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J E Karp

Publications and source records attributed to J E Karp.

At least 73 records · Page 4Linked to original sources
PubMed1990

Cure of acute myelocytic leukemia in adults: a reality.

Adult acute myelocytic leukemia (AML) is a curable disease in responsive patients with aggressive treatment in remission. Over the past decade at the Johns Hopkins Oncology Center, AML has been treated with either allogeneic bone marrow transplantation or with intensive timed sequential treatment using high dose cytarabine in remission. With either treatment modality comparable cure rates were obtained. The role, if any, of randomized trials to adequately determine the preferred treatment for appropriate patients has yet to be defined.

Adolescent↗
PubMed1990

Effects of rhGM-CSF on intracellular ara-C pharmacology in vitro in acute myelocytic leukemia: comparability with drug-induced humoral stimulatory activity.

Human acute myelocytic leukemia (AML) marrow cells respond to stimulation with increased proliferation and enhanced intracellular metabolism of the cytotoxic antimetabolite 1-B-D arabinofuranosylcytosine (ara-C). Our previous studies have focused on the drug-induced humoral stimulatory activity (HSA) present in serum following initial cytoreduction which augments in vitro growth and biochemical pharmacology. The activity of HSA likely relates to the presence of multiple stimulators. The effect of 18-hr culture in purified recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (1 ng/ml) on in vitro AML marrow cell [3H]dThd incorporation into DNA, intracellular ara-C activation to the triphosphate form (ara-CTP), and subsequent ara-CTP retention were determined in leukemic cells of 11 patients and compared with cells similarly cultured in HSA-containing sera. The stimulatory effects of rhGM-CSF and HSA on both growth and pharmacologic parameters were comparable for each AML population, with maximal response to both regulators detected for FAB M2. These data demonstrate that GM-CSF acts similarly to HSA as an active stimulator of leukemic cell proliferation and net intracellular ara-C metabolism in vitro, and support clinical trials designed to examine the role of rhGM-CSF in enhancing ara-C cytotoxicity by increasing the growth fraction of drug-responsive target cells in vivo.

Adult↗
PubMed1989

Phase I and pharmacodynamic study of taxol in refractory acute leukemias.

Taxol, a novel antimicrotubule agent that enhances tubulin polymerization and microtubule stability, was administered to adults with refractory leukemias as a 24-h i.v. infusion in a Phase I study. The primary objectives were to determine the maximum tolerated dose of taxol administered on this schedule to patients with acute leukemias and describe the nonhematological toxicities which became dose limiting. The starting dose, 200 mg/m2, was based on the maximum tolerated dose in solid tumor trials, in which myelosuppression precluded dose escalation. Seventeen patients received 28 evaluable courses at 200, 250, 315, and 390 mg/m2. Severe mucositis limited further dose escalation. Other nonhematological effects included peripheral neuropathy, alopecia, myalgias, arthralgias, nausea, vomiting, diarrhea, and an acute pulmonary reaction that was presumptively due to taxol's Cremophor vehicle. Mean peak taxol plasma concentrations at all dose levels were in the range of concentrations that were previously demonstrated to induce microtubule bundles, a morphological effect associated with cytotoxicity, in leukemia cells in vitro. Pretreatment blasts from 12 patients were incubated with taxol ex vivo. Taxol-induced microtubule bundles were apparent in the blasts of eight patients who also had cytoreduction of tumor, and sensitivity to bundle formation was related to the magnitude of antitumor activity. In contrast, taxol did not induce microtubule bundles ex vivo in the blasts of the other four total nonresponders. Based on this study, the maximum tolerated doses and recommended Phase II doses for taxol, limited by nonhematological toxicity and administered as a 24-h i.v. infusion to patients with refractory leukemias, are 390 and 315 mg/m2. Phase II trials at these myelosuppressive doses are required to determine taxol's activity in the treatment of leukemias. In addition, further evaluation of microtubule bundle formation ex vivo in Phase II studies is necessary to determine the ultimate utility of this assay in assessing tumor sensitivity to taxol.

Acute Disease↗
PubMed1989

Secondary acute myelocytic leukemia after adjuvant therapy for early-stage breast carcinoma. A new complication of cyclophosphamide, methotrexate, and 5-fluorouracil therapy.

The occurrence of treatment-related hematologic malignancies after adjuvant therapy with alkylating agents for gastrointestinal cancers, ovarian carcinoma, and breast cancer and after treatment for Hodgkin's disease, non-Hodgkin's lymphoma, germ-cell tumors, and multiple myeloma has been well documented. Adjuvant chemotherapy is frequently used for the treatment of early stage breast cancer, and to date there has been no increase in the incidence of secondary myelodysplastic syndromes or acute leukemia after cyclophosphamide-based regimens when compared with surgical controls. This report describes two patients who developed acute myelocytic leukemia only after exposure to cyclophosphamide, methotrexate, and 5-fluorouracil adjuvant therapy. These two cases of acute leukemia, which developed 3 years after diagnosis of breast cancer and initiation of chemotherapy, were characterized by trilineage dysplasia and pancytopenia, and had abnormalities of chromosomes 5 and 7: characteristics consistent with treatment-related leukemia. Many women are diagnosed with early stage breast cancer each year who are potential candidates for adjuvant therapy. Although certain subgroups of patients have been shown to benefit from adjuvant therapy, continued efforts must be directed at identifying responders so that others will not be exposed to the additional risks of chemotherapy.

Aged↗
PubMed1989

Listeriosis in the setting of malignant disease. Changing issues in an unusual infection.

Thirteen cases of Listeria monocytogenes infection occurred at the Johns Hopkins Oncology Center over a 10-year period, representing 0.09% of all admissions. These cases principally occurred in patients with underlying hematologic of lymphoreticular malignancy, but in all patients other causes of immune suppression were also present. Corticosteroids were the most frequent exogenous cause of immune suppression. Bacteremia was detected more frequently than meningitis and in contrast to earlier reports, bacteriologic cure was achieved in 12 of 13 patients. Therapeutic success appeared to be related to early institution of effective antimicrobial agents. Despite eradication of infection, seven of the patients were dead within three months from progression of their underlying disease. The overall survival rate of cancer patients with listeriosis is therefore a function of the underlying malignancy and not the infection.

Adult↗
PubMed1989

Ophthalmic manifestations of leukemia.

We prospectively examined the eyes of 120 patients with leukemia. Only 38% of patients had normal results of examination. Leukemic infiltrates were present in 3% of patients, other findings related to leukemia were seen in 39% of patients, and 20% of patients had unrelated abnormalities. Visual loss was seen in at least 5% of the patients in this study.

Adolescent↗
PubMed1989

Leukemic retinopathy. Relationship between fundus lesions and hematologic parameters at diagnosis.

The authors examined 117 consecutive patients with acute leukemia within a few days of diagnosis. Sixty-six patients had acute nonlymphocytic leukemia, and 51 had acute lymphocytic leukemia. Forty-two percent of the patients had abnormal ocular findings related to leukemia. The authors found an association between the presence of intraretinal hemorrhages and thrombocytopenia for all patients. In addition, patients with acute lymphocytic leukemia and intraretinal hemorrhages had lower hematocrit levels than did those without such hemorrhage. The presence of anemia was related to the findings of white-centered hemorrhages in patients with acute nonlymphocytic leukemia. The presence of cotton-wool spots was not associated with hematologic parameters. Intraretinal hemorrhages, white-centered hemorrhages, and cotton-wool spots were all found more frequently in adults than in children.

Adolescent↗
PubMed1989

Cures of leukemia with aggressive postremission treatment: an update of timed sequential therapy (Ac-D-Ac).

A cure rate can be obtained with intensive cytoreductive treatment given to a subset of patients with acute myelocytic leukemia in bone marrow remission. This report updates our experience with postremission timed sequential therapy using cytarabine and daunorubicin (Ac-D-Ac) and compares it with other brief, aggressive strategies including bone marrow transplantation. The median disease-free survival (DFS) of all patients treated in remission is 2.5 years with a greater than 40% probability of DFS at 8 years. These results are similar to those achieved with bone marrow-ablative and other intensive but nonablative treatment plans.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

A two-step timed sequential treatment for acute myelocytic leukemia.

Since 1980, adults with acute myelocytic leukemia (AML) have been treated on two clinical studies using intensive timed sequential therapy. All patients ages 16 to 80, including those with secondary AML (SAML) and those with AML preceded by a hematologic disorder (AHD), were treated, regardless of medical complications at the time of diagnosis. The first study combined high doses of cytarabine (ara-C, AC) and daunorubicin (DRN, D) in sequence (Ac2-D-Ac) and resulted in a complete remission rate of 55%. A group of these patients selected by functional status was able to receive a second course of therapy in remission, which resulted in a disease-free survival (DFS) of greater than 40% at 7 years. Because of toxicity in that study, 114 patients were entered on a second trial initiated 4 years ago, using a less aggressive first course, with amsacrine, to achieve a stable remission (Ac2-D-Amsa). This first treatment was followed by a more intensive second course (Ac6-D-Ac). With this two-step approach, a higher complete remission (CR) rate (76% for de novo AML and 54% for SAML-AHD) was achieved, and more patients were able to receive the second course of therapy. At the current median follow-up of 26 months, the median duration of DFS and overall survival are 11 and 14 months for patients with de novo AML. Age less than or equal to 55 is the most significant prognostic factor for both prolonged DFS and overall survival, with median durations of 17 and 18 months, respectively, for these younger patients. Patients with SAML-AHD remain relatively refractory to treatment despite aggressive chemotherapy, with median durations of DFS and overall survival of 9 months and 5 months, respectively.

Adolescent↗
PubMed1989

Cutaneous eruptions of lymphocyte recovery.

Macular and papular eruptions are ascribed to various causes, often drug-related hypersensitivity or toxicity. We observed patients with cutaneous eruptions during hospital admissions for induction or augmentation chemotherapy in the treatment of leukemia. In 10 of 14 patients, macular and papular eruptions occurred in a strikingly similar pattern, at the earliest recovery of peripheral lymphocytes, after chemotherapy-induced nadir of the leukocyte count. A concomitant sharp, transient rise in temperature accompanied the eruption of lymphocyte recovery. Skin biopsy specimens were obtained from 8 of these 10 patients and showed a superficial, perivascular mononuclear cell infiltrate. Immunohistochemical analysis of the cellular infiltrate was performed. The rash of lymphocyte recovery may be due to the actual return of immunocompetent lymphocytes to the peripheral circulation and skin after the chemotherapy-induced nadir of the leukocyte count. These observations suggest that macular and papular eruptions relate to specific immunologic events.

Aged↗
PubMed1989

In vivo cell growth and pharmacologic determinants of clinical response in acute myelogenous leukemia.

A predictable increase in the proliferative rate of malignant cells remaining after initial cytoreduction in vivo forms the rationale for timed sequential therapy (TST) with 1-B-D-arabinofuranosylcytosine (ara-C) for adult acute myelogenous leukemia (AML). The relationship between in vivo leukemic cell growth, intracellular ara-C metabolism, and clinical response to ara-C-containing TST was evaluated by comparing AML marrow cell growth kinetic and biochemical pharmacologic determinants obtained before therapy (day 0) and at the predicted peak of in vivo postdrug residual tumor proliferation (day 8). Serial measurements of DNA synthesis and net intracellular ara-C metabolism demonstrated marked increases in both determinants in day 8 residual tumor when compared with the pretreatment cells for newly diagnosed adults achieving complete remission but not for TST-refractory patients. The interrelationship of AML cell proliferation and biochemical pharmacology together quantitate cytotoxicity measured by both achievement and duration of remission and serve to predict eventual clinical outcome in response to TST with ara-C where both growth and favorable pharmacokinetics are intrinsic to the success of the drug schedule.

Adult↗
PubMed1988

Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases.

PURPOSE: The syndrome of idiopathic hyperammonemia occurs in patients who have received high-dose cytoreductive therapy for the treatment of hematologic malignancy. It is characterized by abrupt alteration in mental status and respiratory alkalosis associated with markedly elevated plasma ammonium levels in the absence of any identifiable cause, and frequently results in intractable coma and death. Our goal was to survey clinical and pathologic manifestations of the disorder and discuss treatment options. PATIENTS AND METHODS: Plasma ammonium levels were measured in patients on the acute leukemia service or on the bone marrow transplant service at The Johns Hopkins Hospital, and a level more than twice normal was considered diagnostic of hyperammonemia. The syndrome was identified in nine patients; in eight, hyperammonemia occurred after administration of intensive cytoreductive therapy that resulted in profound leukopenia. The disorder occurred in the ninth patient two months after allogeneic bone marrow transplantation. RESULTS: Three of the nine patients survived an episode of idiopathic hyperammonemia; one patient subsequently died of leukemia and one of recurrent idiopathic hyperammonemia. The one long-term survivor is currently alive and well without neurologic sequelae 250 days after autologous bone marrow transplantation. CONCLUSION: Because neurologic function can deteriorate rapidly, early recognition of this disorder and close monitoring of the patient's neurologic status are critical.

Adolescent↗
PubMed1988

An approach to intensive antileukemia therapy in patients with previous invasive aspergillosis.

PURPOSE: In an attempt to decrease the risk for reactivation of life-threatening invasive aspergillosis (IA) during subsequent myelosuppression in patients with previously diagnosed IA who were receiving antileukemic treatment, we evaluated the role of intensive antifungal therapy with amphotericin B and 5-fluorocytosine administered prophylactically throughout the antileukemic regimen and induced granulocytopenia to prevent IA reactivation without compromising the intensive chemotherapy. PATIENTS AND METHODS: During a 30-month period, 10 patients with acute myelogenous leukemia and primary IA developing during initial antileukemia induction therapy and severe granulocytopenia (less than 100/mm3) underwent 14 subsequent courses of intensive marrow aplasia-producing chemotherapy during early complete remission or at leukemia relapse. All patients had evidence of ongoing IA healing by lung computerized tomography (CT) prior to reinstitution of intensive chemotherapy. Nine patients receiving 13 chemotherapy courses also received aggressive prophylactic anti-IA therapy with amphotericin B (1.0 mg/kg/day) and 5-fluorocytosine beginning at least 48 hours prior to antileukemia therapy institution and continued until the time of granulocyte recovery. RESULTS: All nine patients receiving aggressive antifungal therapy survived without clinical evidence of IA reactivation. Transient radiographic evidence of IA reactivation during granulocytopenia was detected by lung CT during two of the 13 chemotherapy courses. In contrast, the patient who did not receive anti-IA prophylaxis had both clinical and radiographic evidence of IA reactivation during severe granulocytopenia and died. Anti-IA prophylaxis was achieved without irreversible nephrotoxicity, prolonged marrow suppression, alteration of antileukemia treatment, or negative impact on clinical outcome relative to acute leukemia. CONCLUSION: This approach of antifungal prophylaxis in adults with acute leukemia and documented primary IA occurring during initial induction chemotherapy has been successful in preventing clinically significant IA reactivation during subsequent granulocytopenic courses, and allows for administration of additional intensive antileukemia therapy.

Adult↗
PubMed1988

Diagnosis and successful treatment of fusariosis in the compromised host.

We present six cases of fusariosis caused by Fusarium solani that were diagnosed over a three-year period in 166 adult patients undergoing chemotherapy for acute leukemia. Necrotic skin lesions were evident in four patients, fungemia in three, and a deep cellulitis around a great toe nail at the time of a febrile illness in two. The mean minimal inhibitory concentration (MIC) of amphotericin B was 3.3 micrograms/mL and of miconazole, 5.3 micrograms/mL; all isolates were resistant to 5-fluorocytosine. All patients received amphotericin B (1.0-1.5 mg/kg per d) plus 5-fluorocytosine. In contrast to results found in the literature, five patients had resolution of their infections, and the one patient who died had necropsy evidence of disseminated fusariosis. Review of our cases and of the literature did not reveal a definitive source for the organism or its portal of entry. Fusarium spp. must be recognized as opportunistic pathogens that cause a potentially fatal infection in compromised patients.

Adult↗
PubMed1988

Acute leukemia expressing the normal human hematopoietic stem cell membrane glycoprotein CD34 (MY10).

Thirty-one cases of acute leukemia with blast cells greater than or equal to 70% positive for the hematopoietic stem cell Ag, CD34 (MY10, HPCA-1), were identified from the University of Nebraska Medical Center and The Johns Hopkins Oncology Center over an 18-month period. Fourteen of the cases were classified as early B-lineage ALL, 3 cases were other ALL subtypes, and 14 of the cases were ANLL. Five of the 17 cases of ALL expressed one or more myeloid-associated surface Ags, 3 ANLL cases expressed CD10 (CALLA, J5), and T-lymphoid Ags were present in 12 of 31 cases (1 T-cell ALL, 3 of 16 B-lineage ALL cases, and 8 of 14 ANLL cases). Eleven of 12 CD34+ ALL cases studied had abnormal karyotypes; only 7 of 12 CD34+ ANLL cases studied had abnormal karyotypes, and 3 of these were CD10+ ANLL. Six cases were Ph1 positive, including the one mature B cell ALL, 4 early B-lineage ALL, and 1 CD10+ ANLL case. Good and poor prognosis subgroups of high frequency of expression of CD34 leukemias could be identified, generally, as would have been predicted by previously defined criteria. Thus, of the 10 Ph1-negative early B-lineage ALL patients, 9 achieved CR (90%). At the other extreme, the CR rate of CD10- ANLL was 4 of 11 (36%). The leukemias characterized by greater than or equal to 70% of cells positive for CD34 form a relatively undifferentiated subset of the leukemias which may show features associated with more than one lineage, and if CD10- and myeloid morphology, may respond poorly to therapy.

Antigens, CD34↗
PubMed1988

Bacterial and host factors affecting Pseudomonas aeruginosa colonization versus bacteremia in granulocytopenic patients.

In order to evaluate bacterial factors which might predispose to P. aeruginosa colonization or bacteremia in the granulocytopenic patient, 132 isolates recovered from 44 oncology patients were evaluated for antigenic serotype, iron correctable sensitivity to pooled human serum, antibiotic susceptibility, production of lecithinase, elastase, protease, gelatinase, pyocyanin and pyoverdin. Similarly, potential host factors, primarily total iron binding capacity, were evaluated in a subpopulation of acute leukemia patients composed of 13 control patients without P. aeruginosa cultured during their hospital course, 11 colonization only patients and 15 P. aeruginosa bacteremia patients. No significant differences were observed between strains recovered from bacteremia vs. colonization patients for extracellular enzyme activity, pigment production, serum sensitivity and antigenic serotype. Significant differences were observed between bacteremia and colonizing strains for antibiotic susceptibility to ticarcillin, 40% vs. 76% (P less than 0.002); piperacillin, 44% vs. 86% (P less than 0.006); and cefsulodin, 60% vs. 90% (P less than 0.02). Of the host factors evaluated in the acute leukemia patients, significant differences were observed between the TIBC nadir of control patients and both colonization patients (P less than 0.0002) and bacteremia patients (P less than 0.0004). P. aeruginosa bacteremia was associated with the temporal occurrence of TIBC nadir and the detection of the organism. These data suggest a possible role for beta-lactam antibiotic resistance and host iron binding capacity as determinants and possible predictors of P. aeruginosa sepsis in the granulocytopenic patient.

Adult↗
PubMed1988

Systemic infection and colonization with and without prophylactic norfloxacin use over time in the granulocytopenic, acute leukemia patient.

Patients undergoing intensive antileukemic chemotherapy and profound granulocytopenia are susceptible to overwhelming infections, particularly those arising from disease- and therapy-related gastrointestinal tract damage. We have previously demonstrated that the ability to suppress bacterial colonization of this site with oral norfloxacin prophylaxis (400 mg every 12 h) affects the incidence and distribution of aerobic gram-negative bacterial infections and the overall management of infectious complications in this patient population. We have now determined the broad impact of continuous, long-term use of oral norfloxacin on aerobic gram-negative bacterial infection and colonization, overall management of presumed and documented infections during marrow aplasia and emergence of clinically significant antibiotic resistant pathogens during intensive antileukemic chemotherapy. Oral norfloxacin prophylaxis administered throughout the course of induced granulocytopenia continues to afford effective protection by suppressing the development of aerobic gram-negative infections, particularly those arising from the gastrointestinal tract, and preventing the acquisition or emergence of multiply resistant pathogens. A long-range effect of norfloxacin on pathogens colonizing the respiratory tract is also detected, with inhibition of acquired drug resistance occurring at that site as well. For these reasons, norfloxacin continues to be an excellent agent for oral prophylactic use in this patient population.

Administration, Oral↗