-
Amy Sexauer, Alexander Perl,
Xiaochuan Yang,
Michael Borowitz,
Christopher Gocke,
Trivikram Rajkhowa,
Christian Thiede,
Mark Frattini,
Grant E Nybakken,
Keith Pratz,
Judith Karp,
B Douglas Smith,
Mark Levis
[show abstract]
[hide abstract]
ABSTRACT: A hallmark of cancer is the disruption of differentiation within tumor cells. Internal tandem duplication mutations of the FLT3 kinase (FLT3/ITD) occur commonly in acute myeloid leukemia (AML) and are associated with poor survival, leading to efforts to develop FLT3 kinase inhibitors. However, FLT3 inhibitors have thus far met with limited success, inducing only a clearance of peripheral blasts with minimal marrow responses. Quizartinib is a novel potent and selective FLT3 inhibitor currently being studied in clinical trials. In 13 out of 14 FLT3/ITD AML patients with normal karyotype treated with quizartinib, we observed terminal myeloid differentiation of marrow blasts in association with a clinical differentiation syndrome. The single patient whose blasts failed to differentiate had a pre-existing C/EBPα mutation, while another developed a C/EBPα mutation at disease progression, suggesting a mechanism of resistance to FLT3 inhibition. In vitro, in primary blasts co-cultured with human bone marrow stroma, FLT3 inhibition with quizartinib induced cell cycle arrest and differentiation rather than apoptosis. This is the first description of terminal differentiation of cancer cells in patients treated with a tyrosine kinase inhibitor. These data highlight the importance of the differentiation block in the pathogenesis of AML. (NCI clinical trials # NCT00989261).
Blood 09/2012; · 9.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chronic myeloid leukemia (CML) is a hematopoietic disease characterized by expansion of myeloid blood cells. It is caused by the t(9;22) chromosomal translocation that results in the expression of the fusion tyrosine kinase BCR-ABL. Tyrosine kinase inhibitor (TKI) therapy has led to long-term remissions, but patients remain BCR-ABL+. There is agreement that TKIs do not kill CML stem cells; however, it is controversial whether this is because of a lack of BCR-ABL kinase inhibition in CML stem cells or because CML stem cells do not require BCR-ABL for survival. In this issue of the JCI, Corbin and colleagues provide definitive evidence that BCR-ABL is kinase active in CML stem cells and that TKIs inhibit this kinase activity without affecting CML stem cell survival. Rather, CML stem cells revert to a normal dependence on cytokines for survival and proliferation. These results demonstrate that the CML stem cell is not BCR-ABL addicted and have important implications for developing curative therapeutic approaches to CML.
The Journal of clinical investigation 01/2011; 121(1):22-5. · 15.39 Impact Factor
-
Mark Levis,
Farhad Ravandi,
Eunice S Wang,
Maria R Baer, Alexander Perl,
Steven Coutre,
Harry Erba,
Robert K Stuart,
Michele Baccarani,
Larry D Cripe, [......],
Gunnar Juliusson,
Mark R Litzow,
Stephen Petersdorf,
Miguel Sanz,
Hagop M Kantarjian,
Takashi Sato,
Lothar Tremmel,
Debra M Bensen-Kennedy,
Donald Small,
B Douglas Smith
[show abstract]
[hide abstract]
ABSTRACT: In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.
Blood 01/2011; 117(12):3294-301. · 9.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The myeloid malignancies include the myeloproliferative neoplasms (MPN) including chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). A growing body of evidence documents that these diseases are caused by genetic mutations that constitutively activate tyrosine kinases. They include the BCR/ABL in CML, the V617F JAK2 in Philadelphia chromosome-negative MPN, and the Flt3 ITD and TKD mutations in AML. Trials of the ABL kinase inhibitor, imatinib, have revolutionized the treatment of CML, and there are ongoing studies with other kinase inhibitors in MPN and AML. Here we review results of recent studies with first-generation JAK2 inhibitors in the treatment of MPN and second-generation ABL and Flt3 inhibitors in CML and AML, respectively. It is becoming apparent that although these kinase mutations have similar effects in vitro, each of the diseases has unique features that alter the use of kinase inhibitors in the clinic.
Current Oncology Reports 11/2010; 12(6):358-65. · 2.55 Impact Factor
-
Dan T Vogl,
Stephen V Liu,
Elise A Chong,
Selina M Luger,
David L Porter,
Stephen J Schuster,
Donald E Tsai, Alexander Perl,
Alison W Loren,
Steven C Goldstein,
Sunita D Nasta,
Charalambos Andreadis,
Patricia A Mangan,
Kimberly Hummel,
Don L Siegel,
Eli Glatstein,
Edward A Stadtmauer
[show abstract]
[hide abstract]
ABSTRACT: High-dose melphalan with autologous stem cell support improves survival as part of initial therapy for myeloma. Previous studies of pre-transplant induction regimens have compared paraprotein response rates but not long-term outcomes after transplant. We reviewed the records of all patients with multiple myeloma who received an autologous stem cell transplant at the University of Pennsylvania Medical Center. We compared outcomes for 69 patients who received high-dose melphalan conditioning after January 1, 2003 as part of initial therapy for myeloma, including 41 patients who received anthracycline-based induction (VAD or DVD) and 28 patients who received thalidomide and dexamethasone induction. Baseline characteristics in these two groups were not different, though potentially clinically important differences were apparent in assignment to post-transplant consolidation and maintenance therapy. Despite similar response rates during induction therapy, thalidomide and dexamethasone induction was associated with better progression-free survival (hazard ratio 0.18, P = 0.011) after transplant. This effect persisted in multivariable regression models including baseline characteristics and post-transplant treatment. Overall survival was not different between the two groups. These results suggest that the use of thalidomide during induction therapy may lead to improved long-term outcomes after transplant. Future trials comparing induction therapies should examine progression-free and overall survival after transplant to confirm this benefit.
American Journal of Hematology 01/2008; 82(12):1071-5. · 4.67 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We describe a 58-year-old man with acute lymphoblastic leukemia who developed diffuse left ventricular myocardial calcification during an episode of sepsis seen at computed tomographic imaging.
Journal of Thoracic Imaging 12/2007; 22(4):343-5. · 0.98 Impact Factor
-
Donald E Tsai,
Selina M Luger,
Allison Kemner,
Cezary Swider,
Ami Goradia,
Ewa Tomczak,
Doris DiPatri,
Adam Bagg,
Peter Nowell,
Alison W Loren, Alexander Perl,
Stephen Schuster,
James E Thompson,
David Porter,
Charlambos Andreadis,
Edward A Stadtmauer,
Steven Goldsteini,
Richard Ghalie,
Martin Carroll
[show abstract]
[hide abstract]
ABSTRACT: All-trans-retinoic acid has dramatically changed the treatment paradigm for acute promyelocytic leukemia, however, it has no significant activity in non-M3 acute myeloid leukemia (AML). In vitro, bexarotene, a retinoid X receptor agonist inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts from patients. We hypothesized that there may be similar activity in patients with AML. We report on two patients with relapsed or refractory non-M3 AML treated with bexarotene monotherapy. After initiating treatment, both patients showed leukemic differentiation in their peripheral blood and reduction in bone marrow blasts to less than 5%. One patient had a significant improvement in her platelet count with loss of platelet transfusion needs. Differentiation syndrome occurred in one patient and was successfully treated with steroids and discontinuation of bexarotene. These data suggest that bexarotene has clinical activity in non-M3 AML and may be able to induce myeloid differentiation in vivo.
Cancer biology & therapy 02/2007; 6(1):18-21. · 2.64 Impact Factor
-
Journal of Clinical Oncology 05/2006; 24(12):1950-1. · 18.37 Impact Factor
-
Anthony R Mato,
Brett E Riccio,
Li Qin,
Daniel F Heitjan,
Martin Carroll,
Alison Loren,
David L Porter, Alexander Perl,
Edward Stadtmauer,
Donald Tsai,
Alan Gewirtz,
Selina M Luger
[show abstract]
[hide abstract]
ABSTRACT: Tumor lysis syndrome (TLS) is defined by metabolic derangements occurring in the setting of rapid tumor destruction. In acute myelogenous leukemia (AML), TLS frequency, risk stratification, monitoring, and management strategies are based largely on case series and data from other malignancies. A single-center, retrospective cohort study was conducted to estimate TLS incidence and identify TLS predictive factors in a patient population undergoing myeloid leukemia induction chemotherapy. This study included 194 patients, aged 18-86 years, with AML or advanced myelodysplastic syndrome undergoing primary myeloid leukemia induction chemotherapy. Nineteen patients (9.8%) developed TLS. In univariate analysis, elevated pre-chemotherapy values for uric acid (P < 0.0001), creatinine (P = 0.0025), lactate dehydrogenase (LDH) (P = 0.0001), white blood cell (P = 0.0058), gender (P = 0.0064) and chronic myelomonocytic leukemia history (P = 0.0292) were significant predictors. In multivariate analysis, LDH (P = 0.0042), uric acid (P < 0.0001) and gender (P = 0.0073) remained significant TLS predictors. A predictive model was then designed using a scoring system based on these factors. This analysis may lay the groundwork for the development of the first evidence-based guidelines for TLS monitoring and management in this patient population.
Leukemia and Lymphoma 05/2006; 47(5):877-83. · 2.58 Impact Factor
-
David L Porter,
Bruce L Levine,
Nancy Bunin,
Edward A Stadtmauer,
Selina M Luger,
Steven Goldstein,
Alison Loren,
Julie Phillips,
Sunita Nasta, Alexander Perl,
Steven Schuster,
Donald Tsai,
Ambika Sohal,
Elizabeth Veloso,
Stephen Emerson,
Carl H June
[show abstract]
[hide abstract]
ABSTRACT: Donor lymphocyte infusions (DLIs) induce potent graft versus tumor (GVT) effects for relapsed chronic myelogenous leukemia (CML) after allogeneic stem cell transplantation (SCT) but are disappointing for other diseases. Disease resistance can occur if donor T cells are not appropriately activated in vivo. Ex vivo T-cell activation might overcome disease-induced anergy and augment GVT activity. We performed a phase 1 trial of ex vivo-activated DLI (aDLI) for 18 patients with relapse after SCT. Activated donor T cells are produced through costimulation with anti-CD3- and anti-CD28-coated beads. Patients with aggressive malignancies received induction chemotherapy, and all patients received conventional DLI (median, 1.5 x 10(8) mononuclear cells/kg) followed 12 days later by aDLI. Activated DLI was dose escalated from 1 x 10(6) to 1 x 10(8) CD3+ cells per kilogram in 5 levels. Seven patients developed acute graft versus host disease (GVHD) (5 grade I-II, 2 grade III), and 4 developed chronic GVHD. Eight patients achieved complete remission, including 4 of 7 with acute lymphocytic leukemia (ALL), 2 of 4 with acute myelogenous leukemia (AML), 1 with chronic lymphocytic leukemia (CLL), and 1 of 2 with non-Hodgkin lymphoma (NHL). Four complete responders relapsed while 4 remain alive in remission a median 23 months after aDLI. Overall, 10 of 18 remain alive 11 to 53 months after aDLI. Adoptive transfer of costimulated activated allogeneic T cells is feasible, does not result in excessive GVHD, and may contribute to durable remissions in diseases where conventional DLI has been disappointing.
Blood 03/2006; 107(4):1325-31. · 9.90 Impact Factor
