Maurizio Tribalto

Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients.

The efficacy of alternating vincristine, melphalan (M), cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP) polychemotherapy was compared with the M and prednisone (MP) regimen as induction treatment in multiple myeloma (MM). Three hundred four MM patients entered this study between March 1983 and July 1986; the analysis was performed in December 1989. The treatment groups did not show significant differences with respect to major prognostic factors. Median overall survival was 33.8 months. In the VMCP/VBAP and MP arms, after 12 induction chemotherapy cycles, 59.0% and 47.3% (P less than .068) of the patients achieved an M component reduction greater than 50%. No significant difference was observed in the two treatment arms in terms of remission duration (21.3 v 19.6 months, P less than .66) and survival (31.6 v 37.0 months, P less than .28). Patients younger than 65 years did not show any advantage from the alternating polychemotherapy. At diagnosis, the plasma cell labeling index (LI) and serum beta-2 microglobulin (beta 2-m) were evaluated in 173 and 183 patients, respectively. A significantly reduced survival was observed for patients with LI greater than or equal to 2% (16.4 months) or beta 2-m greater than or equal to 6 mg/L (20.4 months). Even in these poor-risk subgroups, VMCP/VBAP was not superior to MP.

Incidence of chromosome abnormalities and clinical significance of karyotype in de novo acute myeloid leukemia

Cytogenetic studies with high-resolution banding were performed on specimens from 132 consecutive patients with de novo acute myeloid leukemia (AML). All patients were treated according to therapeutic protocols in the same institution. Clonal abnormalities were detected in 97 of the 124 patients in whom an adequate number of mitoses was obtained (78.2%). Neither sex, FAB classification, WBC, or the extent of bone marrow infiltrate affected the rate of chromosomal aberrations, whereas patients younger than 40 years had a greater proportion of normal karyotypes (p = 0.047). Two different chromosomal classifications were evaluated: the presence of normal and abnormal metaphases (NN-AN-AA classification), and a classification in cytogenetic categories, the latter being based on the frequency of cytogenetic abnormalities. Both classifications were found to correlate significantly with the clinical outcome. They also showed independent prognostic significance when age, sex, and FAB morphology were considered in a multivariate analysis. Two abnormalities were closely associated with specific clinical-pathologic subsets of AML. All the 15 patients with t(15;17) had acute promyelocytic leukemia; this translocation was not found in any other subset of AML. Eight of the nine patients presenting rearrangements at 11q23 belonged to a FAB subset with monocytic differentiation (M4 and M5). Our data suggest that cytogenetic findings should influence the therapeutic approach to AML. In particular, young patients with karyotypes associated with poor responses may be considered for more eradicating treatments, including allogenic bone marrow transplantation.

Low plasma cell 3(H) thymidine incorporation in monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma and remission phase myeloma: a reliable indicator of patients not requiring therapy

The kinetics of bone marrow plasma cells were evaluated by means of in vitro 3(H) thymidine incorporation in 143 patients with monoclonal gammopathies. Fifty‐three patients had symptomatic multiple myeloma (MM) at diagnosis, nine were in stable remission, six in unstable remission, and 16 in the relapse phase. Thirty‐seven patients were classified has having monoclonal gammopathy of undetermined significance (MGUS) and 22 as smouldering myeloma (SM). A thymidine labelling index (LI%) of > 3 at initial diagnosis predicted a very short survival. High LI% values (median 2.8 ± 1.1) were also seen at relapse. However, the major new finding was that the LI% could be used to discriminate precisely between the SM‐MGUS group and the MM patients including stage I disease (P < 0‐0001). Only one patient developed MM during follow up, that being 8 months after the initial diagnosis of SM. During the unmaintained stable remission (plateau) phase a low proliferative activity was also observed (LI%= 0.6 ± 0.2).

Early responder myeloma: kinetic studies identify a patient subgroup characterized by very poor prognosis.

In order to assess the prognostic value of rapid tumor mass reduction in responding multiple myeloma (MM) patients, 100 consecutive patients were analyzed, and bone marrow plasma cell kinetic characteristics were evaluated at diagnosis. Forty-two patients obtained a tumor mass reduction greater than or equal to 50% with three cycles of chemotherapy and within 3 months (early responder myeloma [ERM]), and 23 in greater than 3 months (slow responder myeloma [SRM]). Survival rates in these two groups were not statistically different (P = .07). The labeling index (LI) of bone marrow plasma cells was significantly higher in ERM patients than in SRM patients (1.8 +/- 2.0 v 0.8 +/- 0.7, P = .006). The LI was used to separate the ERM patients into two well-defined subgroups. ERM patients with a LI greater than or equal to 2% showed a median survival of 16.4 months, whereas ERM patients with a LI less than 2% did not reach the median survival at 46.9 months (P less than .0044). Remission duration was also significantly different: 12.2 months in the high LI subgroup and 26.3 months in the low LI subgroup (P less than .0025). Early response itself does not correspond to shorter remission duration and shorter survival, but it is a poor prognostic factor if associated with a high plasma cell proliferative activity.

Minimally differentiated acute myeloid leukaemia (AML-MO): cytochemical, immunophenotypic and cytogenetic analysis of 19 cases

Summary. We describe our experience in the identification of 19 cases of AML‐MO categorized among 200 consecutive AML cases. Leukaemic cells from our cases were morphologically marked by agranuler basophilic cytoplasm, finely dispersed chromatin and prominent nucleoli. In two cases heavily vacuolated and monocytoid‐shaped blasts were also observed. Cytochemistry (MPO, SBB, αANAE, αNBE, NASDCAE, AP, PAS) was negative in 14 cases, five cases expressing a very faint cytoplasmic positivity for αNBE (not exceeding 30% of the blasts) and αANAE (not exceeding 41%) which was sodium fluoride resistant. In these five cases other monocytic markers (e.g. CD14) were not in favour of myelomonocytic differentiation. All the cases were anti‐MPO positive at frequency > 10%. Phenotypic analysis also revealed myeloid features with all the patients having at least one myeloid antigen (CD13, CD33, CD15), Tdt was expressed in nine cases and CD7 in six cases. All cases but one were positive for CD34. Cytogenetic analysis, performed in 16 cases, showed no adequate growth in two cases and no consistent abnormality in four; among the remaining 10 cases no consistent abnormality was observed, the most common finding was trisomy 8 (two cases) and 4 (two cases) and aberrations of chromosomes 2, 3, 5, 7, 9, 12 and 21. No cases of (t9;22), Ph chromosome were observed. Interestingly three out of five patients with faint αNBE/αANAE positivity relapsed as typical M4 (one case) or M5a (two cases).

Conventional induction treatments do not influence overall survival in multiple myeloma.

A retrospective analysis was performed on two subsequent myeloma patient series treated with the same conventional induction treatments, melphalan and prednisone or alternating VMCP/VBAP: 273 were enrolled in the multicentre M83 trial (M83 trial group) from 1983 to 1986; 160 were referred to a single institution (Haemat.To group) from 1986 to 1994. Response to treatment was very similar in the two groups (53% v 50.3%). Remission duration curves merely overlapped (median 20 v 21 months). However, overall survival was significantly longer in the Haemat.To group (43.2 v 33 months, P < 0.04). This difference was due to a prolonged period from relapse or progression to death (21 v 8 months, P < 0.01; 20.8 v 7 months, P < 0.009). Prolonged survival was also observed in poor‐prognosis patients with a serum β2‐microglobulin level > 3 mg/l, in the Haemat.To group (31.8 v 24.2 months, P < 0.04). The same induction treatments produced almost identical response rate and remission duration in both groups, but overall survival was 10 months longer for one group. However, it could be argued that treatment salvage modalities and support therapies have been improved in a decade. Lastly, induction treatments did not influence overall survival.

Cytogenetic analysis is non-informative for assessing the remission rate in chronic myeloid leukemia (CML) patients on interferon-α (IFN-α) therapy

Abstract Cytogenetic analysis is considered pivotal for assessing the remission rate in CML patients on IFN therapy. On the basis of general agreement, at least 25 metaphases should be analyzed in each case. The main limitations to this approach are: 1) the small number of analyzable metaphases generally found in cytogenetic preparations from IFN-α-treated patients; and 2) the inability of this technique for scoring interphase cells. We compared the results of cytogenetic analysis and double-color FISH detection of bcr/abl genes fusion in 13 CML patients on IFN-α therapy (marrow sampling for cytogenetic and FISH analysis was carried out after 12 months in all patients and repeated after 18 months of IFN therapy in patients 4, 6, and 8). In five specimens, 20 to 25 cells were evaluable for cytogenetic examination, in another five no analyzable metaphases were scored, and in the remaining six samples two to 14 cells could be analyzed. With FISH detection at least 100 cells were easily scored in each specimen (mean number, 175). Comparing the results carried out with the two methods in different samples it emerged that cytogenetic analysis led to improper conclusions as regards the rate of Ph positivity, even in those patients where 20–25 metaphases were analyzed. Although many more cases have to be studied to establish the role of FISH analysis in Ph-positive patients, we are of the opinion that cytogenetic analysis is unfit for easily and accurately assessing the actual quality of remission in IFN-treated subjects.

Intermediate-dose (25 mg/m2) intravenous melphalan for patients with multiple myeloma in relapse or refractory to standard treatment.

Intermediate‐dose (25 mg/m2) intravenous melphalan has been evaluated in 34 multiple myeloma patients refractory to standard chemotherapies. The median time from diagnosis to entering of patients into the study was 27 months (range 7–71 months). A response was obtained in 12/34 patients (35%). 4 of 12 responding patients have relapsed and 2 of these have died; 8 responders have not relapsed and are still alive. The median duration of survival after 28 months of follow‐up has not yet been reached in the group of patients responding to treatment. However, the overall median duration of survival for the 34 patients entered into the study was 8 months. The median duration of response was 16 months. Toxicity was limited to leukopenia, thrombocytopenia, nausea and vomiting. This lack of severe toxicity allowed us to administer the drug on an outpatient basis. The response rate and the low toxicity observed in this group of patients are encouraging and suggest that intermediate‐dose intravenous melphalan is an effective and safe second line treatment for patients with multiple myeloma not responding to conventional treatment.

Lack of Correlation between Plasma Cell Thymidine Labelling Index and Serum Beta-2-Microglobulin in Monoclonal Gammopathies

Simultaneous evaluation of bone marrow plasma cell thymidine labelling index (LI) and serum beta-2-microglobulin (SB2M) was performed in 146 patients with multiple myeloma (MM) or monoclonal gammopathy of undetermined significance (MGUS). Eighty patients had MM on diagnosis, 11 were in relapse and 12 were in remission phase; 43 patients had MGUS. All the evaluated patients had normal renal function with a creatinine level less than 1.4 mg%. Overall there was no direct correlation between LI% and SB2M. LI% best reflected the proliferative capacity of the tumor clone itself being less than or equal to 1% in MGUS and MM in remission, but greater than 2% at relapse of MM. SB2M correlated best with the stage of disease and tumor burden. These two factors therefore have different clinical utility: LI is a useful parameter to detect disease stability (e.g., MGUS) or highly proliferative disease (aggressive MM at diagnosis or early relapse). SB2M remains the best single predictor of patient tumor burden and associated survival duration.

Trisomy 4 as the sole karyotypic anomaly in acute biphenotypic leukemia with B lineage markers and in acute minimally differentiated myeloid leukemia (MO)

Trisomy 4 is a recently defined chromosomal aberration in acute leukemia. The first reports suggested that this cytogenetic anomaly belongs to the M4 leukemia subtype of the FAB classification, but recent reports have described this alteration in a wider spectrum of leukemia subtypes. Here we report two cases of trisomy 4 as the sole chromosome anomaly: one was observed in a patient with acute biphenotypic leukemia with B-lineage markers and the second in a patient diagnosed with acute minimally differentiated myeloid leukemia (M0) with myelodysplastic features. To our knowledge these are, respectively, the first and second reports of trisomy 4 as the sole chromosomal anomaly in these leukemia subtypes.