Anastasios Raptis

Gemtuzumab therapy for isolated extramedullary AML relapse following allogeneic stem-cell transplant.

Background A 19-year-old male with primary refractory acute myeloid leukemia received salvage therapy with mitoxantrone and cytarabine combination. He received consolidation therapy 3 months later with a matched-unrelated-donor stem-cell transplant. The disease relapsed in the bone marrow (BM) 9 months after the initial stem-cell transplant, and was successfully treated by repeat transplant from the same donor. Ten months following repeat transplant, the patient presented with an increasing number of extramedullary sites of biopsy-proven disease relapse (i.e. cranial and peripheral nerves, tongue, abdominal wall and chest wall). Repeated biopsy of the BM and chimera study showed no morphologic evidence of leukemic infiltrate with 100% donor-cell population.Investigations Physical examination, complete blood count, BM biopsy, flow cytometry, cytogenetic analysis, chimera study, tongue biopsy, abdominal-wall biopsy, cytology and immunohistochemistry, CT scan of the chest, abdomen and pelvis, MRI of the brain, and cerebrospinal fluid analysis.Diagnosis Isolated extramedullary relapse of acute myeloid leukemia after stem-cell transplant.Management Primary leukemia treatment with idarubicin, cytarabine, etoposide, dexamethasone, tioguanine on protocol and salvage therapy with mitoxantrone and cytarabine combination for primary refractory disease. A matched-unrelated-donor stem-cell transplant for consolidation and donor-lymphocyte infusions were performed, followed by repeat unrelated-donor transplant for leukemia relapse in the marrow, radiation therapy and gemtuzumab ozogamicin for multiple sites of extramedullary leukemia relapse.

Disposition of Imatinib and Its Metabolite CGP74588 in a Patient with Chronic Myelogenous Leukemia and Short‐Bowel Syndrome

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by means of cytochrome P450 3A and excreted primarily in the bile. Although the bioavailability of imatinib mesylate is more than 97%, the exact gastrointestinal site of its absorption is unknown. Liquid chromatography‐mass spectrometry was used to quantitate imatinib and its metabolite CGP74588 in the plasma and jejunostomy output of a patient with newly diagnosed chronic myelogenous leukemia. She had previously lost most of her small bowel and all of her colon as a result of mesenteric artery thrombosis and radiation‐induced colitis and/or proctitis. Imatinib pharmacokinetics in plasma indicated that approximately 20% of the patients 400‐mg dose was absorbed. The jejunostomy output contained 338 mg of imatinib, which was consistent with 320 mg of a nonabsorbed dose plus approximately 23% of the absorbed dose being excreted unchanged in the bile. These data indicate the importance of considering gastrointestinal anatomic abnormalities or disease states when oral imatinib is dosed.

Primary central nervous system post-transplant lymphoproliferative disorders following allogeneic hematopoietic stem cell transplantation

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Extra nodal involvement is common in PTLD, but isolated involvement of the central nervous system (CNS) is extremely rare. Given the rarity of primary CNS-PTLD there is no consensus on optimal treatment. We report a patient who developed Epstein-Barr virus related primary CNS-PTLD following allogeneic HSCT who was treated with the monoclonal anti-CD20 antibody rituximab and reduction of immunosuppression. In addition, we review the literature and discuss treatment options for patients with primary CNS-PTLD following allogeneic HSCT.

Gemtuzumab ozogamicin as first-line treatment in patients aged 70 years or older with acute myeloid leukemia

Elderly patients with acute myeloid leukemia (AML) are generally unable to withstand the rigors of intensive induction chemotherapy and its attendant complications. Gemtuzumab ozogamicin (GO) is an immunoconjugate that had demonstrated activity in recurrent AML.

The Microculture-Kinetic (MiCK) Assay: The Role of a Drug-Induced Apoptosis Assay in Drug Development and Clinical Care

A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development.

Leukapheresis in patients newly diagnosed with acute myeloid leukemia

Hyperleukocytosis is present in 5 to 20 percent of patients with newly diagnosed acute myeloid leukemia (AML). The management of hyperleukocytosis, when symptoms of leukostasis occur, includes intensive supportive care and interventions for rapid cytoreduction. Leukapheresis is a rapid and effective means of cytoreduction and has been used in AML patients. In the current study, we evaluated the outcomes of 68 newly diagnosed AML patients that underwent leukapheresis and the effects of leukapheresis on various laboratory parameters. A total of 127 leukapheresis cycles were performed. The median number of leukapheresis cycles was 2 (range, 1-8). The overall survival for all patients was 4.2 months (95% CI 1.2-9.7 months). The median overall survival for patients who achieved complete remission after induction chemotherapy was significantly higher (19.1 months [95% CI 12.1-41.8 months]) than patients that did not achieve complete remission (0.46 months [95% CI 0.33-0.99 months]). Stepwise logistic regression demonstrated that elevated number of peripheral blasts, low platelet count and elevated bilirubin at AML diagnosis were predictive of death within a week. Leukapheresis was effective in reducing the peripheral blood leukocytes and leukemia blasts and was a safe procedure with regard to organ function, coagulation parameters, red blood cells and platelet count. The high initial response rates in newly diagnosed AML patients fit to receive intensive chemotherapy suggest that leukapheresis could be beneficial in reducing the complications associated with hyperleukocytosis until systemic intensive chemotherapy commences.

IV pentamidine for primary PJP prophylaxis in adults undergoing allogeneic hematopoietic progenitor cell transplant.

IV pentamidine for primary PJP prophylaxis in adults undergoing allogeneic hematopoietic progenitor cell transplant

Fludarabine and cytarabine in patients with acute myeloid leukemia refractory to two different courses of front-line chemotherapy

The most effective regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after two different courses of front-line chemotherapy has not been established. We therefore evaluated the efficacy, toxicity, and prognostic factors for achieving CR following treatment with fludarabine and cytarabine in 25 newly diagnosed AML patients who did not respond to initial therapy with idarubicin and cytarabine followed by mitoxantrone and etoposide. CR was achieved in 32% of patients; in 55% of patients with intermediate-risk karyotype and in 14% with unfavorable-risk. Eight percent died of infectious complications. Median duration of overall survival was 6.6 months (95% CI 3.4 months to ∞); 3.4 months (95% CI 0.8-8.6 months) for patients with an unfavorable-risk karyotype and 18.1 months (95% CI 5.0 months to ∞) with an intermediate-risk karyotype (p=0.02). Our data suggest that poor-risk karyotype patients are unlikely to benefit from third course treatment with fludarabine-cytarabine, and that this regimen merits further investigation in AML patients with good or intermediate-risk karyotype that have persistent leukemia after two courses of front-line chemotherapy.

Mitoxantrone and etoposide in patients with newly diagnosed acute myeloid leukemia with persistent leukemia after a course of therapy with cytarabine and idarubicin.

The most effective regimen for patients with acute myeloid leukemia (AML) who do not achieve complete remission (CR) after one course of cytarabine and an anthracycline has not been extensively studied. We evaluated restrospectively the efficacy, toxicity, and prognostic factors for the achievement of CR following mitoxantrone and etoposide in 74 patients with newly diagnosed AML who did not respond to one course of therapy with cytarabine and idarubicin. CR was achieved in 39% of patients; 14% died of infectious complications; no grade 3 or 4 hepatic toxicities were observed. Median duration of overall survival was 9.0 months (95% CI 5.8–14.9 months). The median duration of relapse-free survival was 11.0 months (95% CI: 9.0–19.3 months). A lower CR rate was associated with unfavorable risk status at diagnosis and higher percent blasts. Our data suggest that the combination of etoposide and mitoxantrone is an effective second-course therapy in patients with newly diagnosed AML.

Correlation of the microculture-kinetic drug-induced apoptosis assay with patient outcomes in initial treatment of adult acute myelocytic leukemia

Abstract Overall survival (OS) with acute myeloid leukemia (AML) remains poor. Determining prognostic factors will help in selecting patients for appropriate treatments. Our aim was to determine whether the level of drug-induced apoptosis (chemosensitivity) demonstrated by the microculture-kinetic drug-induced apoptosis (MiCK) assay significantly predicted outcomes after standard AML induction therapy. A total of 109 patients with untreated AML had blood and/or bone marrow aspirate samples analyzed for anthracycline-induced apoptosis using the MiCK assay. The amount of apoptosis observed over 48 h was determined and expressed as kinetic units of apoptosis (KU). Complete remission (CR) was significantly higher (72%) in patients with high idarubicin-induced apoptosis >3 KU compared to patients with apoptosis ≤3 KU (p = 0.01). Multivariate analysis showed the only significant variables to be idarubicin-induced apoptosis and karyotype. Median overall survival of patients with idarubicin-induced apoptosis >3 KU was 16.1 months compared to 4.5 months in patients with apoptosis ≤3 KU (p = 0.004). Multivariate analysis showed the only significant variable to be idarubicin-induced apoptosis. Chemotherapy-induced apoptosis measured by the MiCK assay demonstrated significant correlation with outcomes and appears predictive of complete remission and overall survival for patients receiving standard induction chemotherapy.