Meletios A. Dimopoulos

Magnetic resonance imaging in the staging of solitary plasmacytoma of bone.

PURPOSE To assess prospectively the role of magnetic resonance (MR) imaging in the staging of patients with a solitary bone plasmacytoma (SBP). PATIENTS AND METHODS Twelve consecutive patients with an apparent SBP underwent MR imaging of both the primary tumor and the thoracic and lumbosacral spine to seek additional foci of marrow involvement that might have been undetected by standard skeletal survey. All patients received megavoltage irradiation (total dose, 40 Gy) to the primary lesion. RESULTS MR imaging of the thoracic and lumbosacral spine showed additional foci of marrow replacement in four of 12 patients, with signal characteristics identical to those of the primary tumor. In all four patients, the abnormal protein persisted at greater than 50% of the pretreatment value following radiation treatment. In contrast, the myeloma protein disappeared or was reduced by greater than 50% in five of the six patients with secretory disease and without additional marrow abnormalities. One of four patients progressed to multiple myeloma 10 months after diagnosis with new lesions on conventional radiographs in the same areas as detected previously by MR imaging. CONCLUSION Four of 12 patients considered to have a SBP by standard criteria may have been understaged, because MR imaging showed additional marrow abnormalities consistent with myeloma. MR imaging of the spine may contribute to the initial staging of SBP, especially since some patients may be cured with radiotherapy.

Impact of complete remission with intensive therapy in patients with responsive multiple myeloma

Clinical outcomes were assessed in 68 consecutive patients with multiple myeloma of high or intermediate tumor mass that had responded to VAD or dexamethasone-based therapy and were consolidated with early intensive therapy and autologous stem cell transplantation. Results were compared with those of 50 comparable patients who refused or were unable to receive intensive treatment for socioeconomic reasons. Following high-dose therapy, the rate of CR increased from 6 to 37%, with median survival prolonged by 10 months. Survival of 21 patients with disease converted from PR to CR (median 8.3 years) was significantly longer than that of similarly-treated patients who remained in PR (median 5.0 years). CR of myeloma represents the major surrogate marker of long survival and the primary goal of myeloablative treatment for patients in PR. Twelve of 18 patients with rapid reduction of myeloma protein (T½ < 0.5 months), and myeloma protein reduction to <1.0 g/dl after primary therapy achieved CR (67%), identifying pretransplant features favorable to intensive therapy. Among 35 patients with slower reduction or higher residual myeloma protein, CR occurred in eight patients (23%) (P < 0.01), for whom other treatments should be considered. The kinetics of response to initial therapy should be considered in selecting patients more likely to achieve CR and consequent long survival after intensive treatment. Bone Marrow Transplantation (2001) 27, 1037–1043.

Primary plasma cell leukaemia

Summary. Among 750 previously untreated patients with multiple myeloma, 27 (4%) presented with plasma cell leukaemia. All but one patient had high tumour mass and, when compared with comparable patients without leukaemia, more frequent extraosseous involvement, thrombocytopenia, high serum lactate dehydrogenase and hypodiploid plasma cells. Most patients also had complex cytogenetic abnormalities. Treatment with standard melphalan‐prednisone was ineffective, with a median survival of 2 months, but more intensive chemotherapy induced responses in approximately one‐half of the patients, with a median survival of 20 months. Primary plasma cell leukaemia usually results from the proliferation and extramedullary expansion of immature plasma cells and requires prompt and intensive chemotherapy.

Prognostic value of cytogenetics in multiple myeloma

Karyotypic studies of bone marrow were conducted in 79 previously untreated patients with multiple myeloma who received a standard programme of chemotherapy. An abnormal karyotype was observed in 46% of patients, virtually all showing multiple abnormalities consistent with a long period of preclinical clonal evolution. Patients with an abnormal pattern showed various aberrations with hyperdiploidy in 64%, pseudodiploidy in 5% and hypodiploidy in 31%. The number of chromosomes affected ranged from two to 19 (median 10), with at least one trisomy in 83%, one monosomy in 75%, and one translocation in 42% of patients. Lymphoma‐like karyotypes were present in 17% of patients with an abnormality but were not associated with atypical clinical features, such as an extramedullary mass, leukaemia, or increased serum lactate dehydrogenase. Monosomy or deletion of chromosome 13 was present in 47% of patients with an abnormal pattern, who lived for a shorter duration (median 10 months) than patients with other abnormalities (median 34 months) or with diploidy (median 35 months). The cause of the short survival of patients with monosomy or deletion of chromosome 13 was not clear, but further studies on the relationship with specific oncogenes are indicated.

Primary therapy of Waldenström's macroglobulinemia with 2-chlorodeoxyadenosine.

PURPOSE To assess the activity of 2-chlorodeoxyadenosine (2CdA) as primary therapy for patients with Waldenströms macroglobulinemia. PATIENTS AND METHODS 2CdA was given to 26 consecutive, previously untreated and symptomatic patients with Waldenströms macroglobulinemia. Two courses were administered to outpatients at a dose of 0.1 mg/kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Responding patients were followed up without further therapy and were scheduled to receive two additional treatments with 2CdA on disease relapse. RESULTS Twenty-two of 26 patients responded to the 2CdA therapy (85%; 95% confidence interval [CI], 65% to 96%), including three patients who achieved a complete response and 19 patients who had a partial response. Treatment was well tolerated, with no acute hematologic toxicity. A marked and sustained reduction of CD4+ lymphocytes occurred in all patients and may have contributed to a fatal infection with disseminated herpes simplex in one patient. With a median follow-up of 13 months, five patients have relapsed and all re-treated patients have responded again to 2CdA. CONCLUSION 2CdA is highly active in previously untreated patients with Waldenströms macroglobulinemia. A limited program of treatment induced responses of good quality and long duration in more than 80% of patients.

Regression of gastric lymphoma of mucosa-associated lymphoid tissue with antibiotic therapy for Helicobacter pylori

Regression of low-grade B cell gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylori with antibiotic therapy was recently shown in a small number of patients with low-volume tumors. A patient with a > 10 cm nodular gastric mucosa-associated lymphoid tissue lymphoma that caused hematemesis and weight loss is described. Antibiotic therapy of H. pylori resulted in full clinical recovery and resolution of the mass lesion and morphological features of lymphoma on routine histological examination. However, monotypic immunostaining of plasma cells persisted in a separate and grossly normal-appearing region of the stomach. Antibiotic therapy may be of benefit in patients with mucosa-associated lymphoid tissue lymphoma with mass lesions and significant signs and symptoms, but periodic search for residual lymphoma is needed.

Fludarabine therapy in Waldenström's macroglobulinemia

PURPOSE To assess the response rate, remission duration, and survival of patients with Waldenströms macroglobulinemia treated with the adenine nucleoside analogue fludarabine. PATIENTS AND METHODS Twenty-eight patients with Waldenströms macroglobulinemia, of whom only 2 were previously untreated, received fludarabine at a dose of 20 to 30 mg/m2 intravenously daily for 5 days (20 patients) or 30 mg/m2 intravenously daily for 3 days (8 patients). Treatment was continued until maximum response was achieved. Responding patients were followed with no further treatment until relapse. RESULTS Ten patients responded (36%), including the 2 previously untreated patients and 8 of 26 patients (31%) who were resistant to prior therapies. Unmaintained remissions lasted for a median of 38 months. There were no fatalities associated with this treatment. Previously untreated patients and those with a primary resistant disease of relatively short duration were more likely to benefit from this treatment. CONCLUSION Fludarabine is an effective salvage agent for the treatment of patients with resistant Waldenströms macroglobulinemia. Further investigations of fludarabine in untreated patients and in combination with other active agents are warranted.

Treatment of Waldenstrom macroglobulinemia with 2-chlorodeoxyadenosine

Waldenstrom macroglobulinemia is a low-grade lymphoid malignancy composed of mature plasmacytoid lymphocytes that produce a monoclonal IgM. The disease usually affects older persons and may produce anemia, lymphadenopathy, elevated serum viscosity, or a combination of these [1]. Chemotherapy with alkylating agent-steroid combinations has induced responses in approximately 50% of previously untreated patients, with a subsequent median survival of about 5 years [1-3]. Fludarabine monophosphate, a nucleoside analog with antitumor efficacy in chronic lymphocytic leukemia and indolent lymphoma, has induced responses in 40% of patients with macroglobulinemic lymphoma who were resistant to standard therapies [4]. 2-Chlorodeoxyadenosine (2CdA), a deoxyadenosine analog that is phosphorylated by deoxycytidine kinase, accumulates as chlorodeoxyadenosine triphosphate (chlorodATP) in cells rich in deoxycytidine kinase [5]. ChlorodATP inhibits enzymes important in DNA repair, leading to DNA strand breaks that may accelerate the process of programmed cell death (apoptosis) [6]. 2-Chlorodeoxyadenosine has been effective in several lymphoid malignancies, the most striking results being in patients with hairy cell leukemia in whom prolonged remissions have occurred after one course of therapy [7, 8]. We evaluated the activity of this compound in patients with Waldenstrom macroglobulinemia, a disorder immunophenotypically similar to hairy cell leukemia [9]. A marked cytoreductive effect was achieved in all newly diagnosed patients and in many patients with resistant disease, with little toxicity. The high frequency of response provides an opportunity for the study of a sequence of effective regimens in patients with Waldenstrom macroglobulinemia and other low-grade lymphatic malignancies. Methods Between January 1991 and February 1992, 29 symptomatic patients with Waldenstrom macroglobulinemia were treated with 2CdA (R. W. Johnson Pharmaceutical Company, Raritan, New Jersey) after informed consent was obtained according to institutional guidelines. The primary reasons for treatment were symptoms from worsening anemia (nine patients); weight loss, night sweats, or fever (six patients); hyperviscosity syndrome (five patients); lymphadenopathy (three patients); palpable purpura and arthralgias due to cryoglobulinemia (two patients); hypercalcemia (two patients); cold agglutinin-induced hemolysis (one patient); and severe peripheral neuropathy (one patient) (Table 1). The median age was 65 years (range, 41 to 80 years), and 19 were men. Among the 20 previously treated patients, 9 had not responded to any previous regimen (primary refractory), 7 patients were relapsing despite chemotherapy (refractory relapse), and 4 patients were relapsing while followed without treatment. The median duration from initial treatment was 9 months for patients with primary refractory disease, and 40 months for patients with relapsing disease. All patients had baseline evaluations that included blood counts, hepatic and renal function tests, bone marrow aspirate and biopsy, immunophenotyping, quantitation of CD4+ and CD8+ lymphocytes, serum and urine protein electrophoreses, and quantitation of serum immunoglobulins. Computed tomography of the abdomen and the pelvis was also done when clinically indicated. Blood counts were repeated weekly, serum electrophoretic studies and quantitation of blood lymphocyte subgroups were repeated monthly, and complete restaging was done after completion of 2CdA therapy. Table 1. Patient Characteristics 2-Chlorodeoxyadenosine was administered to outpatients at a dose of 0.1 mg/kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Two courses of 2CdA were given 4 weeks apart, before removal of the central venous catheter. No further therapy was given during follow-up. Response criteria were similar to those used in evaluating patients with multiple myeloma and in previously published studies of Waldenstrom macroglobulinemia [1, 2, 10]. Response was defined as a sustained decrease by at least 50% of monoclonal IgM synthesis for at least 2 months with more than a 50% reduction of tumor infiltrate at all involved sites. Complete response was defined as disappearance of the abnormal protein by immunofixation, resolution of lymphadenopathy and splenomegaly, and less than 20% lymphocytes in the bone marrow. Results Response Rate Of 29 patients, 18 had a meaningful tumor reduction defined as a 50% reduction of IgM synthesis. One patient achieved a 95% reduction of tumor mass but died on day 70 with pancytopenia and aspergillus pneumonia, and the death was classified as a toxic death. Thus, 17 of 29 patients responded to treatment (59%) (95% CI, 39% to 76%), of whom 1 patient achieved a complete response. All responding patients had rapid relief from the symptoms due to the disease, including the one patient each with cryoglobulinemia and peripheral neuropathy. Remission was induced in all previously untreated patients and in three of four patients relapsing without therapy (Table 2). Among nine patients with primary refractory disease, seven were treated with 2CdA within 12 months of diagnosis, and four patients responded; neither of the two patients with primary resistance for more than 12 months responded. Remissions were achieved in one of seven patients with refractory relapse (Table 2) and in one of four patients resistant to fludarabine monophosphate. Table 2. Response by Disease Status The median time for a 50% reduction of IgM synthesis in previously untreated patients was 1.0 month (range, 0.2 to 2.0 months) (Figure 1). The kinetics of IgM reduction for the nine previously treated patients who responded was identical (median time for 50% reduction, 1.2 months; range, 0.8 to 2.0 months). Even after 2CdA therapy was stopped, gradual reduction of abnormal protein continued in all responding patients along with disease reduction at all involved sites (see Figure 1). Thus, among patients with more than 25% infiltration, bone marrow lymphocytosis was reduced by at least 50% in all 10 responding patients but in only 1 of 5 unresponsive patients (Figure 2). Hemoglobin values of less than 100 g/L increased by at least 20 g/L in 10 of 11 responding patients but did not increase in any of the 8 unresponsive patients (Figure 2). Lymphadenopathy resolved in three of six responding patients and was reduced by more than 50% in the remaining three patients. Figure 1. Immunoglobulin M synthesis with 2-chlorodeoxyadenosine treatment in the nine previously untreated patients. Figure 2. Marrow lymphocytes and hemoglobin levels in patients before and after treatment with 2-chlorodeoxyadenosine. Left. closed circles open circles Right. closed circles open circles With a median follow-up of 7 months (range, 2 to 16 months), one patient has had a relapse after 9 months, and the earliest treated patient remains in remission after 16 months. One patient died in remission of metastatic adenocarcinoma of unknown origin, and two patients died of resistant macroglobulinemia. Toxicity Treatment was well tolerated without serious drug-associated toxicity in all but one patient who was severely pancytopenic before and after 2CdA treatment and died on day 70 with aspergillus pneumonia. Among all patients, the median lowest neutrophil count was 1.5 106/L (range, 0.1 to 5.5 106/L), and the median lowest platelet count was 170 106/L (range, 8 to 331 106/L). The second course of treatment was administered without delay 4 weeks later in 25 patients; in 3 patients, the second course was delayed 1 to 3 weeks and was omitted in 1 patient because of thrombocytopenia that had preceded 2CdA. Four patients required platelet transfusions, three patients developed bronchitis that responded to antibiotics, and two patients developed herpes zoster. A marked decrease in the number of lymphocytes expressing CD4 surface antigen (helper phenotype) occurred in all patients (median, 541 103/L reduced to 117 103/L) (P < 0.01) with slight decrease in lymphocytes expressing the CD8 surface antigen (suppressor phenotype) (median, 343 103/L reduced to 208 103/L) (P = 0.04). With the longest follow-up of 16 months, no recovery of either class of lymphocytes has occurred. No life-threatening opportunistic infections were associated with the marked and prolonged decline of CD4+ lymphocytes. Discussion For many years, a combination of an alkylating agent and a glucocorticoid has been considered the standard therapy for patients with Waldenstrom macroglobulinemia, inducing a response in about one half of previously untreated patients [1-3]. Intermittent courses have usually been administered for long periods and have exposed patients to the risk for complications from pancytopenia and rare occurrences of secondary leukemia [11]. There have been limited trials of other treatments, including doxorubicin [12], high-dose steroids [13], -or -interferon [14, 15], and deoxycoformycin [16], with occasional benefits reported. Fludarabine has induced responses in 40% of patients who had been resistant to previous treatments, a frequency similar to its activity in chronic lymphocytic leukemia [4]. We report a high frequency of response with 2CdA in Waldenstrom macroglobulinemia, primarily among newly diagnosed patients and those resistant for less than 12 months to previous chemotherapy with standard drugs. Responses were usually rapid in onset and continued even after the completion of treatment. Longer follow-up is needed to define any meaningful gain in remission duration and survival, especially because this disease has a long clinical course. Our positive results after only two courses of treatment that were free of serious toxicity support a major role for 2CdA in the treatment of patients with Waldenstrom macroglobulinemia. Despite our promising results, however, randomized, comparative trials are needed to confirm that 2CdA is th

Testicular lymphoma: late relapses and poor outcome despite doxorubicin-based therapy.

PURPOSE To determine the significance of the International Prognostic Index (IPI) score in adults with testicular lymphoma treated with doxorubicin-based regimens. PATIENTS AND METHODS Untreated adults with testicular lymphoma who presented between 1969 and 1993 were studied. Those with Ann Arbor stages III and IV were included if they had a testicular mass at presentation. RESULTS We identified 22 patients, 21 with intermediate-grade and one with high-grade lymphoma. All 10 patients with an IPI score < or = 1 had Ann Arbor stage I disease, whereas the 12 with an IPI score more than 1 had Ann Arbor stage II to IV disease. Complete remission (CR) was achieved in 73% of patients. At 153 months, 22% of all complete responders and 40% and 0% of those with IPI scores < or = 1 and more than 1, respectively, remained in CR (P = .01). With a median follow-up time of 113 months for survivors, the failure-free survival (FFS) rate at 153 months was 16% for all patients or 32% and 0% for those with IPI scores < or = 1 and more than 1, respectively (P = .02). The CNS or contralateral testis were involved in all patients who failed to respond to primary therapy and in 50% of those who relapsed from CR. CONCLUSION The prognosis of patients with testicular lymphoma appears poor despite doxorubicin-based chemotherapy. On the basis of failures in the CNS and contralateral testis, we recommend prophylactic intrathecal chemotherapy and scrotal radiotherapy for all patients. Those with an IPI score < or = 1 can be treated with conventional doxorubicin-based regimens, but those with an IPI score more than 1 should be considered for investigational systemic therapy.

Paraneoplastic Cushing's syndrome as an adverse prognostic factor in patients who die early with small cell lung cancer

The potential role of paraneoplastic Cushings syndrome (CS) was assessed on the clinical course of patients with small cell lung cancer. A retrospective comparison was done of complication and survival rates according to the presence or absence of CS in patients with small cell lung cancer who died within 90 days of initial administration of chemotherapy. The setting was a comprehensive cancer center. Eleven patients with clinical and/or biochemical features of CS were identified from among 90 patients who presented between 1979 and 1989 with previously untreated small cell lung cancer. The group with CS and the control patients were compared in terms of clinicopathologic prognostic factors, treatment, and outcome. Patients with CS were comparable to the control patients in all prognostic factors, including tumor stage and cancer treatment. Eight‐two percent of patients with CS (nine of 11) died within 14 days of initiation of chemotherapy compared with 25% of the control patients (19 of 77). The median survival from initiation of chemotherapy was 12 days for the 11 patients with CS and 27 days for the 77 control patients. In 45% of the patients with CS (five of 11), death was attributed to opportunistic fungal or protozoal infection compared with 8% of control patients (six of 77). paraneoplastic CS is a previously unrecognized adverse prognostic factor for patients with small cell lung cancer. Those with both small cell lung cancer and CS have severe opportunistic infections soon after the initiation of chemotherapy, leading to clinical deterioration and death before antineoplastic benefit from chemotherapy can be achieved. Biochemical control of CS for at least 1 to 2 weeks before initiation of chemotherapy may ameliorate the poor prognosis.