Posted by rob on July 28, 2010 under Uncategorized | 
Hematopoietic progenitor cell collection in patients with chronic myelogenous leukemia in complete cytogenetic remission after imatinib mesylate therapy.
Leuk Lymphoma. 2010 Jul 27;
Authors: Bashir Q, De Lima MJ, McMannis JD, Garcia-Manero G, Shpall E, Kantarjian H, Cortes JE, O’Brien SM, Jones D, Qazilbash M, Wei W, Giralt SA, Champlin RE, Hosing C
The introduction of BCR-ABL tyrosine kinase inhibitors such as imatinib has changed the treatment of chronic myelogenous leukemia (CML). More than 75% of patients achieve complete cytogenetic remission (CCR) after treatment with imatinib, which provides an opportunity to collect minimally involved hematopoietic progenitor stem cell (HPC) products. In order to assess the feasibility of HPC collection in patients with CML, we prospectively enrolled 24 patients who achieved CCR on therapy with imatinib. Two patients could not undergo HPC collection because of coagulopathy. A CD34+ cell yield of >/=2.0 x 10(6)/kg body weight was obtained in 16/22 (73%) patients. Patients who stopped imatinib for at least 3 weeks prior to HPC collection had significantly higher CD34+ cell yields (median: 6.52 x 10(6)/kg body weight) when compared with patients who continued imatinib through the collection (median: 3.74 x 10(6)/kg body weight). Mobilization with granulocyte colony-stimulating factor (G-CSF) did not increase the levels of BCR-ABL transcript. With a mean follow-up of 46 months, all patients but one were in CCR. In conclusion, a significant number of CD34+ cells can be safely collected in patients with CML who are on imatinib therapy, but CD34+ cell yields improve when imatinib is temporarily withheld.
PMID: 20658954 [PubMed - as supplied by publisher]
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Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl.
Cancer Cell. 2010 Jul 13;18(1):74-87
Authors: Gregory MA, Phang TL, Neviani P, Alvarez-Calderon F, Eide CA, O’Hare T, Zaberezhnyy V, Williams RT, Druker BJ, Perrotti D, Degregori J
Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to eradicate Bcr-Abl(+) leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl(+) leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib mesylate in CML cells. This screen identified numerous components of a Wnt/Ca(2+)/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production, and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl(+) acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl(+) leukemias.
PMID: 20609354 [PubMed - indexed for MEDLINE]
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Chronic myeloid leukemia: mechanisms of blastic transformation.
J Clin Invest. 2010 Jul 1;120(7):2254-64
Authors: Perrotti D, Jamieson C, Goldman J, Skorski T
The BCR-ABL1 oncoprotein transforms pluripotent HSCs and initiates chronic myeloid leukemia (CML). Patients with early phase (also known as chronic phase [CP]) disease usually respond to treatment with ABL tyrosine kinase inhibitors (TKIs), although some patients who respond initially later become resistant. In most patients, TKIs reduce the leukemia cell load substantially, but the cells from which the leukemia cells are derived during CP (so-called leukemia stem cells [LSCs]) are intrinsically insensitive to TKIs and survive long term. LSCs or their progeny can acquire additional genetic and/or epigenetic changes that cause the leukemia to transform from CP to a more advanced phase, which has been subclassified as either accelerated phase or blastic phase disease. The latter responds poorly to treatment and is usually fatal. Here, we discuss what is known about the molecular mechanisms leading to blastic transformation of CML and propose some novel therapeutic approaches.
PMID: 20592475 [PubMed - indexed for MEDLINE]
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We report here a patient first diagnosed with Fanconi anemia at age 10. Bone marrow transplantation was performed at age 23 and repeated after an episode of rejection at age 25. Hematologic findings returned to normal, but chronic graft-versus-host disease persisted. Esophageal cancer developed at age 35. Invasion of the bronchus and aorta by the tumor was suspected on computed tomography. Chemoradiotherapy was administered to down-stage the tumor, using low-dose cisplatin and 5-fluorouracil. After two courses of chemotherapy with cisplatin (total dose, 100 mg) and 5-fluorouracil (5000 mg) plus radiotherapy (30 Gy), Grade 3 diarrhea and bone marrow suppression developed, and treatment was discontinued. After resolution of toxicity, a good response to the neoadjuvant therapy was seen on com…
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Posted by rob on July 27, 2010 under Uncategorized |
Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): A therapeutic advances in childhood leukemia (TACL) consortium study.
Pediatr Blood Cancer. 2010 Sep;55(3):421-9
Authors: Gorman MF, Ji L, Ko RH, Barnette P, Bostrom B, Hutchinson R, Raetz E, Seibel NL, Twist CJ, Eckroth E, Sposto R, Gaynon PS, Loh ML
BACKGROUND: Current event-free survival (EFS) rates for children with newly diagnosed acute myeloid leukemia (AML) approach 50-60%. We hypothesize that further improvements in survival are unlikely to be achieved with traditional approaches such as dose intensive chemotherapy or hematopoietic stem cell transplants, since these therapies have been rigorously explored in clinical trials. This report highlights efforts to assess the response rates and survival outcomes after first or greater relapse in children with AML. PROCEDURE: We performed a retrospective cohort review of pediatric patients with relapsed and refractory AML (rAML) previously treated at TACL institutions between the years of 1995 and 2004. Data regarding disease characteristics at diagnosis and relapse, treatment response, and survival was collected on 99 patients and 164 medullary relapses or treatment failures. RESULTS: The complete response (CR) rate following the second therapeutic attempt was 56 +/- 5%. CR rates following a third treatment attempt was 25 +/- 8% while 17 +/- 7% achieved CR following the fourth through sixth treatments. The 5-year disease-free survival in patients achieving CR following a second therapeutic attempt was 43 +/- 7%. The 5-year EFS and overall survival (OS) rates for all patients receiving a second treatment attempt was 24 +/- 5% and 29 +/- 5%, respectively. CONCLUSIONS: This CR rate following a second therapeutic attempt and OS rate in patients with rAML is consistent with the literature. There are limited published data of CR rates for subsequent relapses. Our data can serve as a historical benchmark to compare outcomes of future therapeutic trials in rAML against traditional chemotherapy regimens. Pediatr Blood Cancer. 2010;55:421-429. (c) 2010 Wiley-Liss, Inc.
PMID: 20658611 [PubMed - in process]
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Hematopoietic stem cell transplantation for T315I-mutated chronic myelogenous leukemia.
Ann Transplant. 2010 Jun 28;15(2):68-70
Authors: Basak GW, Torosian T, Snarski E, Niesiobedzka J, Majewski M, Gronkowska A, Urbanowska E, Jedrzejczak WW
Background: The T315I mutation of BCR/ABL gene is known to produce complete resistance of chronic myelogenous leukemia (CML) to all currently available BCR/ABL inhibitors. The data suggesting poor median survival of these patients may indicate that they should be primary candidates for allogeneic stem cell transplantation (alloSCT). However, evidence on efficiency of this treatment modality in CML with T315I mutation is lacking.<br /> Case Report: A 25-year-old patient was diagnosed with Philadelphia chromosome positive CML in accelerated phase. As he did not have an HLA-identical sibling or fully-matched unrelated bone marrow donor, treatment with low dose tyrosine kinase inhibitor – imatinib was initiated. Despite satisfactory hematological remission, he failed to achieve complete cytogenetic remission within the first year of treatment. Moreover, despite escalation of imatinib dosage, the disease relapsed after further 3 months of treatment. Molecular studies revealed T315I mutation of BCR/ABL gene. He responded poorly to interferon alpha (IFN-alpha) and we decided to perform alloSCT from a partially mismatched (8/10 HLA allele match) unrelated donor. The course of transplantation was complicated by staphylococcal sepsis, grade I skin acute GvHD and limited chronic skin GVHD. However, the goal of alloSCT was achieved and the patient remains in complete molecular remission at week +68 post-transplantation.<br /> Conclusions: The clinical course of this case supports the idea that allogeneic hematopoietic transplantation is a viable treatment option for patients with CML bearing T315I mutation.
PMID: 20657522 [PubMed - in process]
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Autophagy is a critical mechanism for the induction of the antileukemic effects of arsenic trioxide.
J Biol Chem. 2010 Jul 23;
Authors: Goussetis DJ, Altman JK, Glaser H, McNeer JL, Tallman MS, Platanias LC
Arsenic trioxide (As2O3) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As2O3 is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As2O3 appears to require activation of the MEK/ERK pathway, but not the AKT/mTOR or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 result in reversal of the suppressive effects of As2O3 on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia (AML) patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As2O3 on AML cells and raise the potential of modulating of elements of the autophagic machinery as an approach to enhance the antitumor properties of As2O3 and possibly other heavy metal derivatives.
PMID: 20656687 [PubMed - as supplied by publisher]
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Posted by rob on July 24, 2010 under Uncategorized |
Ring chromosome 18 abnormality in acute myelogenous leukemia: the clinical dilemma.
J Hematol Oncol. 2010 Jul 22;3(1):25
Authors: Sivendran S, Gruenstein S, Malone AK, Najfeld V
ABSTRACT: The ring chromosome is a circular, structural abnormality composed of either multiple chromosomes or a single chromosome with loss of genetic material at one or both ends. This chromosomal rearrangement is often unstable with frequent recombinations and may be accompanied by either loss or amplification of genetic material.1 Considering that ring chromosomes are rare in acute myelogenous leukemia (AML), it is difficult to risk stratify patient prognosis, particularly when the ring chromosome occurs as the sole abnormality. Here we report a case of a ring chromosome 18 abnormality in a patient with newly diagnosed AML with monocytic differentiation. Cytogenetic analysis demonstrated 46,XY,r(18)(p11q21) karyotype in 19 of 34 evaluated metaphase cells. The patient received induction chemotherapy and subsequent allogeneic cord blood transplant from a sex-matched donor, and remained in hematologic and cytogenetic remission for 120 days post transplant. Soon after, he developed post transplant lymphoproliferative disorder and died of multi-organ failure. Although r(18) chromosomal abnormalities were not classified in the recent updated evidence-and expert opinion-based recommendations for the diagnosis and management of AML (likely due to the small number of reported cases), the patient was treated as high risk with stem cell transplantation. This was based on the unstable nature of the ring chromosome and the poor outcomes described in the literature of patients with sole ring 18 abnormalities.
PMID: 20649984 [PubMed - as supplied by publisher]
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Posted by rob on July 23, 2010 under Uncategorized |
A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects.
Cancer Biol Ther. 2010 Sep 13;10(6)
Authors: Keasey N, Herse Z, Chang S, Liggitt DH, Lay M, Fairman J, Claxton DF
Cationic lipid DNA complex (CLDC) is an immunostimulatory preparation that has significant anti-leukemic effects in multiple murine models of leukemia: BCR-ABL(+) myelogenous leukemia in C3H/HeJ animals and myelomonocytic leukemia in BALB/c mice. Following leukemic challenge, CLDC treatment inhibits tumor cell growth in vivo and extends survival, sometimes resulting in apparent eradication of tumor cells. CLDC induces multiple cytokines including interferon-gamma (IFNgamma), and intravenous treatment results in a more rapid and robust response than subcutaneous treatment. IFNgamma is induced in a dose-dependent manner, and tachyphylaxis results from repeated doses of CLDC. Tachyphylaxis of therapeutic effects is exacerbated at higher doses, thus the optimal survival benefits are seen at intermediate doses. Animals whose leukemia has been successfully treated with CLDC exhibit a survival advantage when faced with a secondary leukemic challenge, suggesting the existence of an adaptive anti-leukemic response. This work demonstrates the effectiveness of CLDC in multiple experimental leukemias and is consistent with a stimulation of a lasting TH(1) anti-leukemic immune response.
PMID: 20647744 [PubMed - as supplied by publisher]
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Occurrences of opportunistic infections in chronic myelogenous leukemia patients treated with imatinib mesylate.
Leuk Res. 2010 Jun 18;
Authors: Anthony N, Shanks J, Terebelo H
PMID: 20646761 [PubMed - as supplied by publisher]
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17-N-Allylamino-17-demethoxygeldanamycin induces a diverse response in human acute myelogenous cells.
Leuk Res. 2010 Jun 18;
Authors: Napper JM, Sollars VE
The goal of this study was to ascertain the specific effects of 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) treatment in human acute myelogenous leukemia (AML). Four human leukemia cell lines were treated with varying doses of 17-AAG followed by analysis of toxicity, apoptosis, proliferation, and cell cycle. Cell cycle analysis revealed that the cells accumulate in G2/M phase within 96h of treatment, although the effect was not equivalent among the cell lines. p21, p53 expression and MDR1 activity were among the possible mechanisms uncovered for the differing responses. Exploiting these differences may allow for more effective combinatory treatments in patients with AML.
PMID: 20646760 [PubMed - as supplied by publisher]
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Posted by rob on July 21, 2010 under Uncategorized |
Erythroid Induction of Chronic Myelogenous Leukemia K562 Cells Following Treatment with a Photoproduct Derived from the UV-A Irradiation of 5-Methoxypsoralen.
ChemMedChem. 2010 Jul 19;
Authors: Salvador A, Dall’acqua S, Sardo MS, Caffieri S, Vedaldi D, Dall’acqua F, Borgatti M, Zuccato C, Bianchi N, Gambari R
Induction of terminal erythroid differentiation can be an efficient strategy to inhibit proliferation of chronic myelogenous leukemia cells. Psoralens, well-known photo-chemotherapeutic agents, were found to be efficient at inducing erythroid differentiation of K562 cells, an in vitro cell line isolated from the pleural effusion of a patient with chronic myelogenous leukemia in blast crisis. The effects of crude pre-irradiated solutions of 5-methoxypsoralen on erythroid differentiation of human leukemic K-562 cells were evaluated. The major photoproduct was characterized and analyzed, and it was found to induce erythroid differentiation of K562 cells and inhibit NF-kappaB/DNA interactions.
PMID: 20645383 [PubMed - as supplied by publisher]
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Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients.
Acta Pharmacol Sin. 2010 Jul 19;
Authors: Li QB, Chen C, Chen ZC, Wang HX, Wu YL, You Y, Zou P
AbstractAim:To investigate the pharmacokinetics of imatinib in Chinese chronic myelogenous leukemia (CML) patients.Methods:Fourty-six naïve Chinese CML patients treated with imatinib (400 and 600 mg daily, n=36 and 10, respectively) were recruited. The correlations of imatinib (400 mg) trough plasma concentrations (C(mins)) with the patients’ characteristics and responses were analyzed.Results:The overall mean (+/-SD, CV%) steady-state C(mins) for imatinib at 400 mg (n=36) and 600 mg (n=10) daily was 1325.61 ng/mL (+/-583.53 ng/mL; 44%) and 1550.90 ng/mL (+/-462.63 ng/mL; 30%), respectively, and no statistically significant differences were found between them (P=0.267). At 400 mg daily, female patients had significantly higher C(mins) than the male patients (P=0.048), and molecular responses were not correlated with imatinib C(mins), but they were correlated with time elapsed before imatinib therapy.Conclusion:The results suggest that Chinese CML patients have higher imatinib C(mins) than their Caucasian counterparts and that the optimal initial imatinib dose for them requires further investigation.
PMID: 20644548 [PubMed - as supplied by publisher]
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Researchers at Duke University Medical Center have identified a mechanism that could explain how patients move into the worst phase of chronic myelogenous leukemia (CML). Their findings implicate a protein called Mushashi that prevents cells from maturing, creating a large population of immature cells, which is one of the hallmarks of CML. This same molecular pathway may also be related to other aggressive leukemias, as well as solid tumors like glioblastoma (a severe form of brain cancer) and breast cancer… (Source: Health News from Medical News Today)
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Posted by rob on July 20, 2010 under Uncategorized |
Regulation of myeloid leukaemia by the cell-fate determinant Musashi.
Nature. 2010 Jul 18;
Authors: Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, Zhao C, Lagoo A, Gerrard G, Foroni L, Goldman J, Goh H, Kim SH, Kim DW, Chuah C, Oehler VG, Radich JP, Jordan CT, Reya T
Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.
PMID: 20639863 [PubMed - as supplied by publisher]
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Targeted therapy of chronic myeloid leukemia.
Biochem Pharmacol. 2010 Sep 1;80(5):584-91
Authors: Sullivan C, Peng C, Chen Y, Li D, Li S
Inhibition of BCR-ABL with kinase inhibitors has become a well-accepted strategy for targeted therapy of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML) and has been shown to be highly effective in controlling the disease. However, BCR-ABL kinase inhibitors do not efficiently kill leukemic stem cells (LSCs), indicating that this therapeutic strategy does not lead to a cure of CML. Development of curative therapies of CML require the identification of genes/pathways that play critical roles in survival and self-renewal of LSCs. Targeting of these key BCR-ABL downstream genes provides an opportunity to eradicate LSCs, as shown in our work that identifies the Alox5 gene as a key regulator of the function of CML LSCs. Immediate clinical trials are necessary to test the effectiveness of targeting a key BCR-ABL downstream gene in eradicating LSCs in CML patients. In this review, we will discuss current targeted therapies of CML using BCR-ABL kinase inhibitors, with a focus on the importance of developing a targeted therapy of CML through identification of target genes in CML LSCs.
PMID: 20470758 [PubMed - indexed for MEDLINE]
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Posted by rob on July 19, 2010 under Uncategorized |
(Duke University Medical Center) Researchers at Duke University Medical Center have identified a mechanism that could explain how patients move into the worst phase of chronic myelogenous leukemia (CML). Their findings implicate a protein called Mushashi that prevents cells from maturing, creating a large population of immature cells, which is one of the hallmarks of CML. (Source: EurekAlert! – Medicine and Health)
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Posted by rob on under Uncategorized |
Researchers have identified a mechanism that could explain how patients move into the worst phase of chronic myelogenous leukemia (CML). Their findings implicate a protein called Mushashi that prevents cells from maturing, creating a large population of immature cells, which is one of the hallmarks of CML. (Source: ScienceDaily Headlines)
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Posted by rob on July 16, 2010 under Uncategorized |
Differential effects of ketoconazole and primaquine on the pharmacokinetics and tissue distribution of imatinib in mice.
Anticancer Drugs. 2010 Aug;21(7):695-703
Authors: Soo GW, Law JH, Kan E, Tan SY, Lim WY, Chay G, Bukhari NI, Segarra I
Imatinib, a selective inhibitor of c-KIT and Bcr-Abl tyrosine kinases, approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, shows further therapeutic potential for gliomas, glioblastoma, renal cell carcinoma, autoimmune nephritis and other neoplasms. It is metabolized by CYP3A4, is highly bound to alpha-1-acid glycoprotein and is a P-glycoprotein substrate limiting its brain distribution. We assess imatinib’s protein binding interaction with primaquine, which also binds to alpha-1-acid glycoprotein, and its metabolic interaction with ketoconazole, which is a CYP3A4 inhibitor, on its pharmacokinetics and biodistribution. Male ICR mice, 9-12 weeks old were given imatinib PO (50 mg/kg) alone or co-administered with primaquine (12.5 mg/kg), ketoconazole (50 mg/kg) or both, and imatinib concentration in the plasma, kidney, liver and brain was measured at prescheduled time points by HPLC. Noncompartmental pharmacokinetic parameters were estimated. Primaquine increased 1.6-fold plasma AUC(0)–> infinity, C(Max) decreased 24%, T(Max) halved and t(1/2) and mean residence time were longer. Ketoconazole increased plasma AUC(0)–>infinity 64% and doubled the C(Max), but this dose did not affect t(1/2) or mean residence time. When ketoconazole and primaquine were co-administered, imatinib AUC(0)–>infinity and C(Max) increased 32 and 35%, respectively. Ketoconazole did not change imatinib’s distribution efficiency in the liver and kidney, primaquine increased it two-fold and it was larger when both the drugs were co-administered with imatinib. Ketoconazole did not change brain penetration but primaquine increased it approximately three-fold. Ketoconazole and primaquine affect imatinib clearance, bioavailability and distribution pattern, which could improve the treatment of renal and brain tumors, but also increase toxicity. This would warrant hepatic and renal functions monitoring.
PMID: 20629201 [PubMed - in process]
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We describe a patient with an acute eruption of asymptomatic, erythematous, edematous, oval plaques studded with pinpoint, nonfollicular pustules on her torso and proximal extremities caused by sulfamethoxazole-trimethoprim (SMZ-TMP). This 40-year-old female had a history of chronic myelogenous leukemia unresponsive to etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab, and fludarabine (EPOCH-RF) therapy. She subsequently received a matched, related-donor peripheral blood stem cell transplant and donor lymphocyte infusion (DLI of TH2 cells). She presented on posttransplant day 15 (post-DLI day 1) with acute onset of the aforementioned eruption (). There were no vesicles, bullae, or mucosal lesions and experienced no fever, chills, lymphadenopathy, angioedema, or g…
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