Jeane P. Hester

Treatment of neutropenia-related fungal infections with granulocyte colony-stimulating factor-elicited white blood cell transfusions: a pilot study.

Neutropenia-related fungal infections can be life-threatening despite antifungal therapy. We evaluated the role of recombinant granulocyte colony-stimulating factor (rG-CSF)-elicited white blood cell (WBC) transfusions in patients with neutropenia-related fungal infections. Adult patients with hematologic malignancies, absolute neutrophil counts (ANC) <500/μl and fungal infections refractory to amphotericin b, received daily transfusions of rg-csf-elicited and irradiated wbc transfusions from related donors. donors received 5 μg/kg/day of rg-csf subcutaneously. donors achieved a mean anc of 29.4 × 103 per microliter. The mean yield of neutrophils per transfusion was 41 × 109 (range, 10–116). Fifteen patients received a median of eight transfusions (range, 3–16). Fourteen patients had received rG-CSF for a median of 12 days. The median ANC baseline was 20/μl. Eleven patients had favorable responses and eight of them remained free of infection 3 weeks after therapy. Favorable responses occurred among patients with better Zubrod performance status (median, 3 vs 4) and shorter duration of both profound neutropenia (median, 15 vs 25 days) and active infection (median, 8 vs 17 days). The mean 1- and 24-h post-transfusion ANCs were 594/μl (range, 98–1472/μl) and 396/μl (range, 50–1475/μl), respectively. Adverse reactions were observed in nine of 35 donors and in the recipients of six of 130 transfusions. rG-CSF-elicited WBC transfusions may be a safe and promising approach for treating neutropenia-related fungal infections.

Photopheresis therapy for cutaneous T-cell lymphoma

BACKGROUND Cutaneous T-cell lymphoma is a chronic peripheral lymphoma in which aggressive combined therapy elicits high response rates but does not improve survival. Photopheresis therapy has reportedly induced remissions and prolonged survival in patients with advanced disease. OBJECTIVE We studied all patients who began photopheresis treatment between February 1988 and July 1994 to determine whether we could confirm the remission rates of previous studies, to evaluate variables that might predict a response, and to discover whether an accelerated delivery system would improve the remission rate or response time. METHODS After an oral dose of methoxsalen was administered, a leukocyte-enhanced quantity of blood was exposed to UVA radiation for 1.5 hours and returned to the patient. With our accelerated system, 6 x 10(9) cells were irradiated in nine cycles. Treatments were given on 2 consecutive days once a month. RESULTS Among 34 patients whose results could be evaluated, the overall response rate (complete and partial remissions) was 50%; most patients had mild side effects. All responders except one had erythroderma. Responders had a decrease of 75% in mean skin scores, whereas nonresponders had an increase of 21%. CONCLUSION Photopheresis appears to be effective for selected patients with erythrodermic cutaneous T-cell lymphoma, although we did not achieve as high a remission rate as previously reported by others.

Intensive combination chemotherapy (ROAP 10) and splenectomy in the management of chronic myelogenous leukemia.

To investigate the role of intensive chemotherapy in chronic myelogenous leukemia (CML), we treated 37 patients who had Philadelphia-positive benign-phase disease with rubidazone 300 mg/m2/d 1 (or daunorubicin 30 mg/m2/d X 4), cytosine arabinoside 80 mg/m2/d X 10, vincristine 2 mg/d 1, and prednisone 100 mg/d X 5 (ROAP 10), every four weeks for a median of three cycles. This treatment was followed by splenectomy and by subsequent maintenance therapy with 1 to 5 g hydroxyurea daily in intermittent courses. After a median follow-up of 42 months (range, 24 to 54 months), 20 patients (54%) remain in benign phase. The projected median survival is 52 months, and the three-year survival rate is 67%. Six patients (16%) developed blastic crisis, and eight died in the benign phase. A significant cytogenetic response, defined as a fall in the percentage of Philadelphia-positive cells to less than or equal to 30%, occurred in 18 (53%) of 34 patients who had serial cytogenetic studies. Six patients (18%) had reductions to 35% to 90%, whereas ten remained 100% positive. Cytogenetic response lasted for a median of six months from the time of maximal response (range, 1 to 18 months). Blastic crisis or accelerated disease developed in seven (44%) of the 16 patients who manifested minimal or no cytogenetic response, compared to only two of the 18 patients (11%) who achieved a significant cytogenetic response. Toxicity, which resulted in one death, was due to myelosuppression and consisted of febrile episodes during neutropenia (24% of courses), documented infections (8% of courses), and bleeding (8% of courses). ROAP 10 intensive therapy produces moderate survival improvement for CML patients compared to a matched historical control group of patients treated at our institution, but it has considerable myelosuppressive toxicity. The Philadelphia chromosome response is an important treatment-related prognostic factor.

Clinical course and response to treatment of patients with acute myelogenous leukemia presenting with a high leukocyte count

The natural history and response to treatment of 46 patients with acute myelogenous leukemia and a pretreatment leukocyte count of 100,000/μl or higher were reviewed to identify the clinical features and response characteristics to the treatment of this group of patients. While the response rate of 52% was similar to that of patients with lower leukocyte counts, remission durations were shorter and related inversely to the height of the initial leukocyte count and to the number of treatment courses necessary to achieve a complete remission. A high incidence of hemorrhagic deaths was observed during the first 8 days of treatment. These hemorrhages occurred at a time when the leukocyte count was falling secondary to chemotherapy and the platelet count was still greater than 15,000/μl. Pretreatment coagulation disorders and poor performance status were factors associated with this fatal complication. Antimetabolites to rapidly arrest leukemic cell proliferation and leukapheresis to avoid further leukostatic plug formation may be useful immediate measures to reduce the incidence of these fatal hemorrhages until the underlying pathogenic mechanisms have been elucidated.

Increased Granulocyte Collection with the Blood Cell Separator and the Addition of Etiocholanolone and Hydroxyethyl Starch

A total of 201 leukaphereses have been performed on 73 donors to collect granulocytes for transfusion to infected leukopenic recipients. The pretreatment of the donor with etiocholanolone and the addition of hydroxyethyl starch to the extracorporeal circulation significantly increased the total number of granulocytes collected. Adverse side effects were minimal. The majority of donors underwent the procedure on 13 occasions over a period of eight weeks. Follow‐up donors two or more years later has revealed no long‐term adverse side effects from leukapheresis or from the addition of etiocholanolone and hydroxyethyl starch.

TGF-Beta inhibits the in vitro induction of lymphokine-activated killing activity

SummaryEmploying serum-free media, human peripheral blood mononuclear cells, and purified recombinant interleukin-2 (IL-2), conditions were observed in which the development of IL-2-driven cytotoxic activity was suppressed. The cytotoxic activity of such IL-2-generated lymphokine activated killing (LAK) was tested against natural killer-resistant cultured tumor cells (Daudi, Raji, and a glioma). LAK generation was inhibited by addition of some normal sera, normal platelets, or some tumor cells. Because recent reports have indicated that transforming growth factor-beta (TGF-beta)-like factors are often secreted by tumors and the acidic alpha granules of platelets and can be present in sera, we tested the effect of purified human TGF-beta on the activation of LAK. Our results indicated that TGF-beta is very suppressive for LAK induction, and can completely prevent both the IL-2-driven proliferation and cytotoxicity at concentrations as low as 5 ng/ml. Titrations of IL-2 and of TGF-beta indicated that the suppression is dose-dependent and can be avoided by employing higher levels of IL-2. It was also found that the suppressive effect of TGF-beta can be overcome by washing suppressed cell populations and further culture in low levels of IL-2. Collectively, these data indicate that TGF-beta can be a potent inhibitor of LAK generation under standard activation conditions, but that this effect is regulated by the relative level of IL-2 and may be overcome and/or reversed in vitro.

Collection of peripheral-blood diploid cells from chronic myelogenous leukemia patients early in the recovery phase from myelosuppression induced by intensive-dose chemotherapy.

PURPOSE To evaluate whether intensive chemotherapy followed by peripheral stem-cell (PSC) collections during early hematopoietic recovery results in a higher percentage of diploid cell collections in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). PATIENTS AND METHODS Fifty-five adults with Ph-positive CML received intensive chemotherapy with daunorubicin and high-dose cytarabine (ara-C) (DAUNO-HDAC; 26 patients) or fludarabine, high-dose ara-C, and mitoxantrone (FAM; 29 patients). Collections of the peripheral mononuclear cells were initiated when the WBC count was > or = 0.8 x 10(3)/microL. Simultaneous peripheral and marrow samples were subjected to cytogenetic studies. RESULTS Thirty-eight of 55 patients (69%) were able to undergo the PSC collections. The rate of collection was higher in chronic phase (26 of 30 patients; 87%) than in accelerated (11 of 17; 65%) and blastic phases (1 of 8; 12%). Among the 30 patients in chronic phase, cytogenetic analyses of PSC showed cytogenetic responses (Ph-positive < 95%) in 60%, which were major (Ph < 35%) in 43% and complete (Ph = 0%) in 27%. Seven of 19 patients with simultaneous studies (37%; 23% of total) had a significantly lower percentage of Ph-positive cells in the peripheral collection compared with the marrow collection; one had the reverse phenomenon (5%; 3% of total). Cytogenetic responses were modest in both peripheral and marrow collections in CML accelerated and blastic phases. Myelosuppression-associated complications were frequent, resulting in febrile episodes in 76% of patients. CONCLUSION PSC collection during early hematopoietic recovery from intensive chemotherapy allowed the collection of diploid-rich stem cells, mostly in chronic-phase CML. The approach could be used for in vivo purging before autologous stem-cell transplantation (ASCT).

White Blood Cell Transfusions for Control of Infections in Neutropenic Patients

Four hundred and fifty‐four leukocyte transfusions from unrelated donors with chronic myelogenous leukemia were given to 128 patients during 179 febrile episodes with a median circulating granulocyte count prior to leukocyte transfusions of 80/cm. Forty‐nine per cent of the serious and life‐threatening infections responded to a combination of granulocyte transfusions and appropriate antibiotic therapy. Minor complications occurred in approximately 25 per cent of patients and more severe toxicity was seen in only 2 per cent. No deaths were attributed to leukocyte transfusions.

Long-term results of CAP therapy in chronic lymphocytic leukemia

This study was designed to study the efficacy and toxicity of an adriamycin-containing regimen (CAP: cyclophosphamide, adriamycin, and prednisone) in patients with previously untreated chronic lymphocytic leukemia (CLL). CAP was given to clinical complete remission followed by 18 months of cyclophosphamide-prednisone (CP) maintenance. Forty-seven patients with previously untreated CLL were treated. These patients initially presented with advanced stage (Rai III or IV) or had less advanced stage (Rai 0-II) patients and demonstrated evidence of disease progression. Patients received 750 mg/m(2) of cyclophosphamide intravenously on day 1, 50 mg/m(2) of adriamycin intravenously on day 1 and 100 mg/day of prednisone on days 1-5. Courses were repeated at 3-week intervals until clinical CR, at which time maintenance with cyclophosphamide and prednisone (CP) was commenced. A maximum cumulative dose of 450 mg/m(2) of adriamycin (9 courses of CAP) was given. Twenty (43%) of 47 patients obtained a CR and 11 (23%) obtained a partial remission. Bone marrow biopsy criteria were used to define response in addition to clinical and peripheral blood responses. All patients have been followed for 10 years. The median survival was 259 weeks. No patient remains in remission. No impact of response on survival was found. Surprisingly, the response rate and survival were higher and longer for patients with more advanced stages and higher tumor burdens. The median survival times for patients with Rai stage IV and Binet stage C disease were 93 months and 81 months, respectively. Although the regimen was well tolerated, three patients, each with an antecedent cardiac risk factor, developed congestive heart failure. Adriamycin containing regimens can be safely given to elderly patients with CLL and show promise in the treatment of advanced stage disease.

Inhibition of lymphokine-activated killer cell generation by blocking factors in sera of patients with head and neck cancer

SummaryCytolytic activation of peripheral blood lymphocytes by recombinant interleukin-2 (rIL-2) in patients with squamous cell carcinoma (SCC) of the head and neck may be inhibited by serum blocking factors, and this could influence therapeutic efficacy. Peripheral blood lymphocytes from 21 patients with this disease and 17 controls were incubated with 10–1000 U rIL-2 for 6 days in supplemented complete medium (containing 10% fetal calf serum) or the same medium plus 10% autologous serum. After washing the effector cells, we determined their cytotoxicity against K562 and MDA1386, a lymphokine-activated-killer(LAK)-sensitive SCC cell line, using a51Cr-release assay. Patient sera inhibited LAK-generated lysis of both MDA 1386 and K562, while control sera from healthy persons inhibited LAK-generated lysis of MDA1386. The blocking activity of patient sera tended to be greater than that of control sera. The sera of patients with untreated or recurrent disease and those who were free of disease had equivalent inhibitory capacity. The serum blocking factor acted in a dose-dependent manner, and inhibition was overcome by increasing the dose of rIL-2. Levels of circulating immune complexes (measured by the Clq binding method) did not correlate significantly with inhibition. A clinical protocol of repeated plasma exchange in patients with advanced and recurrent squamous cell carcinoma of the head and neck allowed sequential study of one patientss serum before, during, and after treatments. Plasmapheresis removed serum inhibitory factors, albeit temporarily. The activity of serum blocking factors in patients with this disease can be modulated by increasing doses of rIL-2 and by plasma exchange. This modulation may be important to improving clinical response rates for patients undergoing immunotherapy.