joseph Kuhn ◽

Suncica Hukic ◽

Nyla Langford ◽

...

Keyword(s):

Follicular Lymphoma ◽

Conflicts Of Interest ◽

Single Agent ◽

Hematologic Toxicity ◽

Variable Intensity ◽

Vaccine Treatment ◽

Common Grade ◽

Idiotype Vaccine ◽

Grade 3 ◽

Abstract Submission

Abstract Abstract 2691 Over the last two decades, idiotypic vaccination has shown evidence of biological efficacy, clinical efficacy and clinical benefit in some subsets of patients with follicular lymphoma. Despite this, no idiotype vaccine has yet obtained regulatory approval. A phase-I clinical trial is currently being conducted to assess safety and immunogenicity of therapy with bendamustine and prednisone (BP) followed by administration of a novel, recombinant idiotype vaccine in which the idiotype protein is produced in tobacco plants. Patients eligible for the study are those with relapsed follicular lymphoma whose prior treatment has included rituximab. Use of rituximab is prohibited in this trial due to its potentially negative interference with vaccination as a consequence of the prolonged B-cell depletion that characteristically follows its administration. Subjects enrolled in the study who achieve and maintain either a complete (CR) or partial (PR) response for at least 4 months following BP therapy undergo idiotype vaccination. The response to initial BP therapy prior to vaccine administration is the subject of this report. At the time of abstract submission, fourteen patients have completed four monthly cycles of bendamustine (120 mg/m2 IV on day 1 and 2) and prednisone (100 mg PO on day 1 through 5). Of the thirteen patients evaluable for clinical response, eleven (85%) have achieved a CR and two (15%) a PR. Six patients maintained their response for at least 4 months and went on to receive idiotypic vaccine. The other six patients are currently in the 4-month protocol specified off-therapy period between chemotherapy and vaccination. One patient, who achieved a CR, relapsed during this period and was not vaccinated. With this exception, and with an overall median follow-up of 5 months (range: 2–12 months), all other responses described above have been maintained. Currently, toxicity data are available for 54 cycles of BP. There was no grade 4–5 non-hematologic toxicity. Grade 3 non-hematologic toxicity was recorded in 5/14 (36%) patients and in 9/54 (17%) cycles, respectively, and included hyperglycemia, diarrhea, nausea, dehydration and hypotension. Grade 1–2 non-hematologic toxicities were relatively common and in line with those previously reported for the BP regimen. Only 1/54 BP cycles was delayed due to grade neutropenia. In this case, the planned cycle was administered two weeks later. Overall grade 4 hematologic toxicity was recorded in 4/14 (14%) patients and in 7/54 (13%) cycles, respectively, and included neutropenia and lymphopenia. Grade 3 hematologic toxicity was recorded in 9/14 (64%) patients and after 21/54 (39%) cycles, respectively, and included leukopenia, neutropenia, lymphopenia and thrombocytopenia. Overall, lymphopenia was the most common grade 3–4 hematologic toxicity. Grade 1–2 hematologic toxicities were common, expected, and included anemia, leukopenia, neutropenia, lymphopenia and, occasionally, thrombocytopenia. Data are available for four patients to analyze post-chemotherapy B- and T- cell recovery.Patientlymphocytes/mlCD3(+)CD4(+)CD8(+)CD19(+)nl range1000–4000960–2600540–1660270–930122–632pre*post*prepostprepostprepostprepostA71311664717702281402505953618B8892545711343445822672568076C878944632632360113272538132198D16627761080590698171399404266109*pre=before first dose of chemotherapy, post=4 months post chemotherapy These preliminary data indicate that BP is a very effective and well tolerated chemotherapy regimen in patients with relapsed follicular lymphoma who have been previously received rituximab therapy. Our data also suggest that, in some patients, BP can cause a lymphopenia of variable intensity that may not fully recover four months after the last chemotherapy cycle. Studies of idiotype vaccine-induced humoral and cellular immune responses and their correlation with the presence of lymphopenia are ongoing. Updated results will be available at the time of the meeting. The authors wish to acknowledge Drs. Ralph Heaven, Larry Barker, Jairo Olivares, Thomas Anderson, Carl Chakmakjian, Barry Cooper, Amir Faridi, Vinay Jain, Pankaj Khandelwal, Janice Marshall, Anton Melnyk, Robert Mennel, James Turner Disclosures: No relevant conflicts of interest to declare.

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Absolute Monocyte Count in Follicular Lymphoma Patients Treated with Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

Blood ◽

10.1182/blood.v120.21.1574.1574 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1574-1574

Author(s):

Reina Watanabe ◽

Naoto Tomita ◽

Kumiko Kishimoto ◽

Satoshi Koyama ◽

Eriko Ogusa ◽

...

Keyword(s):

Prognostic Factor ◽

Follicular Lymphoma ◽

Conflicts Of Interest ◽

Clinical Stage ◽

Univariate Analysis ◽

International Prognostic Index ◽

World Health ◽

Serum Lactate Dehydrogenase ◽

Monocyte Count ◽

Chop Therapy

Abstract Abstract 1574 Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL), with a highly variable natural history ranging from an indolent disease to a rapidly progressive one such as its transformation to aggressive NHL. We have used the Follicular Lymphoma International Prognostic Index (FLIPI) that uses patient- or tumor-specific characteristics for the risk-stratification of patients with FL at the time of diagnosis. The tumor microenvironment, including variable monocyte-derived cell infiltration, has recently shown to play an important role in the clinical course of FL patients. Wilcox et al. showed that an elevated absolute monocyte count (AMC) is associated with inferior overall survival of FL patients receiving varying treatment strategies (Wilcox RA, et al. Leuk Lymphoma 2012). We retrospectively evaluated the prognostic changes in AMC at diagnosis in FL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy alone. This study included 157 consecutive FL patients treated with the R-CHOP therapy at 1 of the 7 participating hospitals between 2001 and 2009. Since 2001, the Yokohama City University Hematology Group in Japan uniformly and curatively treated patients with FL, except for those with stage 1 FL; the patients were treated with 6 cycles of standard R-CHOP therapy for 21 days. Patients who showed partial response (PR) after the initial 4 cycles were administered a total of 8 R-CHOP cycles, and those who did not show PR after the initial 4 cycles or patients in whom the disease progressed at any given time received salvage therapy. Patients who had bulky masses at diagnosis received involved field radiation following 6—8 cycles of R-CHOP therapy. Patients for whom the doses had to be reduced by more than 20% were excluded from the study. The study included 80 men and 77 women, with a median age of 63 years at diagnosis (range, 18—80 years). The FL of the 157 patients were classified as grade 1 (n = 65), grade 2 (n = 60), grade 3a (n = 20), and grade 3b (n = 12) according to the World Health Organization (WHO) scheme. The median AMC at diagnosis was 349 cells/μL (range, 10—1110 cells/μL). The median observation period for surviving patients was 45 months. The 5-year progression-free survival (PFS) estimated for the entire cohort was at 71.3%. The differences in the PFS when patients were stratified according to their AMCs were not significant. The effect of the following variables on PFS were assessed: (1) AMC > 390 cells/μL; (2) age > 60 years; (3) hemoglobin level < 120 g/L; (4) elevation of serum lactate dehydrogenase levels; (5) nodal areas > 4; and (6) advancement of clinical stage. In the univariate analysis, the presence of more than 4 nodal areas (hazard ratio [HR] = 2.65, 95% CI, 1.58—4.47, P < 0.001) and advanced clinical stage (HR = 2.75, 95% CI, 1.26—6.03, P= 0.01) were associated with inferior PFS. However, in the multivariate analysis, the association between the presence of more than 4 nodal areas and survival was found to be significant (HR = 2.33, 95% CI, 1.28—4.24, P = 0.006). Therefore, both univariate and multivariate analyses indicate that AMC was not a prognostic factor for PFS. There was no statistically significant correlation between AMC and FL patients' clinical outcome. AMC is not a prognostic factor in FL patients treated by R-CHOP. Disclosures: No relevant conflicts of interest to declare.

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Phase II Study of Carfilzomib (CFZ) Combined with Other Anti-Myeloma Agents in Relapsed-Refractory Multiple Myeloma (RRMM) - Updates on the UARK Compassionate Use Protocol

Blood ◽

10.1182/blood.v118.21.2947.2947 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2947-2947 ◽

Cited By ~ 1

Author(s):

Saad Usmani ◽

Jackie Szymonifka ◽

Rachael Sexton ◽

Susan Panozzo ◽

Bijay Nair ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase Ii ◽

Research Funding ◽

Cox Regression ◽

Phase Ii Study ◽

Univariate Analysis ◽

Cell Transplant ◽

Compassionate Use ◽

Refractory Multiple Myeloma ◽

Grade 3

Abstract Abstract 2947 Background: CFZ is an epoxomicin derivative with ability to irreversibly inhibit proteosomes. It has been shown in preclinical and early clinical studies to have activity in newly diagnosed as well as RRMM. We have previously reported on the UARK compassionate use phase II study of CFZ which allowed for the addition of other anti-MM drugs in RRMM. We are now presenting data with 7 additional patients and longer follow-up, with data cut-off on August 9 2011. Methods: All patients with relapsed or resistant refractory multiple myeloma were eligible for the trial. First cycle CFZ was given at 20mg/m2 IV day 1, 2, then 27mg/m2 IV days 8, 9, 15, 16 every 28 days; 4mg of dexamethasone (DEX) was given with each CFZ dose. In the absence of at least PR, CFZ dose was escalated to 36 mg/m2 IV and DEX increased to 20mg. Additional anti-myeloma drugs were added Cycle 2 onwards in absence of PR. 16-day continuous infusion cisplatin (3–5 mg/m2/d) and doxorubicin (1.5–3 mg/m2/d) were commonly added from Cycle 2 onwards, along with other novel agents. Cox regression modeling was employed for overall survival (OS) and progression free survival (PFS). Results: 81 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 32%, ISS stage >=II was seen in 72% of patients, cytogenetic abnormalities (CA) in 68%, and GEP-defined high risk in 53% of patients. 77 patients had prior autologous stem cell transplant. 63 patients (78%) had at least 2 transplants. All 81 patients had received regimens containing bortezomib, thalidomide, lenalidomide, melphalan or steroids. At least 1 cycle of treatment was administered to all 81 patients enrolled, 69% of patients received >1 cycle of treatment and only 19% received >5 cycles. 71 patients (88%) discontinued therapy primarily due to progression, death or toxicity. 5% patients achieved nCR/CR/sCR, additional 19% patients had stable disease. OS benefit was observed in patients receiving >= cycle 3 (HR= 0.40, p=0.006) on univariate analysis and multivariate analysis (HR=0.09, p<0.001) with adjustment for GEP-defined risk status. Most common toxicities, counting all toxicities (>=grade 3) were thrombocytopenia (84%), anemia (77%), leukopenia (73%), hypophosphatemia (58%), hypokalemia (27%) and fatigue (25%). Grade 1–2 peripheral neuropathy (PN) was present at baseline in 53%, >grade 3 PN was observed in 7% (6/81) after cycle 1, whereas >grade 3 PN was observed in 8% (1/12) >5 cycles.OS and PFS at 12 months were 41% and 5%, respectively (Figure 1). Conclusions: The data presented herein, confirm and extend the previously reported results on CFZ demonstrating anti-myeloma activity and clinical benefit, alone and in combination with other agents, in our heavily pre-treated RRMM population. Surprisingly, worsening or new PN was not observed in majority of patients. Utilizing the novel proteasome inhibitor CFZ in combination with other anti-MM agents on a compassionate basis afforded us the opportunity to make observations regarding potential clinical synergy of particular combinations. In particular, combination of CFZ-DEX with lenalidomide and vorinostat has shown promise in a subset of RRMM patients. Disclosures: Barlogie: Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

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Pomalidomide (Pom) in Relapsed and Refractory Multiple Myeloma (RRMM) - theUARK Compassionate Use Protocol,

Blood ◽

10.1182/blood.v118.21.3995.3995 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3995-3995

Author(s):

Saad Usmani ◽

Sarah Waheed ◽

Jackie Szymonifka ◽

Susan Panozzo ◽

Nathan M Petty ◽

...

Keyword(s):

Research Funding ◽

Cox Regression ◽

Univariate Analysis ◽

Progression Free Survival ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Compassionate Use ◽

Free Survival ◽

Kaplan Meier ◽

Grade 3

Abstract Abstract 3995 Background: Pom is a third generation immunomodulatory drug (IMiD) which has demonstrated safety and efficacy in RRMM with prior exposure/resistant to other IMiDs and bortezomib. This is the first report on the UARK Pom compassionate use experience in RRMM. Methods: First cycle Pom was given at 4mg orally Days 1–21 every 28 days; dexamethasone (DEX) was given to 9/23 patients at doses varying from 12 to 40 mg on schedules ranging from Days 1–4, weekly, twice a week, or three times a week. In the absence of at least PR, Pom dose was escalated to 5mg. 1patient also received bortezomib and 1 patient received bortezomib and cytoxan. Cox regression modeling was employed for univariate and multivariate analyses, whereas Kaplan-Meier curves were used for overall survival (OS) and progression free survival (PFS). Results: 23 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 43%, ISS stage >=II was seen in 78% of patients, cytogenetic abnormalities (CA) within 6 months in 80%, and GEP-defined high risk in 41% of patients. 22/23 patients (96%) had prior autologous stem cell transplant. 19/23 patients (83%) had at least 2 transplants. All 23 patients had disease progression after having received regimens containing bortezomib, thalidomide, lenalidomide, melphalan and steroids. At least 1 cycle of treatment was administered to all 23 patients enrolled, 52% of patients received >1 cycle of treatment and only 13% received =>5 cycles. 10 patients (43%) discontinued therapy primarily due to progression or death. 5/23 (22%) patients achieved PR, 57% had stable disease. A trend towards PFS benefit was observed in patients receiving cycle 2 (HR=0.30, p=0.215) on univariate analysis and multivariate analysis (HR=0.40, p=0.48) after adjusting for GEP-defined risk status (HR=2.69, p=0.16). Most common toxicities, counting all toxicities (>=grade 3) were: thrombocytopenia (70%), leukopenia (61%), anemia (43%), hypophosphatemia (35%) and hypokalemia (26%). Overall and progression- free survival at 12 months were 52% and 30%, respectively. Conclusions: Pom demonstrates anti-myeloma activity in this advanced RRM population, especially in a sub-population with GEP-defined low-risk disease. Disclosures: Barlogie: Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

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Tazemetostat (TAZ) in relapsed/refractory (R/R) follicular lymphoma (FL): Propensity-score matched analysis of E7438-G000-101 trial outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18627 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18627-e18627

Author(s):

David Proudman ◽

Deepshekhar Gupta ◽

Dave Nellesen ◽

Alex Wong ◽

Jay Yang ◽

...

Keyword(s):

Propensity Score ◽

Single Agent ◽

Objective Response ◽

Prior History ◽

Cell Transplant ◽

Phase 2 ◽

Matched Sample ◽

Hematopoietic Stem ◽

Disease Characteristics ◽

Baseline Characteristics

e18627 Background: Oncology drug development often requires the use of non-randomized, open-label, phase 2 basket studies to better understand the early activity and safety of a potential new therapy. As such, baseline demographics and disease characteristics may differ between cohorts which can impact the perception of efficacy between cohorts. TAZ, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was approved by the US FDA after demonstrating single-agent, antitumor activity in a phase 2 study in adults with wild-type (WT) or mutant (MT) EZH2 R/R FL who had received ≥2 prior systemic therapies (NCT01897571). Differences between the cohorts in baseline characteristics known to be prognostic for clinical outcomes were noted, with the WT EZH2 cohort enrolling more patients with poor-risk features. This analysis assessed outcomes in the 2 groups after minimizing differences in baseline characteristics by creating a matched sample of directly comparable WT and MT patients. Methods: Propensity scores for each WT (n = 54) and MT (n = 45) EZH2 patient in the study were generated, based on the likelihood of being selected given their baseline characteristics. Characteristics identified for inclusion in the model were chosen if they were prognostic based on peer-reviewed literature and where larger differences were observed between cohorts at baseline: ECOG performance status, number of prior lines of anticancer therapy, progression of disease within 24 months, double refractory status, and prior history of hematopoietic stem cell transplant. Patients were matched 1:1 on propensity score, using a nearest-neighbor approach with caliper restrictions. Baseline covariates between the two matched groups were found to be sufficiently balanced. Objective response rate (ORR) point estimates were measured for the matched WT and MT EZH2 groups, and progression-free survival (PFS) was described using Kaplan-Meier analyses. Results: The propensity-matched sample included 56 patients (28 WT and 28 MT). Prior to matching, ORR was 35% (95% CI [22%, 48%]) in the WT and 69% (95% CI [55%, 83%]) in MT EZH2 groups; after matching, the ORR was 50% (95% CI [31%, 69%]) and 71% (95% CI [54%, 88%]), respectively. Median PFS was 11.1 months (95% CI [5.4, 16.7]) in the WT and 13.8 months (95% CI [11.1, 22.1]) in the MT EZH2 groups prior to matching, and 14.3 months (95% CI [11.1, inf]) and 14.8 (95% CI [10.7, inf]) months in the WT and MT EZH2 matched groups, respectively. Conclusions: As expected, efficacy remained higher in the MT EZH2 group; however, after adjustment, the ORR and PFS improved in the WT EZH2 group. This hypothesis-generating analysis suggests that outcomes in patients with WT EZH2 R/R FL treated with TAZ may have been more similar to those in the MT EZH2 group in the phase 2 trial had the baseline disease characteristics been more equally matched.

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Gemcitabine as a Single Agent in the Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.12.3786 ◽

1999 ◽

Vol 17 (12) ◽

pp. 3786-3792 ◽

Cited By ~ 90

Author(s):

A. Fosså ◽

A. Santoro ◽

W. Hiddemann ◽

L. Truemper ◽

N. Niederle ◽

...

Keyword(s):

Partial Response ◽

Confidence Interval ◽

Karnofsky Performance Status ◽

Performance Status ◽

Single Agent ◽

World Health ◽

Hematologic Toxicity ◽

Grade 3 ◽

Health Organization ◽

Hodgkin's Lymphomas

PURPOSE: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Thirty-one patients with B-cell intermediate or high-grade NHL (Working Formulation) were enrolled onto the study. The median age was 61 years, with a Karnofsky performance status of ≤ 80% in 65% of patients. Forty-eight percent had stage III or IV (Ann Arbor Classification) at study entry. Pretreatment consisted of one, two, or three chemotherapeutic regimens in nine, 11, and 11 patients, respectively. Gemcitabine 1,250 mg/m2 was administered intravenously over 30 minutes on days 1, 8, and 15 of a 28-day schedule. RESULTS: Thirty patients were assessable for efficacy, and 31 were assessable for toxicity. No complete responses were observed, but six patients showed a partial response, 11 stable disease, and 13 progressive disease. The overall response rate was 20% (95% confidence interval, 8% to 39%) for assessable patients and 19% (95% confidence interval, 8% to 34%) for the intent-to-treat analysis. The median duration of partial response was 6 months (range, 3.7 to 15+ months). Nonhematologic World Health Organization grade 3 toxicity included hepatic toxicity in four patients and infection in two. Hematologic toxicity was observed as grade 3 anemia in three patients, grade 3 leukopenia in two patients, grade 3/4 neutropenia in two patients, and grade 3/4 thrombocytopenia in six patients. CONCLUSION: The present schedule of gemcitabine displays modest efficacy and mild toxicity in pretreated aggressive NHL.

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Intra-Follicular Proliferation Rate Is a Powerful Independent Prognosticator in Follicular Lymphoma.

Blood ◽

10.1182/blood.v104.11.4571.4571 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4571-4571

Author(s):

Ad Koster ◽

Hedwig A. Tromp ◽

John M. Raemaekers ◽

George F. Borm ◽

Marius A. MacKenzie ◽

...

Keyword(s):

Follicular Lymphoma ◽

Univariate Analysis ◽

Proliferation Rate ◽

Rank Test ◽

Low Grade ◽

Prognostic Impact ◽

Bulky Disease ◽

Histologic Grading ◽

Grade 3 ◽

Mib 1

Abstract Several prognostic scores are used to predict the outcome of patients with follicular lymphoma (FL). Histologic grading is widely used, but poorly reproducible. Scoring systems such as the (FL)IPI consist of surrogate clinical markers that probably reflect underlying biological phenomena. We hypothesized that the proliferation rate of the intra-follicular neoplastic cells in FL may predict clinical outcome. Proliferating cells were identified by using the Mib-1 antibody in pre-treatment lymph node biopsies of 51 patients. In each section 200 cells per follicle were assessed in five follicles. The proliferation ratio (PR) was defined as (no. of Mib-1 positive cells/ total no. of cells) x 100. The PR was assessed only in the follicles, since many proliferating, non-malignant cells are present in the inter-follicular area. The inter-observer variability was assessed by repeating this procedure for 25 cases by a second investigator blinded to the outcome of the first assessment, resulting in a correlation coefficient of 0.81 (p < 0.001). All patients participated in a prospective multicenter trial on first-line treatment with the combination of 8 cycles of CVP (cyclophosphamide, vincristine and prednisone) chemotherapy plus interferon-alpha2b, followed by interferon-alpha maintenance in responding patients until relapse or progression. For statistical analysis the Kaplan-Meier product limit method, the log-rank test, the Cox proportional hazard model and the Mann-Whitney-U test were used. The median age of the patients was 53.3 years; 37 patients had stage IV disease; in nine patients a wait and see interval preceded the treatment (median duration 13 months). A low IPI score was present in 27 patients, intermediate in 20 and high in one. (three patients unknown). After central revision of the original diagnosis six patients were classified as grade 3 FL, 45 as grade 1 or 2. The overall median PR was 16.9 (3.1–49.2). In grade 1 and 2 FL the median PR was 16.1, in grade 3 it was 24.2 (p = 0.02). After a median follow-up of 71 months the median progression-free survival (PFS) for all patients was 25 months. The median PFS was not reached in the patients with the PR below the median compared to only 15 months in the patients with the PR above the median (p = 0.00059). In patients with the PR below median, overall survival was not reached compared to only 42 months in patients with a high PR (p = 0.0019). The PR maintained its prognostic impact on PFS and OS when tested as a continuous variable (p = 0.016 and 0.053 resp.). When the six patients with grade 3 FL were excluded from the analysis, the results remained significant. Other parameters that were significantly associated with a worse OS in univariate analysis were male sex, the presence of bulky disease and intermediate or high IPI. In multivariate analysis the association of high PR with a worse OS remained significant. We found that in FL intra-follicular proliferation rate is a strong independent prognostic factor of PFS and OS. Grade 3 FL appeared to have a higher PR than low grade FL, although numbers are small in this study. PR assessment is easy, relatively fast and reproducible. When confirmed in larger series, the intra-follicular PR could be used instead of histologic grading in identifying the aggressive types of follicular lymphoma, requiring other types of treatment.

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