Pierre Noel

Plasma cell leukemia: An evaluation of response to therapy

Forty-three patients with plasma cell leukemia were seen at the Mayo Clinic. Twenty-five (58 percent) had primary plasma cell leukemia (diagnosis first made in the leukemic phase) and 18 (42 percent) had secondary plasma cell leukemia (leukemic transformation of a previously diagnosed multiple myeloma). Patients with secondary plasma cell leukemia were older, had a greater incidence of lytic bone lesions, had a lower platelet count, and had a larger M-protein in the serum than did patients with primary plasma cell leukemia. The median survival was 6.8 months for patients with primary plasma cell leukemia and 1.3 months for patients with secondary plasma cell leukemia. In patients with primary plasma cell leukemia, multiple alkylating agents produced a higher response rate than did melphalan, but the median time from treatment to progression or death was not significantly improved with such therapy. Review of the literature also suggests that the response rate is higher with combination chemotherapy than with single alkylating agents. Patients with secondary plasma cell leukemia usually show resistance to any type of chemotherapy and have a short survival.

Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenström's macroglobulinemia.

PURPOSE To determine the natural history of amyloidosis associated with Waldenströms macroglobulinemia and immunoglobulin M (IgM) monoclonal gammopathy. PATIENTS AND METHODS From January 1968 to September 1990, 50 patients with a serum IgM monoclonal protein and biopsy-proven amyloidosis were evaluated at the Mayo Clinic. There were 32 men and 18 women (age range, 43 to 93 years). RESULTS Percentages of patients presenting with cardiac, renal, hepatic, and pulmonary amyloid were 44%, 32%, 14%, and 10%, respectively. Forty-two percent of the patients had an M protein value greater than 1.5 g/dL, and 12% had an M component greater than 3 g/dL. Subcutaneous fat, rectum, and bone marrow showed amyloid in 84%, 72%, and 50%, respectively, providing a simple technique for diagnosing amyloidosis. The bone marrow biopsy was consistent with Waldenströms macroglobulinemia in 10, a plasma-cell proliferative disorder in 10, and lymphoma or a lymphoproliferative disorder in 11; results were normal, nondiagnostic, or hypercellular in 17. Forty-three of 50 patients died. The median survival of the entire group was 24.6 months. Fifty-three percent of deaths were due to cardiac amyloid, 12% to respiratory failure, 7% to macroglobulinemia, 7% to liver failure, and 7% to kidney failure. CONCLUSION The presence of amyloid cardiomyopathy and an increased creatinine concentration at diagnosis had an adverse impact on survival. Of the 22 patients who presented with cardiomyopathy, the median survival was 11.1 months, with only two surviving longer than 5 years. The median survival of the 28 patients without cardiomyopathy at diagnosis was 27 months, with eight 5-year survivors (P = .013). All eight amyloid deposits studied stained for Ig light chain, indicating that this amyloidosis is of the primary (AL) type.

Incidence of Chronic Lymphocytic Leukemia in Olmsted County, Minnesota, 1935 Through 1989, With Emphasis on Changes in Initial Stage at Diagnosis

Objective To determine whether the stage at the time of diagnosis of chronic lymphocytic leukemia (CLL) had changed during a 55-year period. Design We conducted a study of the cohort of residents of Olmsted County, Minnesota, who had been diagnosed as having CLL during the period from 1935 through 1989. Material and Methods By analysis of medical records, patients with CLL were characterized by Rai stage, absolute lymphocyte count, age at diagnosis, need for therapy, and reported cause of death in nonsurvivors. Trends for these variables were analyzed by decade throughout the study period. Results The overall annual incidence rate of CLL per 100,000 population in Olmsted County increased from 2.6 in the 1935 through 1944 period to 5.4 in the 1975 through 1984 period; however, the increasing rate was found only for those 50 years of age or older and was especially dramatic for those 75 years old or older. Analysis of Rai stage over time demonstrated an increase in the proportion of cases diagnosed as Rai stage 0. In addition, the median absolute lymphocyte count decreased, the median time to initiation of therapy increased, and the median age of patients with Rai stage 0 CLL at the time of diagnosis increased over time. Overall, 54% of patients had received therapy for CLL by the time of last follow-up. Among the nonsurvivors, CLL was documented as the underlying or a contributing cause of death in 69%. Conclusion The overall increase in CLL was thought to be due to enhanced methods of early diagnosis and improved health care for the elderly population. Thus, artifact may best explain the observed trend, although we cannot exclude the possibility of an actual increase in incidence rates over time.

Myelodysplastic syndromes: Pathogenesis, diagnosis and treatment

Our understanding of the biology of leukemia and myelodysplasia is still only partial. The diagnosis of myelodysplasia is often based on quantitative and qualitative findings in the peripheral blood and bone marrow. These findings are often shared by other disorders. There is a need for sensitive and inexpensive laboratory tests to determine clonality and karyotypic abnormalities in this disorder. Future classifications of these syndromes will need to be based on morphologic and biologic markers that are closely linked to disease progression, response to treatment, and survival. Our limited understanding of the pathogenesis of MDS decreases the specificity and effectiveness of our therapeutic interventions. Agents that are minimally toxic such as CRA, danazol, 1,25-dihydroxyvitamin D3, androgens, and pyridoxine are seldom useful. Antileukemic therapy and allogeneic bone marrow transplantation have a major role to play in patients younger than 45 years of age; in older patients these treatment modalities remain controversial because of their toxicity. Hematopoietic growth factors, used alone or in combination, may improve the quality of life and improve survival of patients with MDS. Growth factors may also decrease treatment-related mortality associated with chemotherapy and bone marrow transplantation and render these treatment modalities available for a higher percentage of patients. The development of more specific differentiating agents may permit hematopoietic differentiation while minimizing side effects.

Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion

Systemic mastocytosis with an associated hematologic non-mast cell lineage disease is a rare subtype of systemic mastocytosis. This study describes a patient with systemic mastocytosis associated with chronic basophilic leukemia and a PRKG2-PDGFRB fusion gene. This patient had a complete response to imatinib mesylate. See related perspective on page 6. Background Translocations involving region 5q31-32 (PDGFRB) have been reported in a variety of myeloproliferative diseases and are often associated with significant peripheral eosinophilia. We report an unusual case of a patient presenting with peripheral basophilia and systemic mastocytosis in whom cytogenetic analysis revealed a t(4;5)(q21.1;q31.3). Design and Methods We used molecular analyses to determine the role of PDGFRB in this case. The patient was treated with imatinib. Results Fluorescence in situ hybridization (FISH) documented a breakpoint in PDGFRB. In agreement with this, the patient responded very well to imatinib with resolution of clinical symptoms, basophilia, and mast cell disease. Molecular analyses revealed that PDGFRB, encoding an imatinib-sensitive tyrosine kinase, was fused to PRKG2. The fusion gene incorporates the first two exons of PRKG2 fused to the truncated exon 12 of PDGFRB, resulting in the disruption of its juxtamembrane domain. Functional studies confirmed that the activity and transforming properties of PRKG2-PDGFRβ were dependent on the disruption of the auto-inhibitory juxtamembrane domain. Conclusions Our results identify a second case of the PRKG2-PDGFRB fusion and confirm the unusual PDGFRB breakpoint associated with this fusion. This work also illustrates the use of imatinib for the treatment of specific cases of systemic mastocytosis.

Long-term results of laparoscopic splenectomy for immune thrombocytopenic purpura

OBJECTIVE To assess the results of laparoscopic splenectomy as a treatment for immune thrombocytopenic purpura (ITP). MATERIAL AND METHODS We conducted a retrospective study of all patients who underwent laparoscopic splenectomy for ITP at our institution between August 1992 and May 1997. RESULTS Of 27 patients who underwent attempted laparoscopic splenectomy for ITP at our institution during the study period, 26 had completion of the procedure without conversion to an open splenectomy. The median postoperative hospital stay was 1.5 days, and no postoperative deaths occurred. In one patient, pancreatitis developed postoperatively. In four patients, splenectomy failed--two initially and two subsequently--and reinstitution of medical therapy was necessary. The other patients have remained free of medication, and 19 patients have platelet counts greater than 100 x 10(9)/L. The 3-year actuarial success rate was 81.5%. Response to corticosteroid therapy preoperatively may be an indicator of success of splenectomy. CONCLUSION Laparoscopic splenectomy is safe and allows prompt recovery. Long-term response rates are similar to those achieved with open splenectomy.

Chromosome Abnormalities in Malignant Hematologic Disorders

Certain chromosome abnormalities have been detected in routine cytogenetic studies of patients with hematologic disorders. This article is a cytogenetic and clinical review of 28 structural and 15 numeric chromosome abnormalities. As a group, the structural abnormalities involved 40 different chromosome breakpoints and included 13 types of translocations, 8 deletions, 3 isochromosomes, 3 inversions, and 1 duplication. The numeric abnormalities included 4 types of monosomy, 10 trisomies, and a near-haploid category. We determined the relative frequency for each of these anomalies in our practice by reviewing the results of 1,228 consecutive specimens studied between 1979 and 1984 in which a chromosomally abnormal clone was found; 61% of these specimens had one or more of the selected anomalies. The three most common translocations were 9;22 translocations (378 specimens), 8;21 translocations (15 specimens), and unbalanced abnormalities derived from 1;7 translocations (13 specimens). The two most common deletions were those involving the long arm of chromosomes 5 (101 specimens) and 20 (65 specimens). The most common isochromosome was i(17q) (33 specimens). The two most common types of monosomy were loss of a Y chromosome (118 specimens) and monosomy 7 (97 specimens). The three most common trisomies were + 8 (161 specimens), +21 (53 specimens), and +19 (31 specimens). Each of the 43 anomalies was observed in patients with different types of hematologic disorders, but in most cases one kind of neoplasm usually predominated.

Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase

The prognosis for patients with Philadelphia-negative myeloproliferative neoplasms (MPN) who evolve into acute myeloid leukemia (AML) or blast phase (MPN-BP) is extremely poor. Although allogeneic stem cell transplantation (allo-SCT) is considered potentially curative, very few patients have been reported who have undergone allo-SCT for MPN-BP; therefore the success rate remains unknown. In a retrospective review, we identified 13 patients with an MPN transformation to blast phase after a median 9 years (range 5 months to 30 years); 8 (median age 55) continued to allo-SCT within 6 months. Induction chemotherapy cleared blood/marrow blasts in 60% (6/10) (2 declined therapy, 1 had early death). At the time of allo-SCT, 5/8 patients were in complete remission (CR) of their leukemia or had returned to MPN chronic phase (CP), 2 had residual blood blasts and 1 was refractory with >5% marrow blasts. At follow-up (median 20.3 months), 6 patients are alive in CR of both their leukemia/MPN. All 5 patients in CR/CP at pre-allo-SCT remain alive in remission, while 2/3 with persistent blood/marrow blasts relapsed and expired. We conclude that MPN-BP can be cured by allo-SCT in a significant percentage of patients, but that adequate leukemic clearance prior to allo-SCT offers an optimal outcome.

Trauma-Induced Coagulopathy: From Biology to Therapy

Trauma is a leading cause of death and disability. Hemorrhage is the major mechanism responsible for death during the first 24 hours following trauma. One quarter of severely injured patients present in the emergency room with acute coagulopathy of trauma and shock (ACOT). The drivers of ACOT are tissue hypoperfusion, inflammation, and activation of the neurohumoral system. ACOT is a result of protein C activation with cleavage of activated factor VIII and V and inhibition of plasminogen activator inhibitor-1 (PAI-1). The resuscitation-associated coagulopathy (RAC) is secondary to a combination of acidosis, hypothermia and dilution from intravenous blood and fluid therapy. RAC may further aggravate acidosis and hypoxia resulting in a vicious cycle. This review focuses on the biology of the trauma-associated coagulopathy, and reviews current therapeutic strategies.

The erythroid leukemias: A comparative study of erythroleukemia (FAB M6) and Di Guglielmo disease

Pure erythroid malignancies, such as Di Guglielmo disease (DG), in which the predominant immature elements are proerythroblasts, are excluded from the French-American-British (FAB) classification for acute leukemia and do not fit neatly into any of the categories of myelodysplasia. This retrospective review compares the clinical and laboratory features of DG and erythroleukemia (FAB M6) among 37 cases treated at a single institution over a 7-year period. DG was defined as >30% proerythroblasts and the absence of a myeloblastic component. Clinical and laboratory features were similar in both subtypes. High proportions of secondary leukemias and prior myelodysplastic syndromes (MDS) were noted (M6, 13 of 26 cases; DG, five of 11 cases; p = 0.85). Pancytopenia was common at presentation in both groups [median white blood cells (WBC), 2,600/mm3; HgB, 8.65 gm/dl; platelets, 38,000/microl]. Two-thirds of studied cases had chromosomal abnormalities typified by major karyotypic abnormalities (MAKA) involving three or more chromosomes. Abnormalities involving chromosome 5 and/or 7 occurred in 47% (48% M6 and 45% DG). Both erythroid malignancies carried a poor prognosis (M6, 6.0-month median survival; DG, 4-month survival; p = 0.74). Among those patients choosing aggressive rather than palliative therapy, higher remission rate (80 versus 25%) and survival advantage (11.5 versus 2.5 months) were seen in M6 compared to DG. However, only two long-term survivors exist. The similar clinical and laboratory features, cytogenetic patterns, and poor survival data suggest that the FAB classification schema should be modified to include DG.