Denise Pereira

A long-term retrospective study of young women with essential thrombocythemia

OBJECTIVE To describe presenting clinical manifestations, long-term disease complications, prognostic indicators, and outcome of pregnancy for women younger than 50 years with essential thrombocythemia. PATIENTS AND METHODS We retrospectively reviewed the records of all patients with essential thrombocythemia evaluated at Mayo Clinic, Rochester, Minn, between 1969 and 1991 and identified 74 young women (median age, 35 years; range, 18-48 years) with essential thrombocythemia. The diagnosis was based on previously established criteria. Median follow-up was 9.2 years (range, 0.2-26.2 years). RESULTS Overall survival was similar to that of an age- and sex-matched control population. Thrombotic events (except superficial thrombophlebitis) occurred at and after diagnosis in 11 patients (15%) and 13 patients (18%), respectively. A history of thrombosis at diagnosis was significantly associated with recurrent thrombosis (P = .03). A platelet count higher than 1500 x 10(9)/L at diagnosis was significantly associated with gastrointestinal tract bleeding and subsequent development of venous (but not arterial) thrombosis (P = .04). Major hemorrhagic events occurred in only 3 patients (4%) after diagnosis. Only 1 patient developed acute leukemia. Thirty-four pregnancies occurred in 18 patients. Of these, 17 (50%) resulted in live births. Of the 17 patients with unsuccessful pregnancies, 14 had spontaneous abortions, 1 had an ectopic pregnancy, and 2 had elective abortions. Preconception platelet count, thrombotic history, or specific therapy was not useful in predicting pregnancy outcome. CONCLUSION Young women with essential thrombocythemia can expect long survival with a low incidence of life-threatening thrombohemorrhagic complications or acute leukemia. There is an increased incidence of first-trimester miscarriages that may not be influenced by specific therapy.

Autotransplant conditioning regimens for aggressive lymphoma: are we on the right road?

High-dose chemotherapy and autologous stem cell transplant (ASCT) is the standard approach for chemosensitive, relapsed aggressive non-Hodgkins lymphoma (NHL). Various conditioning regimens have been used as treatment before ASCT and disease-free (DFS) and overall survival (OS) rates range from 34 to 60% and 26 to 46%, respectively. To date, few comparative randomized trials have been performed and no regimen has demonstrated superiority to another. Reduction of disease relapse remains the major hurdle for improving patient outcome and in vitro and in vivo purging of lymphoma cells has not necessarily enhanced results. Rituximab pre-mobilization and post-transplant appear to provide better response rates with OS approaching 87–91% at 2–3 years. Newer approaches with radioimmunotherapy may raise DFS to 78% and OS to 93%, albeit with short follow-up. Advances in the conditioning regimens and supportive care have reduced transplant-related mortality to less than 10%. In this review we discuss commonly utilized conditioning regimens, describe their pros and cons and address purging and present conditioning strategies. Owing to the poor outcome with conventional chemotherapy in mantle cell, Burkitts and T-cell lymphoma, we propose the standard approach of front-line ASCT for these high-risk lymphoma patients. Finally, we will present novel strategies, which can enhance the anti-lymphoma effect, at the same time reducing toxicity, to improve the outcome of ASCT in NHL patients.

Therapeutic Options in Patients With Lymphoma and Severe Liver Dysfunction

OBJECTIVES To determine the long-term outcome of patients presenting with synchronous lymphoma and severe liver dysfunction and to describe the outcome of patients treated with initial mechlorethamine-based therapy used as a bridge to more conventional chemotherapy. PATIENTS AND METHODS We reviewed the clinical course of all patients diagnosed as having lymphoma who presented with severe liver dysfunction and received intravenous mechlorethamine between September 1988 and February 2003 at the Mayo Clinic in Rochester, Minn. RESULTS Forty-one patients were identified, 33 (80%) of whom had newly diagnosed, previously untreated lymphoma. Thirty-seven (90%) had non-Hodgkin lymphoma, and 4 (10%) had Hodgkin disease. Thirty-four patients (83%) had stage IV disease, and 31 (84%) of 37 had an intermediate-high International Prognostic Index. The median total bilirubin level before therapy was 10.7 mg/dL (range, 2.5-30.2 mg/dL), and the median alkaline phosphatase level was 982 U/L (range, 233-3415 U/L). In addition to mechlorethamine, 34 patients (83%) received concomitant corticosteroids, and 12 (29%) received concomitant rituximab. Twenty-two patients (54%) had sufficient improvement in liver function to receive subsequent standard chemotherapy. Nine patients (22%) are alive and disease-free at a median of 31 months (range, 4 to > or = 87 months) after mechlorethamine treatment. Factors associated with improved overall survival included improvement in bilirubin levels (P < .001) and receiving subsequent standard chemotherapy (P = .001). CONCLUSION Mechlorethamine, high-dose corticosteroids, and rituximab are useful therapeutic interventions for this unique group of patients with lymphoma and severe liver dysfunction. Substantial clinical improvement and long-term survival are possible.

Rituximab for treatment of chemoimmunotherapy naive marginal zone lymphoma

Marginal zone lymphomas (MZL) represent a group of lymphomas originating from B lymphocytes normally residing in the marginal zone of secondary lymphoid follicles. These lymphomas are classified into nodal MZL, splenic MZL, or extranodal MZL of the mucosa associated lymphoid tissue (MALT) type according to the primary involvement site [1]. In the Non-Hodgkin’s Lymphoma Classification Project, MZLs constituted approximately 9% of the lymphomas [2], mainly accounted by MALT lymphomas. Although eradication of Helicobacter pylori (H. pylori) is considered the initial therapy of choice for patients with localized H. pylori-positive gastric MALT and radiation is frequently used to treat other localized MALT or nodal MZL, there is no uniformly established therapy for patients with other presentations. Following the report on efficient control of MALT lymphomas with a single agent rituximab by Conconi et al. [3], starting October 2003 our lymphoma program decided to use this therapeutic regimen in all the newly diagnosed patients with chemoimmunotherapy naı̈ve MZL, who were older than 18 years of age, had biopsy-proven MZL according to the World Health Organization classification criteria, and were not eligible or refused to receive radiation therapy as a single modality therapy for stage I disease or splenectomy for splenic marginal zone lymphoma. Previous radiation therapy and antibiotics for Helicobacter pylori did not preclude use of rituximab. Until December 2005, when we changed our program guidelines, a total of 16 patients, representing all the patients with MZL eligible for this treatment based on our guidelines, were treated with rituximab and represent the basis of this report. Rituximab was administered weekly for four consecutive weeks at a dose of 375 mg/m by slow intravenous infusion following standard guidelines. Response to the therapy was evaluated 6 – 8 weeks after completion of the fourth dose of rituximab by standard criteria. In the case of gastric MALT lymphomas, endoscopies with biopsies from abnormally appearing mucosa or from at least four random normally appearing gastric mucosa sites were performed to assess the response to treatment. The primary end points of this report were overall response rate including complete response (CR) and partial response (PR) and time to treatment failure (TTF), defined as the time from initiation of rituximab therapy to disease progression, administration of additional therapy because of failure to achieve at least PR or death. The median age of the 16 treated patients (Table I) was 55 years (range 30 – 82). There were three patients with nodal MZL, one patient with splenic MZL, and 12 patients with extranodal MALT, including three with gastric and nine with nongastric presentation. All cases underwent central histologic review by an expert lymphoma pathologist confirming MZL diagnosis. Three patients received radiation therapy for localized disease at 2, 6, and 36 months prior to rituximab. Two of the three patients with gastric MALT lymphoma were H. pylori-positive but failed to respond to a course of antibiotic therapy.

Zidovudine-based lytic-inducing chemotherapy for Epstein - Barr virus-related lymphomas

Abstract Treatment of Epstein–Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDS-PCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT–methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT–hydroxyurea treatment resulted in dramatic responses in patients with AIDS-PCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas.

Autologous transplantation for relapsed non-Hodgkin's lymphoma using intravenous busulfan and cyclophosphamide as conditioning regimen: a single center experience

High-dose chemotherapy with autologous SCT has become standard of care for patients with relapsed aggressive non-Hodgkins lymphoma (NHL). To improve safety and efficacy of this treatment, new conditioning regimens are being developed. We retrospectively reviewed clinical data of patients with relapsed NHL treated at our institution with i.v. BU and CY (BU/CY) as conditioning regimen for autologous SCT between January 2000 and April 2005. We identified 43 patients (24 men, 19 women, median age 50) with diffuse large B-cell lymphoma (n=28), follicular lymphoma (n=8), mantle cell lymphoma (n=4) and peripheral T-cell lymphoma (n=3). Following salvage chemotherapy, there were 26 complete responses, 13 partial responses and 4 stable diseases. Median time to neutrophil and platelet recovery was 11 and 13.5 days, respectively. Treatment-related toxicities included nausea/vomiting, diarrhea and mucositis. The 100-day mortality was 9%: sepsis (n=1), pneumonia (n=1) and hepatic veno-occlusive disease (n=2). Twenty-one patients were followed until death and twenty-one surviving patients were followed for a median of 29 months (range 0.4–76). Three-year estimates of event-free survival, progression-free survival and overall survival were 35, 39 and 43%, respectively. We conclude that i.v. BU/CY is a safe and effective conditioning regimen for autologous SCT in relapsed NHL.

Azacitidine combined with gemtuzumab ozogamicin in patients with relapsed/refractory acute myeloid leukemia

Relapsed/refractory acute myeloid leukemia (AML) is associated with a poor prognosis and a median overall survival of less than 1 year [1]. Allogeneic hematopoietic stem cell transplant (HSCT) remains the standard of care in this setting. For those patients without available donors or with significant contraindications to transplant, therapeutic options are limited. Many of the chemotherapy regimens for relapsed/refractory AML are dose-intensive and cannot be easily applied in heavily pretreated patients. Azacitidine was demonstrated to significantly prolong survival over conventional care regimens in patients with intermediate-2/high-risk myelodysplastic syndrome and in elderly patients with AML, in two phase III trials [2,3]. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin that showed promising results in elderly patients with relapsed AML [4]. Recently, its commercial marketing was voluntarily discontinued in the USA after the post-approval trial (S0106) failed to demonstrate any improvement in response rates when GO was added to standard induction therapy in previously untreated patients with de novo non-M3 AML [5]. Azacitidine and GO have acceptable tolerability profiles and non-cross-resistant mechanisms of action, rendering their combination a viable option in heavily pretreated patients with AML. Furthermore, an overall response rate of 70% was reported in previously untreated elderly patients with AML treated with the combination of azacitidine and GO [6]. Following presentation of the preliminary results of this trial [7], a number of patients with relapsed or refractory AML have been treated with azacitidine followed by GO in our institution as a bridge to HSCT or to improve survival while preserving patients’ quality of life. After approval by our institutional review board, we identified eight patients with relapsed/refractory AML who were treated with the azacitidine–GO combination between 2005 and 2009 at Jackson Memorial Hospital and Sylvester Comprehensive Cancer Center through the institutional tumor registry and medical record searches. All patients were documented to have CD33þ AML by flow cytometry on peripheral blood or bone marrow aspirate. All patients received the institutionally standardized azacitidine–GO regimen that included azacitidine 75 mg/m intravenously or subcutaneously on days 1–7 and GO 3 mg/m on day 8. The rest period between cycles was at the discretion of the treating physician and varied between 2 and 8 weeks. Complete remission (CR) was defined as (i) absence of blasts in the peripheral blood, (ii) normal marrow with 5% blasts, (iii) neutrophil count of 41.06 10/L, and (iv) platelet count of 41006 10/L. Patients who met all CR criteria but for whom a repeat bone marrow biopsy was not performed after azacitidine–GO therapy were defined to have a clinical response. Toxicity data were gathered from physician notes according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

High-dose glucocorticoids improve renal failure reversibility in patients with newly diagnosed multiple myeloma.

One-fifth of the newly diagnosed multiple myeloma (MM) patients present with renal failure (RF) [1-3]. Glucocorticoids (GCs) may improve RF in MM by (1) rapid reduction of paraprotein production, (2) lessening inflammation and fibrosis in renal parenchyma, and (3) decreasing serum calcium level. We hypothesized that lower dose GCs may be less effective in restoring renal function and retrospectively compared the RF reversibility between the newly diagnosed MM patients who were treated with GCs equivalent to ≥160 mg DX over 4 days (high-dose GC group, n = 16) versus those who were treated with <160 mg (low-dose/no GC group, n = 8). There was no difference in age, baseline calcium, and creatinine levels between the two groups. Renal function was restored in seven patients in the high-dose GC group (44%) and in none of the patients in the low-dose/no GC group (P = 0.026). The only other factor found to impact the RF reversibility was the delay of GC initiation. Four and 1 patients developed a severe infection in the high- and low-dose/no GC groups, respectively. The use of higher dose GCs in the newly diagnosed MM patients who present with RF increases the likelihood of renal function restoration.

Comparison of Cancer Care and Outcomes between a Public Safety- Net Hospital and a Private Cancer Center

We compared the cancer outcomes and care-associated service defects between Jackson Memorial Hospital (ABC), a large public safety-net hospital, and Sylvester Comprehensive Cancer Center (XYZ), a private not-for-profit cancer center in patients with stage II–III colorectal cancer (CC) who received adjuvant chemotherapy (AC) and in patients with diffuse large B cell lymphoma (DLBCL). Colorectal cancer patients treated at ABC were more likely to have undergone urgent surgery. While in the CC cohort, three-year overall survival and relapse-free survival rates were significantly higher among patients treated at XYZ compared with those treated at ABC, there was no significant difference between patients treated for DLBCL in the two hospitals. Colorectal cancer patients treated at ABC were more likely to have undergone urgent surgery, to have delays before surgery or during chemotherapy, and to experience a system/patient-related service defect; whereas were less likely to complete a full course of AC.

Impact of Cytomegalovirus Viral Load on Probability of Spontaneous Clearance and Response to Preemptive Therapy in Allogeneic Stem Cell Transplantation Recipients

The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150 IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV <350 IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P = .02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV <350 IU/mL and those who started at CMV >350 IU/mL (44% versus 57%; P = .42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P = .001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P = .02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P <.0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150 IU/mL is associated with a >80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350 IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.