Carl Richard Meier

Randomized comparison of interferon α and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon α and hydroxyurea

The optimum treatment conditions of interferon (IFN) α therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.

Melphalan and Prednisone (MP) versus Vincristine, BCNU, Adriamycin, Melphalan and Dexamethasone (VBAM Dex) Induction Chemotherapy and Interferon Maintenance Treatment in Multiple Myeloma

277 untreated multiple myeloma patients of stage 1 (n = 33), II (n = 106) and III (n = 138) entered the study. Patients of stage II presenting a progressive tumor (n = 64) initially or during observation (n = 14) were treated with MivP (remissions: 61%). 138 patients of stage III were randomized to receive MivP or VBAMDex treatment. 51% of MivP treated patients responded versus 70% of the VBAMDex group. 71 responders of stage II and III with stable disease were randomized on Ifn-alpha maintenance versus no maintenance treatment. The relapse rate in both groups was 50% after 7 months. 75% survival was greater than 36 months in stage II and 11 months in stage III patients.

Primary Cardiac Lymphoma Mimicking Left Atrial Myxoma in an Immunocompetent Patient

A 52-year-old obese Hispanic woman presented in March 2005 with a 1-week history of dizziness, leg swelling, orthopnea, exertional dyspnea, and nonradiating pain in the upper back. In the prior 2 months she also had paroxysmal cough and a 7-kg weight loss, but no fever, chills, or night sweats. She had type 2 diabetes, hypertension, and was status postangioplasty for renal artery aneurysm. She had bilateral jugular venous pulsation and basilar crackles, irregularly irregular rate and rhythm, 2 of 6 intensity systolic ejection murmur at the left sternal border, and trace edema of lower extremities. Notable laboratory values included hemoglobin of 9.3/dL, creatinine of 1.3 mg/dL, and erythrocyte sedimentation rate of 117 mm/h. Normal results included those for cardiac enzymes and HIV serology. Outside transthoracic echocardiography, confirmed after referral for resection, showed a left atrial mass of 7 3 cm that prolapsed intermittently through the mitral valve causing mitral regurgitation (Fig 1). Left ventricular systolic function was adequate. Chest x-ray showed cardiomegaly and mild pulmonary edema. ECG showed atrial fibrillation and lateral lead ST depression. Cardiac catheterization showed coronary artery stenoses up to 90% (of left anterior descending artery) and tumor blood supply from an atrial branch of the circumflex artery. Preoperative diagnosis was left atrial myxoma. Intraoperatively, the tumor was found friable, widely attached to the atrial septum and to the roof of the left atrium laterally to the superior vena cava juncture. A smaller tumor was between trabeculae and in the right lower pulmonary vein. Both were resected, preceded by two-vessel coronary artery bypass graft. The resected mass consisted of several fragments of soft tanbrown tissue (the largest one was 7 6 3.5 cm), together measuring up to 8 cm (Fig 2). On microscopy, fringes of tumor infiltrated adjacent cardiac muscle and other portions were necrotic. Tumor cells were intermediate to large transformed (noncleaved) lymphocytes, many exhibiting a plasmacytoid morphology with round nuclei and eosinophilic cytoplasm; other cells had nuclei with folded or irregular borders (Fig 2). On paraffin immunoperoxidase stains, tumor cells were CD20 coexpressing CD5, BCL-6, BCL-2, and up to 90% MIB-1 (Ki67). They were negative for CD10, EBER, CD23, cyclin D1, HHV8, CD43, CD2, CD138, CD56, immunoglobulin G (IgG), IgA, IgM, and light chains. The final diagnosis was diffuse large B-cell lymphoma. The postoperative course was complicated by cardiac and renal failure requiring transient ventilatory support, and hemodialysis. Obtundation and divergent gaze on day 13 was explained by magnetic resonance imaging, showing multiple small embolic infarctions. CSF cell count was normal and cytology was negative for malignancy. The patient received anticoagulants, recovered neurologically, and spontaneously converted to sinus rhythm on postoperative day 39. Computed tomography imaging showed lymph nodes of up to 1.5 cm in the aortocaval, right iliac, and left inguinal area. Bilateral bone marrow biopsies and aspirate were negative, including cytogenetic and flow cytometry immunophenotyping studies. On day 30 after surgery, cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab chemotherapy was started. After five cycles, it was terminated because of symptoms of undue fatigue. Work-up revealed occlusion of the internal mammary bypass graft to the left anterior descending artery. Transthoracic echocardiography was negative. Computed tomography restaging showed remission of subdiaphragmal lymphadenopathy. Reimaging in March 2007 confirmed complete remission. The patient is currently well 26 months after resection, and 23 months after last chemotherapy. Primary tumors of the heart are rare and 75% are benign. About half of these are solitary myxomas, usually involving the left atrium. Disseminated cancers and lymphomas rarely involve the heart, and usually have no cardiac symptoms. In contrast, primary cardiac non-Hodgkin’s lymphomas (PCLs) involve heart and/or

Randomized Trial of Single Compared With Tandem High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantation in Patients With Chemotherapy-Sensitive Metastatic Breast Cancer

PURPOSE To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients. PATIENTS AND METHODS Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation. RESULTS One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival. CONCLUSION Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.

Weekly Vinorelbine versus Docetaxel for Metastatic Breast Cancer after Failing Anthracycline Treatment

Background: Vinorelbine and docetaxel are active in anthracycline-pretreated, metastatic breast cancer. We compared their efficacy. Patients and Methods: Patients were randomized to receive weekly vinorelbine (VIN) or weekly docetaxel (DOC), 6 weekly doses per 8-week cycle, with optional crossover (X-DOC vs. X-VIN. The primary end point was time to progression (TTP) on initial treatment. Remission induction, survival, and quality of life were secondary end points. Results: Among 122 poor risk patients, a non-significant trend for better TTP was seen for DOC, both on initial and on crossover treatment. Responses were seen on either treatment, but progression was more common with VIN than with DOC, while more patients had a response with X-DOC than with X-VIN. Survival was identical in those receiving only the initial VIN vs. DOC and in the subgroups receiving crossover treatments. Grade 3–4 toxicity, especially hematological toxicity resulting in treatment delay, was more common with VIN. Non-graded toxicity contributed to abandoning DOC. Quality of life scores reflected worse results in patients crossing treatment arms, in either direction. Conclusions: DOC showed marginally better activity but did not improve TTP or other endpoints over VIN in this poor risk population.