-
[show abstract]
[hide abstract]
ABSTRACT: ABSTRACT PTK787/ZK222584 (Vatalanib), an orally active inhibitor of vascular endothelial growth factor receptors (VEGF-Rs), was evaluated in this phase II study of 20 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received once daily PTK787/ZK222584 at a target dose of 1250mg. Eighteen patients were evaluable for response: 1 patient had a complete response (CR), 6 patients had stable disease but subsequently progressed, 10 patients had progressive disease by 3 cycles, and 1 subject withdrew before response evaluation. The patient who attained a CR underwent autologous stem cell transplantation and remains disease free 76 months after study completion. There were no grade 4 toxicities. Grade 3 thrombocytopenia occurred in 20% and grade 3 hypertension occurred in 10%. There were no episodes of grade 3 proteinuria. In conclusion, PTK787/ZK222584 was well tolerated in a heavily pretreated population of DLBCL patients, though its therapeutic potential as a single agent in DLBCL appears limited.
Leukemia & lymphoma 03/2013; · 2.40 Impact Factor
-
David A Rizzieri,
Christopher Crout,
Robert Storms,
Jared Golob,
Gwynn D Long,
Cristina Gasparetto,
Keith M Sullivan,
Mitchell Horwitz,
John Chute,
Anand S Lagoo,
Ashley Morris, Anne Beaven,
Yiping Yang,
Bercedis Peterson,
Zhiguo Li,
Nelson J Chao
[show abstract]
[hide abstract]
ABSTRACT: High relapse rates and infections remain primary causes of failure in nonmyeloablative transplantation. Interleukin-2 (IL-2) may stimulate the immune system and improve outcomes. The primary objective of this pilot study was to evaluate the feasibility of administering IL-2 following a T-cell-depleted nonmyeloablative hematopoietic stem cell transplant.
Patients received T-cell-depleted nonmyeloablative transplant from a matched or mismatched related donor. Those with allogeneic engraftment, <grade 2 acute GVHD at time of study entry, and no severe end organ damage were eligible and received IL-2 starting 6 weeks after the first day of stem cell infusion. Patients received 1 mu/m2 daily for 5 days each week for 4 weeks followed by a 2-week rest period for a 6-week cycle to continue for up to 1 year.
Eight patients aged 28-69 years were treated. Significant toxicities were limited to GVHD of the skin ≤grade 2 in 3 patients and severe fatigue in 4 patients, limiting the duration of therapy. Two of the 8 patients died of relapsed disease and 1 from CMV. With a median overall duration of follow-up of survivors of 48 months, 5 patients (63%) remain alive and in continuous complete remission.
Cancer Investigation 01/2011; 29(1):56-61. · 1.85 Impact Factor
-
Anjali S Advani,
Mazyar Shadman,
Francis Ali-Osman,
Andrew Barker,
Lisa Rybicki,
Matt Kalaycio,
Mikkael A Sekeres,
Carlos M de Castro,
Louis F Diehl,
Joseph O Moore, Anne Beaven,
Ed Copelan,
Ronald Sobecks,
Parisa Talea,
David A Rizzieri
[show abstract]
[hide abstract]
ABSTRACT: We evaluated the complete remission (CR) rate in patients with acute myeloid leukemia (AML) in first relapse treated with fixed-dose-rate gemcitabine and mitoxantrone. In addition, we measured multidrug resistance (MDR) proteins on pretreatment bone marrows and correlated expression with outcome.
The study was performed in a 2-stage design. Pretreatment bone marrows were assayed for the MDR proteins (LRP, MDR1, MRP1, SLC28-29A1/A2, ABCC4/C5, and GSTP1) by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR).
Only 5 of the first 24 patients (21%) achieved CR; therefore, the study was terminated. Eleven patients (46%) had poor-risk cytogenetics and the median duration of first CR was 7.3 months. Patients had significant expression of the various MDR genes, with 70% of patients expressing moderate to high levels of GSTP1 by immunohistochemistry. Higher sum total of ABCC4 and SLC29A2 expression measured by RT-PCR was associated with not achieving CR (20.6 vs. 12.1; P = .006). In addition, there was a trend for higher expression of the sum total of the 10 MDR genes (measured by RT-PCR) and not achieving CR (P = .06).
The CR rate in this study was comparable to other regimens used in poor-risk patients. Of interest, ABCC4 and SLC29A2 expression were predictive of achieving CR. The high expression of GSTP1 suggests that this may be a therapeutic target for relapsed AML. Finally, the rapidity and ease of using RT-PCR to quantify MDR in this study may have clinical utility in future trials.
Clinical lymphoma, myeloma & leukemia 12/2010; 10(6):473-6.
-
Christopher A Crout,
Liang-Piu Koh,
Jon P Gockerman,
Joseph O Moore,
Carlos Decastro,
Gwynn D Long,
Louis Diehl,
Christina Gasparetto,
Donna Niedzwiecki,
Jon Edwards,
Leonard Prosnitz,
Mitchell Horwitz,
Jon Chute,
Ashley Morris,
Patricia Davis, Anne Beaven,
Nelson J Chao,
Francis Ali-Osman,
David A Rizzieri
[show abstract]
[hide abstract]
ABSTRACT: We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.
Cancer Investigation 07/2010; 28(6):654-60. · 1.85 Impact Factor
-
David A Rizzieri,
Jenny A O'Brien,
Gloria Broadwater,
Carlos M Decastro,
Prakash Dev,
Louis Diehl, Anne Beaven,
Anand Lagoo,
Jon P Gockerman,
Nelson J Chao,
Joseph O Moore
[show abstract]
[hide abstract]
ABSTRACT: Response and survival in 96 patients with secondary acute myeloid leukemia (sAML) who received aggressive induction chemotherapy was reviewed.
The median follow-up of survivors was 2.3 years. A total of 70 (73%) patients achieved a morphologic complete remission (CR) confirmed by absence of leukemic blasts by flow cytometry.
For all 96 patients, the median event-free survival (EFS) was 8 months, and overall survival (OS) was 13.6 months (range, 1-119 months). Eight patients died shortly after induction therapy because of disease or side effects, and 13 are currently in continuous first remission. The median disease-free survival (DFS) for all 70 patients who achieved a morphologic CR was 9 months (range, 1-51 months), with a 64% chance of surviving 1 year. Patients with AML after previous chemotherapy or radiation therapy had a higher morphologic remission rate compared with those arising from myelodysplastic syndrome or myeloproliferative disease (82% vs 62%; P = .027). However, among the patients from the 2 groups who attained a morphologic remission, there was no difference in terms of CR rate (P = .94), DFS, EFS, or OS (P = .55, .83, and .71, respectively). This is a similar DFS to the group of 7 patients who went directly to ablative allogeneic transplant rather than having induction therapy first. In this population of patients who received aggressive chemotherapy, Charlson comorbidity index or a higher number of factors recognized as high risk in leukemia patients did not affect the chance of OS, DFS, and EFS, although having more recognized leukemia risk factors was related to a lower chance of surviving 1 year. However, it is important to note that those with higher comorbidity indexes were underrepresented in this aggressively treated cohort.
The data from the current study demonstrate that many patients with sAML can tolerate aggressive induction therapy and attain remission, but duration of response and the chance of long-term survival remain poor.
Cancer 06/2009; 115(13):2922-9. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Non-cross resistant drugs given at high-dose intensity may maximise tumor cell kill leading to improved patient outcomes. We investigated the feasibility and efficacy of administering ifosfamide, carboplatin and etoposide +/- rituximab as sequential high-dose single agents. Twenty-two patients with relapsed/refractory Hodgkin lymphoma (n = 9) or non-Hodgkin (n = 13) lymphoma (NHL) were included. Therapy included: cycle 1 ifosfamide (15 g/m(2)), cycle 2 etoposide (900 mg/m(2)) and cycle 3 carboplatin (area under the curve 15). Patients with NHL received rituximab (375 mg/m(2)) with cycles 1 and 2. Blood stem cell collection was performed after etoposide. Primary endpoints were overall response (complete response (CR) + PR) and ability to mobilise stem cells after etoposide. Secondary endpoints were to assess the toxicity of the regimen and to evaluate the ability of patients to proceed to stem cell transplant (SCT). Overall response rate was 54% with CR in 4/22 (18%) subjects and PR in 8/22 (36%). Median progression-free survival was 15 months and overall survival has not been reached at 40 months. Thirteen participants proceeded to SCT. Grade 3/4 thrombocytopenia and neutropenia occurred in 58% of cycles and 91% of subjects respectively. Forty-five percent of patients required hospitalisation for toxicity and two patients died from complications of therapy. Sequential dose intense ifosfamide, etoposide, carboplatin +/- rituximab was more toxic and no more effective than the same drugs given in a conventional fashion.
Leukemia & lymphoma 05/2009; 50(5):741-8. · 2.40 Impact Factor
