Chronic myelomonocytic leukemia: from biology to therapy

Chronic myelomonocytic leukemia represents a distinct myelodysplastic syndrome in which an excess of monocytes is observed both in the blood and bone marrow of the patients. Whereas diagnosis is relatively easy, therapeutic design and efficacy is difficult and no treatment has to date provided complete or significant partial response. In vitro data suggest that the growth and differentiation of myelomonocytic progenitors may be altered inasmuch as monocytic or granulo-macrophagic colonies show spontaneous growth. Different entities may be observed: the childhood form, Juvenile Chronic Myelomonocytic Leukemia (JCML) shows in vitro a typical pattern with constitutive growth of only macrophagic colonies and hypersensitivity to GM-CSF; in the adult form at least two patterns may be observed one close to the JCML form and one more heterogeneous with absence of GM-CSF sensitivity and spontaneous growth of both CFU-GM and CFU-M colonies. Chemotherapy reduces all myeloid colonies in vitro whereas retinoic acid has a selective effect on monocytic colonies with a concomitant increase of CFU-G colonies forwarding an explanation for the correction of pancytopenia observed in some patients. Recent analysis of altered molecular pathways in this disease suggest a common disruption of intracelleular signalling pathways namely the Ras pathway and targetting for drugs with may selectively control or inhibit a constitutive activation may forward novel therapeutic perspectives.     

Favorable cytogenetic abnormalities in secondary leukemia

The authors report on five patients with secondary leukemia (SL) and one of the "specific" chromosomal rearrangements usually encountered in de novo acute nonlymphoblastic leukemia: inv(16), t(15;17), t(8;21), and t(9;11). They were characterized by solid tumor as the primary malignancy in four of five cases, absence of preleukemic phase in all cases, and myelodysplastic features in one of five cases only. All patients achieved complete remission (CR) with aggressive chemotherapy. Only two relapsed, but follow-up is still limited in the three remaining cases. Cytogenetic analysis is important in all younger patients with SL, especially if unusual features (such as absence of preleukemic phase or myelodysplastic features) are found. Aggressive chemotherapy appears to be indicated in those patients if a "specific" rearrangement is found.     

Effects of Porcine Circovirus Type 2 (PCV2) Maternal Antibodies on Experimental Infection of Piglets with PCV2

To determine the effects of porcine circovirus type 2 (PCV2) maternal antibodies on and response to experimental PCV2 infection, 24 piglets were divided into four groups on the basis of the enzyme-linked immunosorbent assay titers of PCV2 maternal antibodies: group A (n = 6; sample/positive [S/P] ratio, <0.2), group B (n = 5; S/P ratio, >0.2 to <0.5), and groups C (n = 8) and D (n = 5) (S/P ratio, >0.5). Piglets in groups A, B, and C were inoculated with PCV2 at day 0 and challenged with PCV2 at day 42. Group D piglets were not exposed to PCV2 at day 0 but were challenged at day 42. Before challenge, seroconversion to PCV2 antibodies occurred in fiveofsix group A piglets, and the antibody level rose above the cutoff level in oneoffive group B piglets. Viremia was detected in fiveofsix, fouroffive, and twoofeight pigs in groups A, B, and C, respectively. After challenge, PCV2 DNA was detectable from 7 to 21 days postchallenge in the sera from sixofsix, fouroffive, threeofeight, and fiveoffive pigs in groups A, B, C, and D, respectively. The results indicated that protection against PCV2 infection conferred by maternal antibodies is titer dependent: higher titers are generally protective, but low titers are not.     

Chronic myeloid leukemia with unusual variant Ph translocation (22;22)(q11;q13). Two cases with chimeric BCR-ABL transcripts

We studied two cases of chronic myelogenous leukemia (CML) with unusual variant Philadelphia (Ph) translocation (22;22)(q11;q13). Southern blot analysis showed a chromosomal break in the BCR gene within the 5.8-kilobase (kb) breakpoint cluster region (bcr), between bcr exons 2 and 3 and between bcr exons 3 and 4, respectively. Chimeric bcr-abl mRNA was detected using polymerase chain reaction (PCR) which amplified, according to the respective bcr breakpoints, bcr exon 2-abl exon II and bcr exon 3-abl exon II junction products. These results further support the involvement, even when not cytogenetically detectable, of the 9q34 chromosomal region in all variant Ph translocations and that BCR-ABL gene fusion products are causally involved in the development of Ph positive CML.     

Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.

PURPOSE: We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. PATIENTS AND METHODS: A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. RESULTS: Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. CONCLUSION: Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.     

Outcome of patients less than 55 years of age with high-risk acute leukemia who did not have an human leukocyte antigen-identical related donor: a long-term study of 97 consecutive patients.

Between January 1993 and December 2000, an unrelated donor search (UDS) was initiated for 97 consecutive patients [46 acute lymphoblastic leukemia (ALL) and 51 acute myeloid leukemia (AML)]. Leukemia was considered to be of poor prognosis in cases of refractory disease (n=70), unfavourable karyotype (n=22) or miscellaneous (n=5). All patients had previously received various chemotherapies and 9 had undergone an autologous stem cell transplantation (SCT). The median age at UDS initiation was 25 (range 2.7-55) years. The median time to identify a suitable living donor or cord blood (CB) was 60 days. Eventually, 33 patients received unrelated allo-SCT (including 9 CB), 12 auto-SCT, 39 chemotherapy and 13 palliative treatment. At a median of 54 months, 18 patients were alive, including 15 in remission. The 4-year overall survival rates were 32%, 37%, 15% and 0% for allo-SCT, auto-SCT, chemotherapy or palliative treatment, respectively. Patients who received either allo- or auto-SCT had better survival than those who did not (P<0.0001). For ALL, only allo-SCT significantly improved survival (P<0.007). Finally, patients who received allo-SCT died less often of relapse than patients who did not (P<0.0001). Unrelated allo-SCT gives a substantial long-term survival and cure in patients with high-risk acute leukemia. For patients who achieve remission and for whom UDS fails, auto-SCT may prove to be a good approach. For patients who fail to enter into remission, intensive salvage chemotherapy has a very limited effect.     

Vincristine efficacy and safety in treating immune thrombocytopenia: a retrospective study of 35 patients

Although vincristine (VCR) is sometimes prescribed for newly diagnosed immune thrombocytopenia (ITP), its efficacy in refractory ITP and sustained efficacy has yet to be demonstrated. We describe our clinical experience and recommend vincristine's correct place in ITP management. This retrospective study analysed data from 35 patients with newly diagnosed (ND), persistent (P) or chronic (C) ITP treated with VCR. The initial response rate, defined as >30 × 10⁹ platelets/L, reached 86% after a median of 7 [interquartile range (IQR) 6–13] days. In ND and P ITP, even when previous therapies were inefficient, initial response was 87.5%, suggesting that this treatment could be used particularly in rescue. Median survival time, without failure or relapse, was 15 months (Kaplan–Meier curve). Predictive factors (univariate analysis) of an initial and long‐term response were a small number of prior treatments received. However, at 2 yr, only seven patients had sustained response. Eight (23%) patients experienced adverse events: neuropathy for seven and bowel obstruction for one. Vincristine efficacy in ITP was confirmed, and it could be a good strategy for treating resistant ITP, especially in emergencies. In this era of new therapeutics, VCR deserves to remain on the list of ITP treatments because of its initial efficacy, safety and low cost.