Sudden blastic crisis and additional chromosomal abnormalities during chronic myeloid leukemia in the imatinib era.

Imatinib has shown significant clinical and cytogenetic success in the treatment of chronic myeloid leukemia. Although resistance has been observed in a proportion of patients, sudden blastic crisis is a rare event during imatinib therapy. We describe a 24-year-old male patient with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase who developed sudden blastic crisis in the 24th month of imatinib therapy, with loss of complete cytogenetic response. At this time, the patient had splenomegaly, severe anemia, thrombocytopenia, and leukocytosis. Bone marrow aspirate revealed the presence of massive blastic infiltration with myeloid morphology. Flow cytometric analysis of the bone marrow cells showed positivity for CD45, CD34, CD13, CD33, CD19, CD41, CD61, and glycophorin-A. Trephine biopsy specimens showed 100% cellular marrow with diffuse infiltrate by blasts. A reticulin stain of the bone marrow biopsy section demonstrated severe diffuse fibrosis. Cytogenetic analysis by fluorescence in situ hybridization (FISH) revealed that 92% of the cells were positive for the BCR/ABL fusion signal and had increased copy numbers for chromosomes 8, 13, 19, and 21. The patient's prognosis was unfavorable. In conclusion, chronic myeloid leukemia remains complex and includes unanswered questions. The presented case with a rare event during imatinib therapy highlights the need for the continued monitoring of residual disease and the development of strategies to eliminate residual leukemia cells in patients showing a complete cytogenetic response.

Imatinib use during pregnancy and breast feeding: a case report and review of the literature.

INTRODUCTION: The development of imatinib as a therapeutic agent targeting BCR-ABL has increased the treatment options for chronic myeloid leukemia (CML) by significantly impacting outcomes, and imatinib is recommended by treatment guidelines as the first-line therapy. However, treatment of maternal CML with imatinib during gestation is not recommended because of the potential risk to the fetus. MATERIALS AND METHODS: We describe the clinical presentation, course and outcome of one pregnant patient with CML who was treated with imatinib. We review all pregnancies associated with imatinib documented in the literature. CASE PRESENTATION: A 27-year-old pregnant patient was diagnosed to have Philadelphia chromosome positive chronic phase CML in August 2007. Imatinib was administered (400 mg/day) between the 21st and 39th weeks of gestation. The patient tolerated the drug well and achieved complete hematological and cytogenetic remission. There were no imatinib-related maternal complications during the pregnancy. Fetal growth remained normal as well as amniotic fluid volume estimation. Labor was induced at the 39th gestational week, resulting in the uneventful vaginal delivery of a healthy male infant without any congenital anomaly. Umbilical cord blood and infant peripheral blood were collected at delivery. No postnatal complications occurred; however, imatinib was present in the umbilical cord blood (338 ng/mL) and in the infant's peripheral blood (478 ng/mL). Breast milk was collected on different postpartum days, and concentrations of imatinib were detected. At 10 months of age, the baby had normal growth and development. CONCLUSIONS: In light of reported cases and our experience, treatment of CML during the second and third trimesters of gestation and breast feeding seems to be safe, but the data are still limited and the effects of chronic exposure of infants to imatinib are not known. We think that each case should be examined and considered independently, and decisions should be individualized.

[Successful treatment of neuroaspergillosis in a patient with acute lymphoblastic leukemia: role of surgery, systemic antifungal therapy and intracavitary therapy]. / Akut lenfoblastik lösemili bir olguda gelisen nöroaspergillozun basarili tedavisi: cerrahi, sistemik antifungal tedavi ve intrakaviter tedavinin rolleri.

Cerebral aspergillosis is a rare condition that generally exhibits a poor response to conventional antifungal drugs. We report here a case of cerebral aspergillosis in a 34-years-old man with acute lymphoblastic leukaemia who was successfully treated with a combination of aggressive neurosurgery, intracavitary instillation of amphotericin B and voriconazole. We aimed to emphazise the roles of surgery, intracavitary therapy and antifungal therapy in the management of neuroaspergillosis. Under amphotericin-B therapy, the patient developed dysarthria and paralysis of the right side of his body. Brain magnetic resonance imaging demonstrated a lesion in the left parieto-occipital region, measuring 7 cm in the greatest dimension. Diagnostic surgery was interrupted due to abundant bleeding. The culture of the aspirate from the lesion yielded Aspergillus flavus. The therapy was switched to voriconazole and caspofungin combination. Due to disease progression during combination therapy, the patient had a second surgical resection resulting in a 75% reduction in lesion size. Following surgical intervention, intracavitary instillation of amphotericin B (0.3 mg/day for 15 days) was performed alongside with combination therapy (voriconazole and caspofungin). Caspofungin was stopped after 42 days, whereas the patient was continued on voriconazole for a total of 100 days. At this point, his brain lesion resolved almost completely. However, leukemia relapsed. The patient died during his treatment course because of neutropenic typhilitis occurring in the aplastic phase. It is stated that in patients with neuroaspergillosis radical neurosurgery leads to better outcomes if performed at an earlier stage. Antifungal treatment of cerebral aspergillosis requires that the drug must cross the blood brain barrier. Voriconazole has the ability to cross the blood brain barrier. The therapy should be prolonged beyond the resolution of all lesions and until reversal of the underlying predisposition. We conclude that the use of neurosurgery and voriconazole together appears to be a reliable and effective treatment modality in patients with cerebral aspergillosis.

Therapeutic plasma exchange plus corticosteroid for the treatment of the thrombotic thrombocytopenic purpura: a single institutional experience in the southern Marmara region of Turkey.

Thrombotic thrombocytopenic purpura (TTP) is a classic, but not a common disorder of hematology. Plasma exchange (PE) was shown to nearly reverse its 90% mortality rate. However, there are still some fatal outcomes in this dramatic disease. We present our experience of plasma exchange plus corticosteroids for the treatment of TTP in our hospital. Patients with TTP diagnosed between January 1996 and January 2005 were identified by a retrospective review of records of the Uludag University Hospital, Bursa (the largest referral center for adults with this disorder in this region with an estimated 2.2 million residents), which performs all therapeutic PE in the southern Marmara region in Turkey. A total of 11 (6 male, 5 female) patients were treated for TTP during this period. The median age was 39 years (range 18-49). One plasma volume exchange daily plus steroid was the principle treatment in all patients. A total of 295 PE sessions were performed. We have obtained six complete responses (CR) and three partial responses (PR) with daily PE and steroid (response rate 9/11). One of our primary refractory patients was saved with pulse steroid+cyclosporine+vincristine. Now, he is disease free for over one year. The other refractory patient did not develop any response to salvage therapy and expired on day 15 with status epilepticus and ventilator related pneumonia (mortality rate 1/11). A CR was obtained with adjuvant treatments in all three PR patients. Only one CR patient developed an early relapse (early relapse rate in CR patients 1/6). She was treated successfully with daily PE plus vincristine. Our median follow up period was 25 months (range 9-108). Considering our local population, our annual incidence is only about 0.63 new cases per one million people. This figure is considerably less than the data from US, which indicated an incidence of 3.7 cases per 1,000,000. To our knowledge, there is no high variability in the incidence of TTP in the different geographical regions of the world. It suggests that considerable number of patients escaped notice. We hope that, demonstrating the successful outcome, this article serves to urge primary physicians to keep in mind the diagnosis of TTP and refer suspected cases quickly.

Invasive pulmonary aspergillosis: role of early diagnosis and surgical treatment in patients with acute leukemia.

BACKGROUND: Aspergillus is a ubiquitous soil-dwelling fungus known to cause significant pulmonary infection in immunocompromised patients. The incidence of aspergillosis has increased during the past two decades and is a frequently lethal complication of acute leukemia patients that occurs following both chemotherapy and bone marrow transplantation. The diagnosis of invasive pulmonary aspergillosis (IPA) according to the criteria that are established by European Organization for the Research and Treatment of Cancer and Mycoses Study Group raise difficulties in severely ill patients. Despite established improvements in field of diagnosis (galactomannan antigen, quantitative PCR, real-time PCR for Aspergillus spp., and findings of computed tomography) and treatment with new antifungals, it is still a major problem in patients with acute leukemia. However, prompt and effective treatment of IPA is crucial because most patients will need subsequent chemotherapy for underlying hematologic disease as soon as possible. CASE PRESENTATION: We report a 33-year-old male patient with acute promyelocytic leukemia diagnosed in 1993 that developed invasive pulmonary aspergillosis due to A. flavus at relapse in 2003. The patient was successfully treated with liposomal amphotericin B and underwent surgical pulmonary resection. The operative course was uneventful. CONCLUSION: This report emphasizes the clinical picture, applicability of recent advances in diagnostic and therapeutic approaches for IPA. For early identification of a patient infected with IPA, a high index of suspicion and careful clinical and radiological examinations with serial screening for galactomannan should be established. If aspergillosis is suspected, anti-aspergillosis drug should be administered immediately, and if a unique pulmonary lesion remains, surgical resection should be considered to prevent reactivation during consecutive chemotherapy courses and to improve the outcome.

Hydatid disease in acute leukemia: effect of anticancer treatment on echinococcosis.

Echinococcosis, also known as hydatid disease or hydatidosis, is a zoonotic illness caused by the larval form of Echinococcus spp. It is highly prevalent in areas where the parasite is endemic such as the Mediterranean region. However, occurrence of echinococcosis and cancer together is rare. We treated and followed approximately 1200 patients with different hematologic neoplastic diseases between 1985 and 2003, and only one of these individuals had concomitant acute leukemia and liver hydatidosis. This report describes the case of a 19-year-old man who had both primary refractoriness of acute leukemia (AML-M4) and liver hydatidosis. Management is discussed. The patient had cystic echinococcosis (CE) of the liver that was classified as CE1 according to the system established by the World Health Organization's Informal Working Group on Echinococcosis. The patient underwent 3 months of treatment with agents that targeted the leukemia (daunorubicin, idarubicin, cytarabine, fludarabine) and its complications (amphotericin B, amphotericin B lipid complex, liposomal amphotericin B). Throughout this period, the size and the contents of the cyst did not change, Echinococcus titers remained unchanged, and the cyst classification remained CE1.

Pregnancy under treatment of imatinib and successful labor in a patient with chronic myelogenous leukemia (CML). Outcome of discontinuation of imatinib therapy after achieving a molecular remission.

Because of the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy. We describe successful pregnancy and delivery, without any congenital anomaly, in a patient with CML under treatment of imatinib. The fetus had been exposed to imatinib for 8 weeks. The patient remained off treatment during gestation and cytogenetic relapse of CML (5 months after discontinuation of imatinib therapy) developed at seventh month of gestation.

The bone marrow aspirate and biopsy in the diagnosis of unsuspected nonhematologic malignancy: a clinical study of 19 cases.

BACKGROUND: Although bone marrow metastases can be found commonly in some malignant tumors, diagnosing a nonhematologic malignancy from marrow is not a usual event. METHODS: To underscore the value of bone marrow aspiration and biopsy as a short cut in establishing a diagnosis for disseminated tumors, we reviewed 19 patients with nonhematologic malignancies who initially had diagnosis from bone marrow. RESULTS: The main indications for bone marrow examination were microangiopathic hemolytic anemia (MAHA), leukoerythroblastosis (LEB) and unexplained cytopenias. Bone marrow aspiration was not diagnostic due to dry tap or inadequate material in 6 cases. Biopsy results were parallel to the cytological ones in all cases except one; however a meticulous second examination of the biopsy confirmed the cytologic diagnosis in this patient too. The most common histologic subtype was adenocarcinoma, and after all the clinical and laboratory evaluations, the primary focus was disclosed definitively in ten patients (5 stomach, 3 prostate, 1 lung, 1 muscle) and probably in four patients (3 gastrointestinal tract, 1 lung). All work up failed in five patients and these cases were classified as tumor of unknown origin (TUO). CONCLUSION: Our series showed that anemia, thrombocytopenia, elevated red cell distribution width (RDW) and hypoproteinemia formed a uniform tetrad in patients with disseminated tumors that were diagnosed via bone marrow examination. The prognosis of patients was very poor and survivals were only a few days or weeks (except for 4 patients whose survivals were longer). We concluded that MAHA, LEB and unexplained cytopenias are strong indicators of the necessity of bone marrow examination. Because of the very short survival of many patients, all investigational procedures should be judged in view of their rationality, and should be focused on treatable primary tumors.

Interleukin-10 and interferon-gamma cytokine gene polymorphisms may be risk factors for chronic myelogenous leukemia.

We investigated the association of cytokine gene polymorphisms with the development of chronic myelogenous leukemia (CML) and whether there is an association between gene polymorphisms Th1 and Th2 or regulatory- type cytokines and CML. Thirty patients with CML and 60 healthy controls were enrolled in this study. All genotyping (TNF-α, TGF-ß, IL-10, IL-6, and IFN-γ) studies were performed using sequence-specific primers PCR (PCR-SSP). Frequencies of IL-10 (-1082, -819, -592) GCC/ATA (p= 0.009) and IFN-γ; +874 T/A (p= 0.037) polymorphisms were significantly greater in the patients with CML. In contrast, significantly lower frequencies of the IFN-γ A/A (p= 0.004) genotype were observed in patients with CML compared with controls. The results suggest that the IL-10 GCC/ATA and IFN-γ T/A polymorphisms are potential risk factors, and that the IFN-γ A/A polymorphism is a protective factor, for CML in this study group.

Comparison of genetic changes between interphase and metaphase nuclei in monitoring CML and APL treatment using DC-FISH technique.

In leukemias, the monitoring techniques on the response after the treatment have clinical importance for evaluating new therapeutic approaches and identifying the risk of relapse. In this study, genetic changes before and after chemotherapy in interphase and metaphase nuclei of bone morrow of adults with provisional diagnosis of leukemia were compared to understand the molecular characterization and pathogenesis of the leukemia for the classification of diagnosis and prognosis. We examined bone morrow cells of 47 chronic myeloid leukemia (CML) cases (29 of 47 at the time of diagnosis, 31 of 47 after chemotherapy) with the bcr/abl translocation probes and of 10 acute promyelocytic leukemia (APL) cases (7 of 10 at the time of diagnosis, 4 of 10 after chemotherapy) with the PML/RARalpha translocation probes by using dual color-flourescence in situ hybridization (DC-FISH). For each case, 400 interphase nuclei and 11 to 25 metaphases nuclei were analysed. The ratios of translocations before and after chemotherapy were compared between interphase and metaphase nuclei. After chemotherapy, though, translocations were detected in interphase nuclei of 29 of the 31 CML and 4 of the 4 APL cases, these translocations were determined in metaphase nuclei of only 14 of the 31 CML and 1 of the 4 APL cases with very low ratios (p < 0.01). The results showed that the rates of translocation positive interphase nuclei were higher than the rates of translocation positive metaphase nuclei (p < 0.01) after chemotherapy, so there may be some factors effecting proliferative activity of metaphase formation in leukemias.

Maternal and fetal outcomes in pregnancy complicated with acute leukemia: a single institutional experience with 10 pregnancies at 16 years.

The incidence of acute leukemia in pregnancy is low and the management of acute leukemia during pregnancy is difficult. We have observed a total of 10 pregnancies in 8 patients. Six of the patients had acute myeloblastic leukemia (AML) and two of them had acute lymphoblastic leukemia (ALL). Three of the pregnancies were diagnosed when the leukemia was in remission, six at the time of leukemia diagnosis and one at the time of leukemic relapse. Six of the pregnancies were found in first trimester, three in the second and one early in the third. Three pregnancies ended with spontaneous abortion, three with intrauterine death and three with medical termination. One of spontaneous abortions and one intrauterine death developed during combination chemotherapy (daunorubicin, cytarabine). Only 1 healthy baby survived from the 10 pregnancies and this child was the not exposed to chemotherapeutic agents. None of the cases had gynecologic and obstetric complications. Five of eight pregnant women with leukemia died because of the primary disease.

Short and long term effects of granulocyte colony-stimulating factor during induction therapy in acute myeloid leukemia patients younger than 65: results of a randomized multicenter phase III trial.

This prospective multicenter phase III clinical trial was designed to assess efficacy and safety of G-CSF as an adjunct to de novo AML remission induction therapy (www.clinicaltrials.gov. NCT00820976). Patients' characteristics were similar in both arms. G-CSF improved severity and duration of leukopenia. Three-year OS were similar (25.6 ± 5.1% vs. 31.8 ± 5.6%) in both arms except for patients with myeloblastic features. Significant factors for better survival were the use of G-CSF (p=0.049), female sex (p=0.05) and single induction cycle (p<0.001) in multivariate analysis. Female patients performed better than male patients. Better survival obtained among female AML patients needs to be validated within the context of cytogenetic analysis.

Successful pregnancy and delivery in a patient with chronic myelogenous leukemia (CML), and management of CML with leukapheresis during pregnancy: a case report and review of the literature.

Although infrequently seen, the management of cancer during pregnancy can be difficult for patients, their families and physicians. The concomitant occurrence of pregnancy and chronic myelogenous leukemia is uncommon. We describe the successful management of a 26-year-old woman in the first trimester of her pregnancy with chronic myelogenous leukemia (CML) in chronic phase by using only leukapheresis. She was treated with leukapheresis until her delivery at 36 weeks of gestation. The procedure was without significant adverse effects on the patient or fetus. We applied a total of 15 leukapheresis treatments throughout the pregnancy. The patient gave birth vaginally to a healthy 2800 g boy at 36 weeks of gestation. We conclude that leukapheresis may provide an alternative treatment to chemotherapy, alpha-interferon or imatinib in pregnant patients with CML, particularly with concern over their potential teratogenic and other adverse effects.