Open-Label, Single-Arm, Phase II Study of Everolimus in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2717-2717 ◽  
Author(s):  
Patrick B. Johnston ◽  
Lauren Pinter-Brown ◽  
Jaqueline Rogerio ◽  
Ghulam Warsi ◽  
Anne Graham ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Pretreated Patients

Abstract Abstract 2717 Background: Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signal transduction pathway, which is central to cellular growth, proliferation, metabolism, survival, and angiogenesis, is implicated in Hodgkin lymphoma (HL) pathogenesis. In a previous phase II study of patients with relapsed/refractory lymphomas, the oral mTOR inhibitor everolimus showed promising clinical activity and acceptable toxicity in a subgroup of 19 heavily pretreated patients with HL (Johnston et al. Am J Hematol 2010;85:320–4). The purpose of this study was to confirm the safety and efficacy of everolimus 10 mg/day in patients with relapsed/refractory classical HL. Methods: In this multicenter, US, phase II study, patients aged ≥18 years with classical HL whose disease progressed after high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) and/or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen were treated with oral everolimus 10 mg/day until disease progression or unacceptable toxicity. Radiological response was assessed every 12 weeks using integrated positron emission tomography/computed tomography with contrast or computed tomography with contrast. The primary endpoint was the overall response rate (ORR) evaluated using modified response criteria for malignant lymphoma (Cheson et al. J Clin Oncol 2007;25:579–86). Secondary endpoints included median progression-free survival (PFS). Adverse events (AEs) were assessed throughout the study and for ≥4 weeks after the last everolimus dose. Results: The results from 37 patients in the safety population with evaluable data are reported in this abstract. Among these 37 patients, 35% were male, and the median age was 32 years. The median times from initial diagnosis to the first and most recent recurrence/relapse were 9 and 38 months, respectively. Of the 37 patients, 54% were pretreated with AHSCT and 95% were pretreated with a gemcitabine-, vinorelbine-, or vinblastine-containing regimen. The percentage of patients who experienced disease progression during prior therapies or discontinued their previous treatment due to disease progression was 73%. The median number of prior medication regimens was 4.5. Twenty-two patients discontinued treatment, including 11 due to disease progression and 8 due to AEs. The ORR was 35%, and an additional 27% of patients had stable disease (Table). The median PFS was 7.2 months (Figure). The most common hematologic AEs were thrombocytopenia (38%) and anemia (22%), and the most common nonhematologic AEs were fatigue (43%), cough (27%), headache (22%), dyspnea (22%), and rash (22%). Grade 3 or 4 drug-related AEs were noted in 12 (32%) patients and most commonly included thrombocytopenia (16%), neutropenia (8%), and anemia (8%). Serious AEs were experienced by 19% of patients; no serious AE occurred in more than 1 patient. Conclusion: Everolimus was associated with a favorable ORR and median PFS duration in highly pretreated patients with relapsed/refractory classical HL, confirming results of a previous study. The AE profile was consistent with that previously observed for everolimus; most AEs were grade 1 or 2 and manageable. These results suggest that further study evaluating everolimus in HL is warranted. Disclosures: Pinter-Brown: Genentech: Speakers Bureau; Spectrum: Honoraria; Celgene: Consultancy; Merck: Consultancy; Allos: Consultancy. Rogerio:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis Pharmaceuticals Corporation: Employment. Graham:Novartis Pharmaceuticals Corporation: Employment. Ramchandren:Seattle Genetics: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Pfizer: Research Funding.

Ofatumumab Added To Dexamethasone In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia. Results From a Phase II Study Of The Czech Leukemia Study Group For Life

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2877-2877 ◽  
Author(s):  
Michael Doubek ◽  
Yvona Brychtova ◽  
Anna Panovska ◽  
Jakub Trizuljak ◽  
Ludmila Sebejova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
In Vitro Testing ◽  
Grade 3

Abstract The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue despite remarkable improvements in prognostication and therapy. One emerging treatment option for relapsed/refractory CLL is the use of high-dose corticosteroids. High-dose methylprednisolone or dexamethasone combined with rituximab are active in relapsed/refractory CLL, but serious infections are frequent and progression-free survival (PFS) is short. The purpose of this clinical trial was to determine the efficacy and toxicity of ofatumumab-dexamethason (O-dex) combination in relapsed or refractory CLL population. The trial was an open-label, multi-center, non-randomized, phase II study. The O-dex regimen consisted of intravenous ofatumumab (Cycle 1: 300mg on day 1, 2000mg on days 8, 15, 22; Cycles 2-6: 1000mg on days 1, 8, 15, 22) and oral dexamethasone (40mg on days 1-4 and 15-18; Cycles 1-6). Premedication consisted of glucocorticoid, paracetamol, and antihistamine before each ofatumumab infusion. All patients received allopurinol, omeprazol, co-trimoxazole, and fluconazole for prophylaxis of tumor lysis syndrome and infections. The O-dex regimen was given for a minimum of 3 cycles, until best response, or a maximum of 6 cycles. Between July 2010 and December 2012, 32 patients (pts.) were recruited at 3 centers. Basic patient characteristics at the start of O-dex therapy were as follows: median age 66 years (range, 50-77); 24 males, 8 females; median CIRS score 7 (0-15); median previous treatment lines 3 (1-10); 30 (94%) pts. were pretreated with fludarabine and 12 (38%) with alemtuzumab; Rai III/IV stage was present in 20 (63%) pts.; 6 (19%) pts. had bulky lymphadenopathy; IgVH genes were unmutated in 30 (94%) pts.; del 11q was present in 6 (19%) and p53 defects (del 17p and/or TP53 mutation) in 8 (25%) pts. The median number of O-dex cycles administered was 6 (1-6). Twenty two (69%) pts. completed at least 3 cycles of therapy. The remaining 9 patients were prematurely discontinued due to CTCAE grade 3/4 infections (7 pts.), disease progression (1 pt.), or uncontrollable diabetes mellitus (1 pt.). Overall responses/complete remissions (ORR/CR) were achieved in 22/5 pts. (69/16%). One patient achieved minimal residual disease negativity (measured by 4-color flow cytometry) at the end of therapy. Median PFS was 10 months. In patients with p53 defects, ORR/CR were achieved in 5/2 pts. (63/25%). The Median PFS was 10.5 months for this subgroup. Median overall survival (OS) has not yet been reached. During therapy, CTCAE grade 3/4 toxicity consisted of bacterial infections (25%), ofatumumab infusion-related side-effects (9%), neutropenia (9%), hyperglycemia (6%), and anemia (3%). No reactivation of herpetic viral infection was observed during the course of therapy. Nine patients died during the follow-up as a result of disease progression (6 pts.), infections (2 pts.), or complications after allogeneic stem cell transplantation (1 relapsed pt.). The median CD20 antigen density in CLL cells was 4766 (881-18515) MESF (molecules of equivalent soluble fluorochrome) units at baseline. At the end of therapy, CD20 density had significantly decreased (median 821 MESF; 443-2637); nevertheless, it was high once more at relapse (median 6619 MESF; 628-21359). In vitro testing of malignant pts. cells sensitivity to dexamethasone and ofatumumab did not show synergistic or additive effect of these compounds in majority of patients. Also, in vitro testing did not clearly predict the outcome of O-dex therapy. Conclusions The O-dex regimen shows relatively high ORR and CR, with promising findings for PFS and OS (including pts. harboring p53 defects), as compared to published data on rituximab plus dexamethasone regimen or ofatumumab in monotherapy. The infectious toxicity in 1/4 of pts. represents the most frequent side effect for this regimen. The study was registered at www.clinicaltrials.gov (NCT01310101). Disclosures: Doubek: GlaxoSmithKline: Research Funding. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding.

scholarly journals Expanding the Indications for Ibrutinib: Complete Remission Obtained By Induction with Ibrutinib Followed By Consolidative Ahsct in Refractory Primary CNS Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5631-5631 ◽  
Author(s):  
Cassidy Brothers
Keyword(s):  
Complete Remission ◽  
Disease Progression ◽  
Salvage Therapy ◽  
B Cell Lymphoma ◽  
Salvage Treatment ◽  
Severe Neutropenia ◽  
High Dose ◽  
Cell Transplant ◽  
Curative Intent ◽  
Hematopoietic Stem

Introduction Primary central nervous system lymphoma (PCNSL) is an exceedingly rare and aggressive sub-type of Non-Hodgkin's Lymphoma. Despite initial polychemotherapy that includes High-Dose Methotrexate (HD-MTX), over half of patients will develop recurrent or refractory disease that requires salvage therapy.1 Ibrutinib, a Bruton's tyrosine kinase inhibitor, has become an alternative for salvage treatment in relapsed or refractory PCNSL (RR-PCNSL) that is particularly useful in patients who are ineligible for re-induction with HD-chemo. In RR-PCNSL, Ibrutinib led to a progression free survival (PFS) of roughly 5 months when used as monotherapy2,3 and 15 months when used as add-on therapy.4 While its role as salvage treatment has been documented, its use to facilitate consolidative autologous hematopoietic stem cell transplant (AHSCT) in RR-PCNSL is not currently known. The following case describes the first known report of a patient with RR-PCNSL who achieved persistent complete remission following Ibrutinib salvage treatment and consolidative AHSCT. Case Description A 64-year-old male presented to the emergency department with a two-week history ptosis, visual abnormalities, confusion, and increasing fatigue. On physical exam, he was found to have bilateral mydriasis, left third nerve cranial palsy, severe left-sided ptosis, and restricted upwards and downward gaze of the right eye. A contrast-CT was performed which showed multiple areas of abnormal enhancement throughout the frontal lobes, corpus callosum, and midbrain associated with significant vasogenic edema. These findings were confirmed on MRI. He underwent a stereotactic guided burr hole biopsy which was consistent with diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry performed on the tissue showed that the neoplastic cells were CD3(-), CD5(-), CD20(+), CD10(-), BCL2(subset +), BCL6(+), MUM1(+) and Cyclin D1(-). Staging CT and bone marrow biopsy showed no evidence of systemic disease. He was diagnosed with PCNSL and went on to receive induction therapy with Rituximab, Methotrexate, Procarbazine, and Vincristine (R-MPV) with curative intent and received a total of 7 cycles. Initially, he had a significant radiographic response with a repeat MRI post cycle 4 showing only a few small areas of residual enhancement. However, after completion of the 7 cycles of R-MPV, his MRI showed evidence of disease progression with both new and enlarging intra-axial lesions. Given his ECOG of 0 and lack of comorbidities, it was decided that he would proceed with salvage treatment with Cytarabine and Etoposide with curative intent for refractory PCNSL. Unfortunately, after only four weeks of receiving cycle one of Cytarabine and Etoposide, a repeat MRI showed evidence of disease progression. He was then transitioned to palliative therapy with prednisone up until December 2017, at which point he was able to obtain Ibrutinib on a compassionate basis. He was started on Ibrutinib salvage therapy and achieved radiographic evidence of complete remission after four months of treatment. There were minimal adverse effects of Ibrutinib therapy, most notably a severe neutropenia requiring a temporary discontinuation of therapy for two weeks. He underwent consolidative AHSCT with Thiotepa, Busulfan and Melphalan conditioning in August 2018. His post-transplant course was complicated by culture negative febrile neutropenia with a subsequent source determined to be Clostridium difficile for which he was treated. An MRI head performed 3 months after his AHSCT showed no evidence of recurrent or residual disease. He continues to be followed by the Hematology Service in Newfoundland and has remained in complete remission since. Conclusions This case demonstrates the feasibility of a salvage approach using Ibrutinib followed by AHSCT when standard salvage options have been exhausted in refractory PCNSL. OffLabel Disclosure: Ibrutinib's indications do not currently include use as a induction treatment prior to AHSCT in refractory/recurrent PCNSL.

High dose CHOP: A phase II study of initial treatment in aggressive non-Hodgkin lymphoma. Cancer and Leukemia Group B 9351

2007 ◽  
Vol 48 (5) ◽  
pp. 870-880 ◽  
Author(s):  
Bruce A. Peterson ◽  
Jeffrey Johnson ◽  
Margaret A. Shipp ◽  
Maurice Barcos ◽  
Jon P. Gockerman ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Initial Treatment ◽  
Phase Ii Study ◽  
High Dose ◽  
Non Hodgkin Lymphoma ◽  
Group B ◽  
Leukemia Group

Phase II Study of Combination of the Hypercvad Regimen with Dasatinib in the Front Line Therapy of Patients with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 837-837 ◽  
Author(s):  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Dan Jones ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Allogeneic Stem Cell Transplant ◽  
Median Response ◽  
Platelet Recovery

Abstract Abstract 837 Background: Combination therapy with cytotoxic chemotherapy and tyrosine kinase inhibitors has improved the outcome for patients with Ph+ ALL with durable remissions in some patients even without an allogeneic stem cell transplant. The dual Src and Abl inhibitor dasatinib has ∼325 times more potent in vitro kinase inhibition than imatinib against BCR-ABL with significant clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL. Aim: To determine the efficacy and safety of combining chemotherapy with dasatinib for treating patients with Ph+ ALL. Methods: In this phase II trial, patients with newly diagnosed Ph+ ALL receive dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in CR continue to receive maintenance dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. Results: We have enrolled in the study 34 patients with untreated Ph+ ALL and 7 patients with 1 prior cycle of chemotherapy (before Ph+/BCR-ABL+ status was known). Patients younger than 50 years old have received a median of 6 cycles (range 2-8) and patients 50 years and older have received a median of 6 cycles (range 1-8). 20 patients are receiving maintenance in CR and two have completed the entire treatment regimen. Median age is 51 years (range 21 – 79); 22 patients were older than 50 years, Median WBC at diagnosis was 13.6 × 109/L (range, 1-276 × 109/L). 12 patients had CNS involvement at presentation. All patients are evaluable for assessment of response to induction; 39 (95%) achieved CR after first cycle or were CR at start. Two patients died before response assessment from infections. Thirty-one of 39 (79%) evaluable patients achieved cytogenetic (CG) CR after 1 cycle; 4 had a major CG response (3 had 5% and one had 15% Ph+), 2 had insufficient metaphases, and 2 are unknown (no CG exam on day 21 marrow). To date, 22 patients (56%) have achieved complete molecular remission (CMR) and another 8 (21%) have achieved a major (but not complete) molecular response (MMR) at a median of 14 weeks from initiation of treatment (range 2 – 59 weeks). Minimal residual disease assessment by flow cytometry is negative in 35 (90%) patients at a median of 3 weeks (range, 2-18 weeks). The median time to neutrophil and platelet recovery for cycle 1 is 18 and 23 days and for subsequent cycles is 15 and 20 days. Grade 3 and 4 adverse events have included bleeding (GI, GU, soft tissue and subdural hematomas)(18), pleural effusions (9), pericardial effusion (1), reversible rise in creatinine (10), deep vein thromboses (6), pulmonary emboli (3), as well as diarrhea, infections, hypophosphatemia, hypokalemia, hypocalcemia, hyperglycemia, and elevated transaminases. With a median follow up of 13 months (range 1-33), 29 patients (71%) are alive and 27 (66%) are in CR; 4 patients died in CR; 1 from an unrelated cardiac event and 3 from infections. Three patients have undergone an allogeneic stem cell transplant. The median disease free survival is 48+ weeks (range,1 to 140+) and the median overall survival is 52+ weeks (range, 3 to 143+). Eight patients have relapsed with a median response duration of 51 weeks (range 23-73) and 6 of them have died. In 5 patients morphological relapse was preceded by flow and molecular relapse. Five relapsed patients had ABL mutations (3 T315I, 1 F359V, and 1 V299L). Conclusion: Combination of chemotherapy with dasatinib is effective in achieving long term remissions in patients with newly diagnosed Ph+ ALL. Disclosures: Ravandi: Bristol Myers Squibb: Honoraria, Research Funding. Kantarjian:Bristol Myers Squibb: Research Funding. Wierda:Genzyme: Research Funding; Genentech: Consultancy, Honoraria. Cortes:Bristol Myers Squibb: Research Funding. O'Brien:Bristol Myers Squibb: Research Funding.

Outcome of High Dose Melphalan with Autologous Hematopoietic Stem Cell Transplant In Myeloma Associated with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2400-2400
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
High Dose Melphalan

Abstract Abstract 2400 Background: Approximately 10% of patients with multiple myeloma (MM) have clinically overt primary systemic light-chain (AL) amyloidosis, and about 30% have concurrent occult AL amyloidosis. The impact of concurrent AL amyloidosis on the prognosis of myeloma is not well known. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) has shown significant activity in both MM and AL amyloidosis. Methods: We performed a retrospective analysis of patients who had concurrent MM and AL amyloidosis and underwent auto HSCT with high dose Melphalan at MDACC between 01/1998 to 05/2010. We identified 41 patients with concurrent MM and AL amyloidosis. Patient characteristics are summarized in Table 1. Twenty -six patients had occult AL amyloid, while 15 had clinically overt disease. Results: Median age at auto HSCT was 56 years (39-77), 58.5% being male with median follow up of 58.7 months from the time of diagnosis and 42.5 months from auto HCT. The median time from diagnosis to auto HCT was 8.9 mos (2.7-102.4 mos). 39% had Salmon Durie Stage III disease and 36.6% had more than one involved site at the time of transplant.Cytogenetic abnormalities were detected in 24.4% of patients. Post transplant hematologic responses were as follows: ≥CR=10 (24%), ≥VGPR=16 (39%), >PR=33 (80.5%), ≥stable disease= 40 (97.6%). Among the patients with overt organ involvement, one had early death. Of the 15 evaluable patients, organ responses were scored using the published consensus guidelines for amyloidosis and were as follows: PR=5 (33.3%), ≥SD=7 (46.7%). No correlation was seen between organ response and hematologic response. The 100-day treatment related mortality (TRM) was 0 and 1-year TRM of 2.4% which is comparable to patients transplanted for MM alone at our center. The median progression-free (PFS) and overall survival (OS) from auto HCT were 33.8 and 58.3 months, respectively.The median PFS and OS from diagnosis were 49.8 and 96 mos, respectively. In multivariate analysis, creatinine ≥ 2mg/dl was associated with a shorter PFS (p=0.043) and hemoglobin <10g/dl showed a trend towards a shorter PFS (p=0.093). None of these variables (Hb <10g/dl, Age>60yrs, Creatinine≥2mg/dl, B2M >3.5mg/l, BM plasma cells>30%) emerged as significant predictors of OS. There was no significant difference in outcome between patients with occult or symptomatic AL amyloidosis for OS (p=0.24) or PFS (P=0.9) Conclusion: In this analysis the outcome of patients with concurrent MM and AL amyloidosis was comparable to patients with MM alone. We believe these patients are acceptable candidates for auto HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber: novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Orlowski: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

Long-Term Follow Up Of a Randomized Phase II Study Of The JAK2-Selective Inhibitor Fedratinib (SAR302503) In Patients With Myelofibrosis (MF)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4047-4047 ◽  
Author(s):  
Animesh Pardanani ◽  
Ayalew Tefferi ◽  
Catriona HM Jamieson ◽  
Nashat Y Gabrail ◽  
Claudia Lebedinsky ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Hematologic Toxicity ◽  
Costal Margin ◽  
Spleen Volume ◽  
Randomized Phase Ii ◽  
Grade 3

Abstract Background We previously reported that patients with MF enrolled in a randomized Phase II study of fedratinib (SAR302503) (ARD11936; NCT01420770) had clinically meaningful reductions in splenomegaly and improvements in MF-associated constitutional symptoms after 24 weeks of treatment (Haematologica 2013;98:S1113). Here, we report updated efficacy and safety results from this study after 48 weeks of treatment (end of Cycle 12). Methods Patients with intermediate risk-2 or high-risk MF were randomized to receive once-daily fedratinib at doses of 300 mg, 400 mg, or 500 mg, for consecutive 4-weekly cycles, until disease progression or unacceptable toxicity. Eligible patients were aged ≥18 years, with palpable splenomegaly (5 cm below costal margin), and a platelet count ≥50 × 109/L. The primary measure for this study was percent change in spleen volume from baseline at the end of Cycle 3 (Blood 2012:120;Abstract 2837. Haematologica 2013;98:S1113). Endpoints for the current analysis included spleen response (≥35% reduction in spleen volume from baseline, assessed by a blinded independent central review by MRI), safety, and changes in bone marrow fibrosis (BMF). Results A total of 31 patients were randomized and treated: median age 63 years, 52% male, 58% primary MF, 58% high-risk MF, 90% JAK2V617F positive. The median numbers of treatment cycles were 12, 14, and 13 in the 300 mg, 400 mg and 500 mg dose groups, respectively, with median durations of exposure of 48.2, 56.2, and 52.4 weeks. At the cut-off date for this analysis, 21 patients (68%) remained on treatment; the most common reasons for treatment discontinuation were adverse events (AEs) (n=5) and withdrawal of consent (n=2). Overall, 58% (18/31) of patients achieved a spleen response at any time during treatment. The median spleen response duration was >35 weeks at all doses (Table). At Week 48, a spleen response was achieved by 30% (3/10), 80% (8/10), and 45% (5/11) of patients in the 300 mg, 400 mg, and 500 mg groups, respectively. Responses were generally maintained across all treatment groups. From Week 24 to Week 48 two additional patients achieved a spleen response (both in the 400 mg group), while one patient in the 500 mg group did not maintain a response (this patient had a fedratinib dose reduction to 200 mg). Changes in BMF up to Week 48 are being evaluated. The most common non-hematologic AE was diarrhea, with a Grade 3 rate of 13% (4/31 patients) but no Grade 4 cases were recorded. The rates of diarrhea decreased after the first cycle of treatment; from Cycle 2, the incidence of diarrhea (any grade) did not exceed 16% (5/31) at any cycle, and only one case of diarrhea was reported at Week 48 (end of Cycle 12). Anemia was the most-common hematologic toxicity, with a Grade 3 rate of 58% (18/31); no Grade 4 cases were reported. All Grades thrombocytopenia occurred in 55% (17/31) of patients, Grade 3 in three patients, and Grade 4 in two patients. Discontinuation of treatment due to AEs occurred in five patients over the 48 weeks (300 mg [n=2]; 400 mg [n=2]; 500 mg [n=1]), with two cases reported after Week 24 (dyspnea and leukocytosis [400 mg]; anemia and thrombocytopenia [500 mg]). There were 2 deaths (one in the 300 mg group due to unknown reasons [85 days after fedratinib discontinuation] and one in the 500 mg group due to disease progression [36 days after fedratinib discontinuation]). No cases of leukemic transformation were reported. Conclusions This updated analysis of the ARD11936 Phase II trial shows that treatment with fedratinib results in durable reductions in splenomegaly in patients with MF. No additional safety signals were observed with prolonged exposure to fedratinib. This study was sponsored by Sanofi. Disclosures: Pardanani: Sanofi, Bristol Myers Squibb, PharmaMar and JW Pharma: Clinical trial support Other. Jamieson:J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Lebedinsky:Sanofi: Employment. Gao:Sanofi: Employment. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau.

Activity of pazopanib in chemo-resistant patients with germ cell tumors (GCT): First results of the open-label, single-group, phase II PAZOTEST-01 trial.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 376-376 ◽  
Author(s):  
Patrizia Giannatempo ◽  
Nicola Nicolai ◽  
Elena Farè ◽  
Daniele Raggi ◽  
Luigi Piva ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Germ Cell ◽  
Disease Progression ◽  
Phase Ii ◽  
Antiangiogenic Therapy ◽  
Germ Cell Tumors ◽  
High Dose ◽  
Single Group ◽  
Open Label ◽  
Pure Seminoma

376 Background: Patients (pts) with germ cell tumors (GCT) who fail to be cured following multiple chemotherapy (CT) courses (± high-dose CT) have an extremely poor prognosis and long-term remissions are anecdotal. Pazopanib (PZP) is a potent and selective, orally available, TKI of VEGFR1, 2, and 3, PDGFRα, PDGFRβ, and cKit. Here we report the initial results of the ongoing open-label, single-group, phase II study which is sponsored by INT Milano (ClinicalTrials.gov NCT01743482). Methods: Pts with refractory GCT received pazopanib 800 mg/day orally until disease progression or evidence of unacceptable toxicity/side effects. Eligibility requirements included failure of at least two platinum-based CT, including high-dose CT. All pts underwent measurement of serum tumor markers (STM), a computed tomography and a FDG-PET after one month of treatment and q2 months thereafter. Results: From May 2013 to July 2013, five pts were enrolled, three in fourth, and two in fifth-line. Median age was 39 (IQR: 33 to 48). Three out of five had failed high-dose chemotherapy (HDCT), two had an extragonadal primary, all pts had at least one elevated STM at baseline, the sole parameter in one patient, two had liver metastases, four pts had a retroperitoneal relapse. Four had elevation of alfafetoprotein (AFP), one of human choriogonadotropin (HCG). Four were nonseminomas, one a pure seminoma. After the first month of treatment, four out of five pts had a decrease in marker levels, one patient had disease progression (PD). Two of the responding pts had a necrotic evolution of disease at computed tomography corresponding to a RECIST and metabolic (PET/CT) progression, two had a stable disease. Two-month follow up is available for three out of four responders: one interrupted PZP for toxicity and had a marker PD, another an increase to baseline levels and the last one a further reduction (pure seminoma, one out of five confirmed response at two months). There were two cases of hepatic toxicities (one G2 and one G3-4 with dose interruption). Conclusions: PZP is endowed with preliminary activity in extensively pretreated patients with GCT. The unique availability of STM in interpreting densitometric and metabolic response might provide insights into response assessment of solid tumors under antiangiogenic therapy. Clinical trial information: NCT01743482.

scholarly journals Lymphocyte Recovery Following Autologous Hematopoietic Stem Cell Transplant in Classical Hodgkin Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2913-2913
Author(s):  
Ashley Rose ◽  
Quinto J Gesiotto ◽  
Leidy Isenalumhe ◽  
Farhad Khimani ◽  
Hien D. Liu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Absolute Lymphocyte Count ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
The Ideal

Abstract Introduction: The standard of care for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) is salvage therapy followed by autologous hematopoietic stem cell transplant (auto-HCT). Pre-apheresis absolute lymphocyte count (PA-ALC) is an independent prognostic factor for overall survival (OS) after transplant. We aimed to evaluate the effect of absolute lymphocyte count following auto-HCT and hypothesized that a higher post-transplant ALC at day +15 (PT-ALC) correlates with improved OS. Methods: A retrospective review was performed on patients with R/R cHL who underwent auto-HCT at Moffitt Cancer Center from 2000-2020. The following patient characteristics were collected: age at diagnosis, gender, initial stage and presence of B symptoms. Pretransplant variables including chemotherapy, number of cycles, response to therapy, and time from last chemo to apheresis were collected. Receiver-operator characteristics (ROC) curve was used to identify the ideal PT-ALC to predict overall survival. Patients were then identified as high ALC versus low ALC. Mann-Whitney, Pearson Chi-square, and Fisher exact test were used to compare baseline characteristics between the two groups. Univariate analysis of overall survival was done using Log-rank testing and Kaplan-Meier curve. Cox-regression analysis was used to evaluate the factors affecting OS. Results: A total of 259 patients were included in the study, with a median age of 35 years (range 14-76). ROC curve was used to identify the ideal PT-ALC affecting OS, and a cutoff value of 300/uL was determined (AUC 0.60; 95% CI: 0.52-0.68, Figure 1). In this cohort, 52 patients (16.6%) had low PT-ALC and 207 patients (65.9%) had high PT-ALC. There was no significant difference between the two groups in regards to patient age, gender, histology type, stage at presentation, number of salvage cycles, number of CD34 cells collected, or number of days required for apheresis. Patients with a high PT-ALC had higher pre-apheresis ALC (p&lt;0.001). There was a trend toward significance with patients with high PT-ALC receiving non-chemotherapy salvage regimens (p=0.07, Table 1). However, PA-ALC was significantly higher in non-chemotherapy regimen (p=0.007). Patients with high PT-ALC had a longer OS after transplant than those with low PT-ALC, with median OS 11.8 years and 7.7 years, respectively (p=0.012, Figure 2). On multivariate analysis, the only factor associated with improved OS was high PT-ALC (p=0.015, Table 2). Conclusions: High PA-ALC and high PT-ALC are both independent prognostic factors for longer OS in patients with relapsed/refractory Hodgkin lymphoma after auto-HCT. High PA-ALC lead to higher PT-ALC. Although most of our patients received chemotherapy as salvage therapy prior to transplant, there was a trend toward higher PT-ALC in patients who received non-chemotherapy regimens. Future studies are required to determine the role of non-chemotherapy salvage regimens in improving lymphocyte counts during the peri-transplant period and, hence, improved survival. Figure 1 Figure 1. Disclosures Gaballa: Beigene: Consultancy; TG therapeutics: Consultancy, Speakers Bureau; Epizyme: Consultancy, Research Funding; Adaptive Biotechnologies: Research Funding; ADC Therapeutics: Consultancy. Chavez: BMS: Speakers Bureau; Merk: Research Funding; ADC Therapeutics: Consultancy, Research Funding; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; AstraZeneca: Research Funding. Shah: Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Incyte: Research Funding; BeiGene: Consultancy, Honoraria; Jazz Pharmaceuticals: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Amgen: Consultancy; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Servier Genetics: Other; Adaptive Biotechnologies: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory. Sokol: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Saeed: Kite Pharma: Consultancy, Other: investigator; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Company: Consultancy; Nektar Therapeutics: Consultancy, Other: research investigator; Other-TG therapeutics: Consultancy, Other: investigator; Other-Epizyme, Inc.: Consultancy; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; MEI Pharma Inc: Consultancy, Other: investigator; MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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