Polymicrobial bacterial or fungal infections: incidence, spectrum of infection, risk factors, and clinical outcomes from a large hematopoietic stem cell transplant center.

BACKGROUND: Infections cause significant morbidity and mortality for patients who undergo hematopoietic stem cell transplantation (HSCT). Cancer patients who develop polymicrobial infection (PI) are at increased risk for poor clinical outcomes, yet very limited data have been published within the HSCT setting. METHODS: An observational study of 901 stem cell transplant recipients was conducted at Northwestern Memorial Hospital to identify the incidence, risk factors and outcomes for HSCT recipients who develop infection(s) with multiple bacterial or fungal organisms. RESULTS: Among 901 HSCT recipients reviewed (675 autografts and 226 allografts), 237 patients (27%) had microbiologically documented microorganisms isolated, including 179 patients (76%) with monomicrobial infection and 59 patients (24%) with multiple microorganisms, of which 34 (14%) were classified as PI, and 25 (10%) as multiple distinct episodes of infection. CONCLUSION: The results show co-infection with multiple organisms during HSCT is relatively rare; however, these patients are at an increased risk for the development of acute graft-versus-host disease, delayed engraftment, and overall mortality.

Amphotericin B deoxycholate nasal spray administered to hematopoietic stem cell recipients with prior fungal colonization of the upper airway passages is associated with low rates of invasive fungal infection.

BACKGROUND: Invasive fungal infections cause major problems during hematopoietic stem cell transplantation (HSCT). Fungal colonization of the upper airway passages occurs frequently, and may serve as a portal of entry for potentially life-threatening fungal infections, especially in immunocompromised patients. METHODS: A clinical practice was instituted at Northwestern Memorial Hospital in Chicago in 2005, to administer amphotericin B deoxycholate nasal spray (ABNS) 0.5% to all HSCT recipients with fungal colonization of their nasal passages, in addition to standard oral antifungal prophylaxis. RESULTS: Among 1945 HSCT patients treated during the study period, 109 patients were identified with positive fungal surveillance cultures. CONCLUSION: Breakthrough fungal infections occurred in only 2 patients (2%), thus in this select group of HSCT recipients, ABNS administration is associated with a very low rate of breakthrough infection.

The International Scoring System (ISS) for multiple myeloma remains a robust prognostic tool independently of patients' renal function.

BACKGROUND: The International Staging System (ISS) is the most widely used staging system for patients with multiple myeloma (MM). However, serum ß2-microglobulin increases in renal impairment (RI) and there have been concerns that ISS-3 stage may include 'up-staged' MM patients in whom elevated ß2-microglobulin reflects the degree of renal dysfunction rather than tumor load. PATIENTS AND METHODS: In order to assess the impact of RI on the prognostic value of ISS, we analyzed 1516 patients with symptomatic MM and the degree of RI was classified according to the Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease (CKD) criteria. RESULTS: Forty-eight percent patients had stages 3-5 CKD while 29% of patients had ISS-1, 38% had ISS-2 and 33% ISS-3. The frequency and severity of RI were more common in ISS-3 patients. RI was associated with inferior survival in univariate but not in multivariate analysis. When analyzed separately, ISS-1 and ISS-2 patients with RI had inferior survival in univariate but not in multivariate analysis. In ISS-3 MM patients, RI had no prognostic impact either in univariate or multivariate analysis. Results were similar, when we analyzed only patients with Bence-Jones >200 mg/day. CONCLUSIONS: ISS remains unaffected by the degree of RI, even in patients with ISS-3, which includes most patients with renal dysfunction.

Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG).

When the novel agents thalidomide, bortezomib and lenalidomide are administered to patients with myeloma in the context of clinical trials, they are associated with a significant improvement in response, progression-free survival and in some studies, overall survival (OS); however, their effect on the outcome of unselected myeloma patients has not been fully assessed. We compared the outcome of 1376 unselected patients with symptomatic myeloma, who started treatment before or after the introduction of thalidomide. The median OS in patients who started treatment after the introduction of novel agents increased by 12 months (48 vs 36 months, P<0.001). This improvement was more pronounced in patients < or =70 years (from 39 to 74 months, P<0.001), but less evident in patients >70 years (from 26 to 33 months, P=0.27). In patients treated after the introduction of novel agents, the international staging system (ISS) could discriminate three groups with significantly different outcomes (5-year survival for ISS stage I, II and III was 66, 45 and 18%, respectively, P<0.001). ISS was also valid in patients who actually received upfront treatment with novel drugs (4-year survival rate was 85, 61 and 26% for ISS stage I, II and III patients, P=0.001).

Dose dependent long-term in vivo remission of AML1/ETO positive acute myeloid leukemia with G-CSF.

In addition to the ability of G-CSF to stimulate the maturation and function of granulocytes, experimental and clinical evidence suggests that induction of leukemia cell differentiation may also be possible. This critical effect has received little attention with respect to its potential therapeutic application in myeloid malignancies. We describe the clinical course of a 62-year-old patient with atypical AML1/ETO-positive AML-M2 who repeatedly displayed a marked, dose-dependent response to G-CSF. He was originally investigated for neutropenia, but declined chemotherapy at diagnosis of AML (40% bone marrow blasts) and commenced G-CSF therapy when a life-threatening chest infection occurred. The bone marrow infiltration regressed and his blood counts normalized after 20 days. A slow relapse occurred over the next 3 months but a second hematological remission was achieved upon reintroduction of G-CSF. He remained well and free of transfusions for 2.5 years, receiving only maintenance G-CSF. Despite the presence of the AML1/ETO transcript, his leukemic blasts always failed to demonstrate the typical morphological, immunological and cytogenetic characteristics of AML1/ETO-AML of M2 subtype. He eventually developed resistance to G-CSF and died from sepsis after cytotoxic therapy. In selected AML cases differentiation therapy with growth factors may emerge as a useful antileukemic strategy, either alone or as an adjunct to established treatment modalities.

Primary renal lymphoma presenting with chronic low-grade fever.

Primary renal lymphoma (PRL) is a rare form of extranodal non-Hodgkin's lymphoma often diagnosed and treated by oncologists and urologists. Pathophysiological and clinical data on PRL are sparse, but the limited reported experience suggests the disease usually has an ominous outcome. As in other renal tumors, comprehensive radiological investigations have a central role in the recognition and final diagnosis of PRL. We describe the presenting features and clinical course of an elderly woman who was found to have PRL after evaluation for persistent low-grade fever. Diagnostic and therapeutic caveats are discussed on the basis of a critical literature review of case reports and descriptions of small series of patients.

Survival and prognostic factors after initiation of treatment in Waldenstrom's macroglobulinemia.

BACKGROUND: Waldenstrom's macroglobulinemia (WM) is an unusual lymphoplasmacytoid lymphoma characterized by the presence of a serum monoclonal immunoglobulin M. Although several studies have evaluated possible prognostic factors of this disease, few have focused on the survival and prognosis of symptomatic patients after the initiation of treatment. PATIENTS AND METHODS: Our study included 122 previously untreated patients with a median age of 67 years who required systemic treatment. Multiple variables were analyzed for their prognostic value on survival after initiation of treatment using univariate and Cox regression multivariate analysis. RESULTS: The median overall survival was 106 months. Pretreatment factors associated with shorter survival were age >/=65 years, splenomegaly, B-symptoms (weight loss, fever or night sweats), hemoglobin <10 g/dl, platelets <100 x 10(6)/dl, albumin <3.5 g/dl and bone marrow lymphoplasmacytic infiltrate >/=50%. In the multivariate analysis, the two variables with independent prognostic value were age >/=65 years and hemoglobin <10 g/dl. Furthermore, we were able to divide our patients into three risk groups based on the presence of two, one or none of these two adverse prognostic factors. The median survival times in the high-, intermediate- and low-risk groups were 46 months, 107 months and 172 months, respectively (P <0.0001). DISCUSSION: Our findings suggest that advanced age and anemia appear to be the two dominant prognostic factors for survival after initiation of treatment in patients with WM. These two readily available parameters can stratify the patients into three distinct subgroups and may help the selection of appropriate treatment.

Treatment of Waldenstrom's macroglobulinemia with single-agent thalidomide or with the combination of clarithromycin, thalidomide and dexamethasone.

To evaluate the activity of thalidomide in Waldenstrom's macroglobulinemia (WM), 20 patients were treated on a dose schedule that escalated from 200 mg/d to 600 mg/d. On an intention-to-treat basis, five (25%) patients achieved a partial response, which was noted within 3 months of treatment. Adverse effects were common and prevented dose escalation of thalidomide in 75% of patients and led to premature discontinuation of treatment in 35%. We subsequently evaluated the oral combination of clarithromycin (500 mg twice per day), low-dose thalidomide (200 mg once daily), and dexamethasone (40 mg once per week). Our preliminary analysis on 12 previously treated patients indicate activity of this regimen in WM: three patients achieved a partial response and two patients demonstrated monoclonal protein reduction of greater than 25%. This combination was associated with a variety of side effects due not only to thalidomide, but also to corticosteroids and to clarithromycin. Our preliminary data indicate that this combination may be a useful salvage regimen for some patients with heavily pretreated macroglobulinemia.

Treatment of Waldenstrom's macroglobulinemia with thalidomide.

PURPOSE: We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom's macroglobulinemia (WM). PATIENTS AND METHODS: Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated. RESULTS: On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance. CONCLUSION: Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant.

Successful treatment of multiple myeloma relapsing after high-dose therapy and autologous transplantation with thalidomide as a single agent.

A 52-year-old dentist with kappa light chain multiple myeloma relapsed 6 months after 180 mg/m2 melphalan and an autograft. A partial remission had been attained after the autograft. Relapse occurred while he was on dexamethasone maintenance therapy. Chemotherapy was not an option due to low blood counts. Thalidomide was administered at relatively high doses (escalated up to 700 mg daily and continued for 4 months). There was a prompt decline in urine protein from 6067 mg/day to 2177 mg/day within a month. The response continued to improve with achievement of near-complete remission within 6 months and a decline in urine protein to 413 mg/day. Subsequently, grade 3 neutropenia and peripheral neuropathy required dose reduction to 200 mg/day. Disease activity parameters continued to improve on the lower dose of thalidomide. Nine months after starting thalidomide, the patient is in near-complete remission, enjoys an excellent quality of life, and has returned to work. We conclude that thalidomide can effectively control myeloma relapsing after high-dose chemotherapy, and may be especially useful in resistant cases or those unable to tolerate further chemotherapy. Bone Marrow Transplantation (2000) 25, 1319-1320.

Outcome of biphenotypic acute leukemia.

BACKGROUND AND OBJECTIVE: Although biphenotypic leukemia is now a defined entity, outcome of this rare form of acute leukemia has not been well documented. We present the first comprehensive study analyzing induction and consolidation therapy of biphenotypic leukemia and correlate outcome to prognostic factors. DESIGN AND METHODS: In this retrospective study, the incidence of biphenotypic leukemia was found to be 3.6% from 693 adult and pediatric acute leukemias referred to our center for treatment over the last 8 years. Of these, 15 were B-lymphoid/myeloid, 8 were T-lymphoid/myeloid, one was T/B lymphoid and one had trilineage differentiation. RESULTS: Induction of remission in de novo cases was achieved in 70% of patients and relapse of disease occurred in 15%. The use of combined lymphoid and myeloid drugs for induction resulted in a high incidence of early deaths (25%). The overall probability of survival at 2 years was 39.4%. Patients with secondary disease had a uniformly poor outcome with low remission rates and high relapse rates. INTERPRETATION AND CONCLUSIONS: Prognosis was most strongly related to the presence of the Philadelphia chromosome (p=0.03) and age under 15 years (p=0.01). We conclude that patients with biphenotypic leukemia should have risk stratification with treatment tailored to their prognostic factors.

Red cell fragmentation (schistocytosis) after bone marrow transplantation.

Red cell fragmentation is often the earliest sign of thrombotic microangiopathy. Days +14, +28 and +42 blood films from 58 allograft and 32 autograft recipients were reviewed blind to determine the incidence and severity of schistocytosis (the number of fragmented red cells per 1000 red cells expressed as a percentage). Schistocytosis was graded as mild (<1%), moderate (1-1.9%) or severe (> or =2%). Schistocytes were seen in 99% of day 14 films (0.1-3.0%, median 0.4%), 97% of day 28 films (0.1-3.2%, median 0.4%), and 98% of day 42 films (0.1-4.3%, median 0.5%). Nine patients (10%) had severe fragmentation and 20 patients (22%) had moderate fragmentation at some time or the other. The difference in the extent of fragmentation between the days was not significant. Allogeneic BMT was associated with more extensive fragmentation than autologous transplantation on day 28 (P = 0.008) and day 42 (P = 0.02). Age, conditioning regimen and diagnosis had no influence. None of the patients followed-up for 6 months after transplant developed full-blown thrombotic microangiopathy. The occasional patient showing mild clinical and laboratory features of hemolysis responded well to adjustment of fluid balance and cyclosporine dose where applicable. Our data indicate that mild red cell fragmentation is a common morphologic finding after transplantation with no clinical significance in the absence of other clinical and laboratory findings suggestive of thrombotic microangiopathy, although patients with moderate or severe fragmentation should be monitored closely.

Graft-versus-myeloma after donor leukocyte infusion: maintenance of marrow remission but extramedullary relapse with plasmacytomas.

Adoptive immunotherapy with donor leukocytes has emerged as a promising strategy for the treatment of myeloma recurrence after allogeneic transplantation. 2.9 x 10(8)/kg donor mononuclear cells containing 1.4% CD34+ and 37% CD3+ cells were administered to a 48-year-old patient with non-secretory plasmablastic myeloma relapsing 9 months after a blood stem cell transplant from his HLA-identical sibling. In view of the extensive marrow infiltration and the aggressive behaviour of the disease, the donor cells were preceded by a course of EDAP chemotherapy. There was rapid clinical improvement, and CR was achieved on day 30 post infusion. However, three subcutaneous plasmacytomas showing anaplastic features developed within a few days. These failed to respond to interferon-alpha and continued to grow for 5 weeks in the absence of marrow plasmacytosis or other evidence of systemic disease. Grade 3 acute liver GVHD developed on day 79 which was controlled with immunosuppression. Overt systemic relapse occurred on day 90 as the GVHD came under control. The course of our case suggests highly proliferative malignant cells may escape the graft-versus-tumour effect of immunocompetent allogeneic cells in extramedullary sites subsequently resulting in overt systemic relapse if left untreated. New approaches are needed to deal with the problem of extramedullary disease recurrence.

Sequential development of myelodysplasia and acute myeloid leukemia but with no karyotypic evolution after autografting in a patient with Philadelphia positive acute lymphoblastic leukemia.

A woman with Philadelphia chromosome-positive c-ALL with +8 and i17q in addition underwent an unpurged blood stem cell autograft after 200mg/m2 melphalan in first relapse. Maintenance therapy with 6-mercatopurine was started following the autograft. Moderate pancytopenia developed after 4 months, and myelodysplasia (refractory anemia) was diagnosed which rapidly evolved into AML. The cytogenetic findings remained unchanged. She also developed CNS disease, but the blasts in the cerebrospinal fluid were lymphoid in character on immunophenotyping. She then received palliative treatment until death. The remarkable features here are the evolution into myelodysplasia and AML with retention of the original complex karyotype, and subsequent coexistence of lymphoid disease in the CNS and myeloid disease systemically. It is possible that the lineage switch and development of myelodysplasia in this case may have been secondary to treatment, but persistence of the original cytogenetic clone makes this unlikely. This may have been the result of some unusual effect of the treatment on the original clone, or expansion of a small unidentified myeloid clone present originally which gained a proliferative advantage due to the ALL-type treatment. This case confirms the aggressive and polymorphic nature of Ph+ ALL which may be the result of origin from an early progenitor cell (stem cell disease).

Subcutaneous CAMPATH-1H in fludarabine-resistant/relapsed chronic lymphocytic and B-prolymphocytic leukaemia.

Seven patients with B-cell leukaemia - six with chronic lymphocytic leukaemia (CLL) and one with B-prolymphocytic leukaemia (B-PLL) - were treated with CAMPATH-1H*, a genetically reshaped CD52 monoclonal antibody, administered subcutaneously (s.c.) three times a week for 6-12 weeks. Four were resistant to, and three had had a short partial remission (PR) following, fludarabine chemotherapy. The patient with B-PLL achieved complete remission and three patients with CLL attained PR; two of the latter were retreated. The three remaining patients were non-responders. Three patients were transfusion-dependent before CAMPATH and all three became transfusion-independent after treatment. The overall median survival from starting CAMPATH-1H was 11 months. Three patients reactivated cytomegalovirus (CMV) during the course of treatment, and two were treated with, and responded to, ganciclovir.

Bilineal acute leukemia of B and T lineage with a novel translocation t(9;17)(p11;q11).

We describe a case of bilineal leukemia in a 5-year old boy with a rare immunophenotype and the novel translocation t(9;17)(p11;q11) as the sole chromosomal abnormality. Two immunologically distinct blast cell subsets expressed T-markers (CD2, CD5, CD7) and common ALL markers (TdT, CD19, CD22, CD10), respectively. Both cell populations were CD34 negative. The patient, who presented with CNS leukemia, responded promptly to standard chemotherapy for lymphoblastic leukemia and remains in complete remission 20 months from diagnosis. Other translocations between chromosomes 9 and 17 have been infrequently reported in a variety of leukemias but as yet their biologic significance is unknown. The clinical course of this case suggests that t(9;17)(p11;q11) may not have an adverse influence on the disease outcome. However, the role of t(9;17) in the pathogenesis of this unusual lymphoid phenotype remains unresolved.

Expression of the immunoglobulin-associated protein B29 in B cell disorders with the monoclonal antibody SN8 (CD79b).

We studied the expression of the immunoglobulin-associated membrane protein B29 in 499 cases of chronic B cell diseases using the monoclonal antibody SN8 (CD79b). SN8 was positive in 5% (17/330) of chronic lymphocytic leukemia (CLL) and 100% (15/15) of B prolymphocytic leukemia. The expression of B29 in other B cell disorders was, as a rule, significantly higher than in CLL. Two thirds of non-Hodgkin's lymphomas in leukemic phase were SN8 positive, including lymphoplasmacytic (45%), follicular (83%), mantle cell (92%) and splenic lymphoma with villous lymphocytes (74%) while only 25% of hairy cell leukemias were SN8 positive. Within CLL, 2.3% of typical cases were SN8+ while 16% of cases with atypical morphology and an increased number of prolymphocytes were SN8+. Our results suggest a useful role for SN8 in the immunophenotypic differentiation of B cell disorders as a marker for non-CLL diseases. The analysis of B29 expression may throw light into the structure of the B cell antigen receptor in B cell malignancies while the distinctive reactivity profile of SN8 has direct applications to diagnosis.

Idarubicin, high-dose cytarabine, and etoposide for induction of remission in acute leukemia.

Between 1990 and 1944, 52 newly diagnosed patients with primary (n = 47) or therapy-related (n = 5) acute myeloid leukemia (AML) under the age of 55 years received an induction chemotherapy protocol (designated BF12) consisting of idarubicin ([IDA] 5 mg/m2), high-dose cytarabine ([HD-Ara-C] 2 mg/m2 per 12 hours, 3-hour infusion), and etoposide ([VP-16] 100 mg/m2, 1-hour infusion) on each of 5 consecutive days. Thirty-seven of 51 assessable patients (72.5%), including all five patients with therapy-related AML, attained remission with one cycle. The overall remission rate was 78.4%. Total therapy of AML, with BF12 followed by two courses of consolidation therapy and allogeneic or unpurged autologous bone marrow transplantation (BMT) in first remission, has resulted in actuarial 3-year survival of 49.9% of consecutive unselected patients with newly diagnosed primary AML (minimum follow-up period, 1 year). Twenty-five patients have received BF12 for relapsed acute leukemia, including 13 relapsing after BMT. Five patients died of toxicity and were not assessable for response. Of the remaining 20 patients, five were refractory, two attained partial remissions, and 13 (65%) achieved complete remission (CR). Four of the 13 patients relapsing after BMT died of toxicity, four were refractory, and five of nine assessable patients (56%) attained CR. We conclude that the combination IDA/HD-Ara-C/VP-16 is highly effective in the treatment of newly diagnosed AML and relapsed acute leukemia.