Showing papers by "Pier Paolo Scaglioni published in 2011"

Successful Treatment of Relapsed and Refractory Extramedullary Acute Promyelocytic Leukemia With Tamibarotene

Abstract: Case Report A 25-year-old man presented in 2004 with extensive ecchymosis and lower extremity compartment syndrome requiring emergency surgery. At this time he was diagnosed with acute promyelocytic leukemia (APL). Conventional cytogenetic analysis of the bone marrow showed additional material on chromosome 7p, whereas molecular studies revealed promyelocytic leukemia gene-retinoic acid receptor alpha (PML-RARA) rearrangement (details of the patient’s cytogenetic and molecular analysis have been previously published). He was treated with all trans retinoic acid (ATRA) and idarubicin followed by two cycles of consolidation chemotherapy with doxorubicin and ATRA. In 2006, while he was on maintenance chemotherapy with methotrexate, 6 mercaptopurine, and ATRA, he developed pain in his shoulder. Diagnostic studies showed promyelocytic sarcoma (PS) of the scapula. A bone marrow biopsy showed relapse in the bone marrow. He was treated with a combination of ATRA, gemtuzumab ozogamicin, and arsenic trioxide (ATO) and achieved a complete molecular remission. In January 2007, he presented with back pain and was diagnosed with PS of the thoracic vertebra, confirmed by both fluorescent in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction, with no evidence of relapse in the bone marrow. He was treated with ATO and idarubicin and local radiation to the affected spine. This resulted in a complete remission and he then underwent matched unrelated allogenic stem-cell transplantation in February 2007, using high-dose cyclophosphamide and busulfan as the preparative regimen. He developed mild chronic graft versus host disease which was controlled with prednisone 10 mg every other day. He did well until January 2009 when he developed cough and shortness of breath. A CT scan of his chest showed a mass, measuring 8.5 2.5 cm in the superior vena cava extending into the right atrium. He underwent surgical resection of this mass revealing PS. His CSF analysis was negative for leukemic cells. He received ATO and ATRA and intensity modulated radiotherapy to the atrium and superior vena cava at a dose of 25.20 Gy in 14 treatments. After the radiation, he was treated with one cycle of high-dose cytarabine. After recovering from the chemotherapy, he was put on maintenance therapy with ATRA and ATO. In September 2009, he developed a mass in the left supraclavicular fossa measuring 2.5 2.2 cm. A biopsy confirmed recurrence of PS and a positron emission tomography (PET) scan showed multiple [F]fluorodeoxyglucose (FDG) avid masses in the soft tissue and bone, in the chest and pelvis. A bone marrow biopsy done at this time did not show any evidence of bone marrow involvement. He did not have any neurological symptoms and he declined a lumbar puncture for CSF analysis. He was treated with gemtuzumab ozogamicin and ATRA, but a repeat PET scan done in December 2009 showed only a mixed response. At this time there were more than 20 FDG avid nodules in the abdomen, chest, and deep muscles and subcutaneous tissues. These nodules ranged from 3 3 mm to 2 2 cm in diameter and standard uptake values in these nodules ranged from 2.2 to 13.6. An FDG avid PS involving the rectum is shown in (Fig 1). At this time he was started on tamibarotene on a compassionate basis at a dose of 6 mg/m/d orally divided into two daily doses for 56 days. He then had a 14-day rest period from medication, followed by resumption of tamibarotene for 28 days, followed again by a 14-day rest period. At this time he began a maintenance schedule, in which tamibarotene was administered in cycles for 28 days in a row followed by 28 days off. No other concomitant chemotherapy was administered. Four weeks after the initiation of tamibarotene, a PET scan showed tumor shrinkage (Fig 2) and 16 weeks after the initiation of the drug a PET scan showed complete resolution of his FDG avid PS sites (Fig 3). Eight months after the initiation of tamibarotene, his PET scan remained negative for FDG avid sites. The drug was well tolerated with only mild headache, nausea, and loss of appetite during the first cycle, with the symptoms improved over subsequent cycles. He is now 12 months out from initiation of tamibarotene with no evidence of disease and we plan to continue therapy indefinitely.

Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo.

Abstract: The BCR/ABL tyrosine kinase promotes leukemogenesis through activation of several targets that include the phosphoinositide 3-kinase (PI3K). Tyrosine kinase inhibitors (TKIs), which target BCR/ABL, induce striking clinical responses. However, therapy with TKIs is associated with limitations such as drug intolerance, inability to universally eradicate the disease and emergence of BCR/ABL drug-resistant mutants. To overcome these limitations, we tested whether inhibition of the PI3K/target of rapamycin (mTOR) signaling pathway has antileukemic effect in primary hematopoietic stem cells and BA/F3 cells expressing the BCR/ABL oncoprotein. We determined that dual inhibition of PI3K/mTOR causes growth arrest and apoptosis leading to profound antileukemic effects both in vitro and in vivo. We also established that pharmacologic inhibition of the mTORC1/mTORC2 complexes is sufficient to cause these antileukemic effects. Our results support the development of inhibitors of the mTORC1/2 complexes for the therapy of leukemias that either express BCR/ABL or display deregulation of the PI3K/mTOR signaling pathway.

Treatment with 5-Azacytidine Accelerates Acute Promyelocytic Leukemia Leukemogenesis in a Transgenic Mouse Model

Abstract: A key oncogenic force in acute promyelocytic leukemia (APL) is the ability of the promyelocytic leukemia-retinoic acid receptor α (PML-RARA) oncoprotein to recruit transcriptional repressors and DNA methyltransferases at retinoic acid-responsive elements. Pharmacological doses of retinoic acid relieve transcriptional repression inducing terminal differentiation/apoptosis of the leukemic blasts. APL blasts often harbor additional recurrent chromosomal abnormalities, and significantly, APL prevalence is increased in Latino populations. These observations suggest that multiple genetic and environmental/dietary factors are likely implicated in APL. We tested whether dietary or targeted chemopreventive strategies relieving PML-RARA transcriptional repression would be effective in a transgenic mouse model. Surprisingly, we found that 1) treatment with a demethylating agent, 5-azacytidine, results in a striking acceleration of APL; 2) a high fat, low folate/choline-containing diet resulted in a substantial but nonsignificant APL acceleration; and 3) all-trans retinoic acid (ATRA) is ineffective in preventing leukemia and results in ATRA-resistant APL. Our findings have important clinical implications because ATRA is a drug of choice for APL treatment and indicate that global demethylation, whether through dietary manipulations or through the use of a pharmacologic agent such as 5-azacytidine, may have unintended and detrimental consequences in chemopreventive regimens.