Prognostic significance of serial determinations of lactate dehydrogenase (LDH) in the follow-up of patients with myelodysplastic syndromes.

BACKGROUND: Early recognition of disease progression in low-risk myelodysplastic syndromes (MDS) is an important decision point concerning intensive therapies. In a screen program searching for dynamic prognostic determinants, we have identified lactate dehydrogenase (LDH) as a most suitable follow-up parameter. PATIENTS AND METHODS: LDH levels were serially determined in 221 patients with de novo MDS (median age 70 years, range 24-94). The increase in LDH was correlated with survival and acute myeloid leukemia (AML) evolution. RESULTS: Confirming previous data, an elevated LDH at diagnosis was found to be associated with an increased probability of AML evolution and decreased probability of survival (P < 0.05). In the follow-up, we found that in patients who progressed (to higher IPSS category or AML), LDH levels were significantly higher in the two 3-month period preceding progression compared with the initial two 3-month period (P < 0.005). In a subgroup of patients, the increase in LDH was accompanied or followed by other signs of disease progression, such as occurrence of thrombocytopenia or appearance of circulating blasts. In multivariate analyses, the LDH increase was found to be an independent prognostic variable. CONCLUSIONS: LDH is an interesting follow-up parameter in MDS, which may assist in early recognition of disease progression and thus help in risk stratification and patient selection for interventional therapies.

Suspect cell convolutes in the bone marrow of a patient with renal cell carcinoma unmasked as atypical convolutes of hairy cells.

We describe a patient who concomitantly presented with renal cell carcinoma (RCC) and hairy cell leukemia (HCL). Hairy cells formed atypical cell convolutes on bone marrow smears that might have been mistaken for tumor metastases.

Survival analysis and AML development in patients with de novo myelodysplastic syndromes: comparison of six different prognostic scoring systems.

A number of prognostic scoring systems for patients with myelodysplastic syndromes (MDS) have been introduced in the past. In the present study, survival and AML evolution were analyzed retrospectively in a total of 180 patients with de novo MDS (observation period: 1989-1999; median age: 71; range 27-93; f/m ratio: 1/1.2). Diagnoses were established according to FAB criteria (RARS, n=37; RA, n=53; RAEB, n=50; RAEB-t, n=19; CMML, n=21). Six different multiparameter scoring systems (the Mufti, Aul, Sanz, Morel, and Toyama scores, and the international prognostic scoring system [IPSS]) were applied. The Aul, Sanz, and Mufti scores were applied to all 180 patients, Morel and Toyama scores to 109 patients, and the IPSS to 102. As assessed by multivariate analysis, the percentage of bm-blasts, hemoglobin, platelet count, neutrophil count, LDH, and karyotype were found to be independent single variables for survival, and bm-blasts, neutrophil count, platelet count, and karyotype for AML evolution. All prognostic scoring systems applied appeared to be highly predictive for survival and AML development (P<0.001). The highest predictive values were found for the Aul, Sanz, and Toyama scores for overall survival, and the IPSS, Toyama, and Morel scores for AML-free survival. In summary, our data show that scoring systems are useful for predicting overall and AML-free survival in patients with MDS. Karyotype-based multiparameter systems appear to be particularly effective in defining MDS patients who are at high risk of transforming to leukemia.

Prognostic value of lactate dehydrogenase activity in myelodysplastic syndromes.

Several prognostic factors for patients with myelodysplastic syndromes (MDS) have been defined in the past. One of these factors appears to be the serum lactate dehydrogenase (LDH) activity. However, the precise predictive value of an elevated LDH level with regard to AML transformation remains uncertain. In this study, the prognostic value of the LDH activity was examined in a cohort of 180 patients with de novo MDS (median age 71 years [27-93]; f/m-ratio 1:1.2; RA: n=53; RARS: n=37; RAEB: n=50; RAEBT: n=19; CMML: n=21). Significant differences in LDH activities were found among FAB groups (P<0.05), and especially among IPSS groups (HIGH: 411+/-574; INT-2: 221+/-90; INT-1: 254+/-145; LOW: 192+/-47 U/l; P<0.05). An LDH level of >/=300 U/l was found to be associated with a significantly shorter median survival (10.3 months) when compared to <300 U/l (33.7 months; P<0.01). Moreover, an LDH activity of >/=300 U/l indicated a reduced AML-free survival in our MDS patients (P<0.01). As assessed by Cox regression, the inclusion of LDH as additional variable into the IPSS system resulted in an improved prediction concerning survival, but not with regard to AML evolution. Together, our data show that a serum LDH activity of >/=300 U/l in MDS is associated with a significantly shorter survival and higher risk to transform to AML. The LDH activity should be considered as an important prognostic factor in MDS.

Fludarabine therapy in Waldenström's macroglobulinemia.

Seven patients with macroglobulinemia (six previously untreated, one with minimal pretreatment) were treated with fludarabine (25 mg/m2/day for 5 days, repeated every 4 weeks). The median age was 58 years. The time from diagnosis to treatment with fludarabine was 4.5 months to 175 months (median 32.6 months). The patients received six (n =5), five (n =1), and three (n = 1) courses of fludarabine. One patient showed only a slight decrease of immunoglobulin (Ig) M (from 5,750 mg/dl to 4,700 mg/dl) and no improvement of anemia. Therefore, treatment was stopped after three cycles. In the other six patients, a marked reduction of IgM levels (from 6,140 mg/dl to 1,220 mg/dl median), a normalization of hemoglobin (from 10.8 g/dl to 12.3 g/dl median), a reduction of lymphocyte count (from 1992/>microl to 652/microl median), and a reduction of beta2 microglobulin (from 2.3mg/l to 1.8 mg/l median) were achieved. A 50% IgM reduction was achieved 5.4 months (median) after the beginning of therapy, and the maximum response was observed 17.3 months (median) after the end of treatment. The responses were sustained without further therapy in six patients for 20.8-55.2 months. In one patient, disease progression was observed 12.5 months after the end of therapy. Fludarabine therapy was well tolerated with few side effects. In three patients, febrile episodes occurred. No opportunistic infections were recorded. We conclude that fludarabine is an effective treatment in previously untreated or in minimally pretreated patients with Waldenström's macroglobulinemia.

Prolonged third remission in a patient with acute promyelocytic leukemia after consolidation chemotherapy with intermittent intermediate dose ara-C and maintenance with intermittent all-trans retinoic acid (ATRA).

The benefit of all-trans-retinoic acid (ATRA) in the front line therapy of acute promyelocytic leukemia (APL) is well established, but its role in postremission therapy and in the treatment of relapse is currently under investigation. Moreover, the impact of cytosine arabinoside (Ara-C) in the therapy of APL has been questioned in recent studies. We report a prolonged third molecular remission (MR) in a patient with hyperleukocytotic APL after induction with ATRA, consolidation chemotherapy (CT) with intermittent intermediate dose Ara-C and maintenance therapy with intermittent ATRA. While the first two remissions were relatively short (8 months and 11 months, resp.), the duration of the third continuous CR (49+ months) is more than twice as long as the length of the two previous remissions combined. In this case Ara-C followed by intermittent ATRA maintenance was a safe and effective therapy for relapsed disease. A third molecular remission of such duration and quality is unusual.

Role of immunological lymphocyte subset typing as a screening method for lymphoid malignancies in daily routine practice.

BACKGROUND: The major diagnostic role of peripheral lymphocyte subset typing is to distinguish between malignant and reactive conditions. METHODS: The present study evaluates the screening efficacy of flow cytometric lymphocyte subset typing for the presence of a lymphoid malignancy. Four hundred samples were analyzed with a combination of anti-T-, B-, and natural killer (NK)-cell monoclonal antibodies. RESULTS: Two hundred and twenty (55%) samples showed a normal distribution of lymphocyte subsets, 73 (18%) samples exhibited unspecific alterations of lymphocyte subsets, 19 (5%) samples exhibited a reactive phenotype typical of Epstein-Barr virus/cytomegalovirus (EBV/CMV) infection, and 88 (22%) samples expressed a phenotype suggestive of lymphoma. The most predictive independent factor of a lymphoma-specific phenotype was the absolute lymphocyte count (P = 0.0001, odds ratio 73.225). Seventy-eight percent of samples containing >/=4 x 10(9)/l lymphocytes and 2% of samples with lymphocyte counts <4 x 10(9)/l exhibited a lymphoma-specific phenotype. The specificity of the referring clinical comment was the second best predictor of a lymphoma-specific typing outcome (P = 0.0001, odds ratio 19.589). The independent predictive values of lymphocyte morphology and of relative lymphocyte counts were of borderline significance. CONCLUSIONS: The use of flow cytometric lymphocyte subset typing as a diagnostic screening method for lymphoma should be restricted to cases of unexplained elevation of absolute lymphocyte counts with or without morphological atypias and to cases with definite clinical symptoms of lymphoma.

Macrocytic anemia and thrombocytosis associated with thymoma: a case report.

Thymomas are often associated with autoimmune disorders. We report on a 45-year-old female patient with thymoma and hypogammaglobulinemia (Good's syndrome) who developed symptomatic macrocytic anemia (Hb 4.4 g/dl, MCV 112 fl) and thrombocytosis (Plt 442 G/l). Besides hypogammaglobulinemia (IgG 589 mg/dl), an inverted ratio of CD4(+)/CD8(+) cells was seen. The bone marrow biopsy showed a slightly hypercellular bone marrow with normal granulopoiesis, normal megakaryopoiesis and a mild dyserythropoiesis without any ring-sideroblasts. The in-vitro stem cell culture from the bone marrow revealed an atypical growth of macroclusters, reduced BFU-E and CFU-GEMM colony growth, whereas the CFU-GM colony growth was within the normal range. The chromosomal analysis showed a normal karyotype. The plasma vitamin B(12) and folate levels were within normal ranges, and we could not detect any autoantibodies. These findings excluded the differential diagnoses pure red cell aplasia (PRCA) and pernicious anemia. After resection of the thymoma of mixed cell type, the macrocytic anemia and thrombocytosis disappeared. The clinical course was complicated by a cerebral palsy and a life-threatening fungal septicemia after surgery. In the third year after thymectomy, hyporegenerative macrocytic anemia and thrombocytosis reappeared and an immunosuppressive treatment with prednisolone (1 mg/kg BW) was started. After initiation of the prednisolone therapy, reticulocyte counts increased and macrocytic anemia as well as thrombocytosis disappeared. The normalization of these laboratory parameters during glucocorticoid therapy suggests that in rare cases the constellation of macrocytic anemia, thrombocytosis and hypogammaglobulinemia may be due to an underlying immunologic mechanism.

Monitoring of minimal residual leukemia in patients with MLL-AF9 positive acute myeloid leukemia by RT-PCR.

Twenty-seven patients with AML and MLL gene rearrangement were analyzed by a reverse transcriptase polymerase chain reaction (RT-PCR) for the MLL-AF9 translocation. The MLL-AF9 fusion transcript was detected in six patients. In five patients, the breakpoint of the AF9 gene was located within the recently described site A; in one patient, a novel breakpoint (AF9 site D) mapped to a position 377 bp 3' of site A. Five patients could be serially monitored for a period of 4-23 months. Two patients became two-step PCR negative in bone marrow and peripheral blood. Molecular remission was achieved rapidly after one cycle of induction chemotherapy. Both patients are in continuous complete remission (CR) at 22 and 15 months, respectively. Two patients who had achieved hematological CR did not become PCR negative and MLL-AF9 fusion transcripts were detectable in all samples after induction and consolidation chemotherapy. One patient relapsed 5 months after achieving CR. The other patient received allogeneic bone marrow transplantation from an HLA-identical sibling 2 months after achieving hematological CR and became PCR negative 4 weeks after transplantation. In the fifth patient, hematological CR could not be achieved with two cycles of intensive induction chemotherapy, and MLL-AF9 transcripts were present in all samples tested. Our data indicate that MLL-AF9 RT-PCR is specific for the t(9;11) translocation. PCR negativity can be achieved in responding patients already 1 month after induction chemotherapy. The fast reduction of MLL-AF9 positive blast cells below the detection limit of RT-PCR seems to be a prerequisite for long-term CR. The results of RT-PCR may be useful for treatment decisions (eg BMT).

Post-transplant acute myeloid leukemia (PT-AML).

Acute myeloid leukemia following organ transplantation (PT-AML) is a rare event with only a few published cases in the literature. We present three patients who developed AML (FAB M1, M5, M4) after renal, double lung or liver transplantation. Molecular analysis detected a t(9;11) in one patient and documented the recipient origin of AML in a second patient. All patients were treated with chemotherapy. Immunosuppression was reduced to cyclosporin A (CsA) and prednisone in two patients and to prednisone alone in one patient. Two patients achieved a complete remission (CR), with a remission duration of 4.6 months in one patient, the other patient died from septicemia after 15.2 months in CR. One patient was refractory to chemotherapy and died from septicemia. This report together with the documented cases in the literature suggests that PT-AML (1) develops after a median interval of 5 years after transplantation with variable latency (range, <1-17 years); (2) is heterogeneous with respect to FAB classification; (3) shows chromosomal and molecular changes typical of therapy-related AML (t-AML: -7, +8, 11q23, inv16, t(15;17)); (4) standard chemotherapy is feasible after reduction of immunosuppression and produces a CR rate of 56% with a median remission duration of 4.6 months and an overall survival of 2.6 months; (5) the major complications are early death (25%), gram-negative septicemia, progressive disease or relapse. This review provides diagnostic and therapeutic experiences and guidelines for the management of this increasing group of post-transplant patients.

Competitive CBFbeta/MYH11 reverse-transcriptase polymerase chain reaction for quantitative assessment of minimal residual disease during postremission therapy in acute myeloid leukemia with inversion(16): a pilot study.

PURPOSE: (1) Quantification of minimal residual disease (MRD) by competitive CBFbeta/MYH11 reverse-transcriptase polymerase chain reaction (RT-PCR) in patients with acute myeloid leukemia (AML) and inversion(16) [inv(16)] during postremission therapy, (2) comparison of this method with conventional two-step RT-PCR, and (3) evaluation of a potential prognostic value. PATIENTS AND METHODS: MRD of six consecutive adult patients with AML and inv(16)(p13;q22) or t(16;16)(p13;q22) who entered complete remission (CR) was monitored by competitive CBFbeta/MYH11 RT-PCR in their bone marrow (BM) during postremission therapy with high-dose cytarabine (HiDAC) or after BM transplantation with a matched unrelated-donor marrow (MUD-BMT) during an observation period of 4.5 to 27 months after initiation of treatment. RESULTS: Competitive PCR showed a gradual decline by at least 4 orders of magnitude after 7 to 9 months in patients in continuous CR (CCR), while one patient who relapsed after 13.5 months only achieved a reduction by 2 orders of magnitude at the end of consolidation therapy. A rapid decrease below the detection limit was observed within 1 month in two patients after MUD-BMT. A temporary reappearance of molecular MRD was observed in these patients during immunosuppression for graft-versus-host disease (GvHD). After reduction of immunosuppression, the level of MRD dropped again below the PCR detection limit. Molecular monitoring by conventional two-step RT-PCR yielded comparable results only when multiple assays per time point were performed, while single-assay RT-PCR gave misleading results. CONCLUSION: Competitive RT-PCR is a valuable tool for molecular monitoring during postremission chemotherapy, as well as after BMT.