Therapy of lymphoid and undifferentiated chronic myelogenous leukemia in blast crisis with continuous vincristine and adriamycin infusions plus high-dose decadron

Thirty patients with Philadelphia chromosome-positive lymphoid (20 patients) or undifferentiated (ten patients) chronic myelogenous leukemia in blast crisis were treated with 0.4 mg of vincristine by continuous intravenous infusion (CIV) daily for 4 days; (doxorubicin) 12 mg/m2 of Adriamycin (Adria Laboratories, Columbus, OH) by continuous intravenous infusion daily for 4 days; and 40 mg of decadron daily on days 1 through 4, 9 through 12, and 17 through 20 (VAD). Course 2 was given starting on day 24 with the addition of cyclophosphamide 1 g/22. Overall nine patients achieved complete remission (30%) and three attained a partial remission (10%), for an overall response rate of 40%. Four patients expired during induction whereas 14 had resistant disease. Response rate was significantly higher for patients with lymphoid compared to undifferentiated morphology (55% versus 10%; P = 0.05). In lymphoid blast crisis, Calla-positive disease was associated with a higher response rate compared to Calla-negative disease (75% versus 25%; P = 0.08). Eleven patients developed infections, and seven had fever without documented infections. The median overall survival was 29 weeks. Median survival was 43 weeks for patients achieving complete remission and 20 weeks for those with resistant disease. Remission duration was 39 weeks. After primary and salvage therapy, nine patients are alive, six of them in continuous remission for 19+ to 112+ weeks. The authors conclude that VAD chemotherapy is an effective regimen with acceptable toxicity in patients with lymphoid blast crisis especially those with Calla-positive disease. Alternate induction regimens for undifferentiated disease and for maintenance therapy are currently being investigated.     

Rheumatoid factors in the sera of patient with gastrointestinal carcinoma

One hundred and nineteen patients with gastrointestinal (GI) malignancy (80 colorectal, 25 gastric and 14 pancreatic carcinoma) were studied for rheumatoid factors (RF), antinuclear antibodies (ANA) and immunoglobulin levels and the findings correlated with size of tumor, stage of disease and survival. Twenty three (19.3%) of the patients were RF seropositive compared to 5.7% of 70 matched controls (P = 0.02). In two thirds of the seropositive patients RF were detected prior to the initiation of treatment. The proportion of RF seropositivity increased significantly in patients with tumors larger than 4 cm and in patients with Stage D disease. The authors found a high incidence of ANA in the patients: 32.4% compared to 8% in normal subjects (P less than 0.01), but the proportion of RF in this group was not significantly different. Survival distributions of the RF positive cases were different from that of the other patients (18 versus 25 months median survival); however, this was not statistically significant. These findings indicate that RF in GI cancer patients sera is not rare and can be related mainly to "tumor load," although not considerably affecting survival.     

LIF: not just a leukemia inhibitory factor

Increasingly it seems that many cytokines are pleiotropic, and individual molecules may have critical roles in several different organ systems. LIF exemplifies this phenomenon: it influences embryogenesis, bone and lipid metabolism, and hematopoietic and nervous system function. Many of LIF's effects are reminiscent of those of IL-1, TNF, and TGF-beta. Further, even within a single system, LIF can display totally different effects, i.e. induction of differentiation of one leukemic cell line vs. stimulation of proliferation of another. The corollary to these observations is that there appears to be many parallels in developmental systems. For instance, in the case of neuronal "lineage commitment," the events that relate to migration of neural crest cells along various pathways and their ultimate arrest in different locales demonstrate sufficient analogies to hematopoietic lineage commitment phenomena that, in a provocative review, Anderson coined the term "neuropoiesis". This type of analogy becomes even more intriguing when one realizes that some of the same molecules are regulating neuronal and hematopoietic "lineage" proliferation and differentiation. In this respect, several interleukins in addition to LIF are important in neuronal development, and nerve growth factor turns out to also be a hematopoietic regulatory molecule. Similar parallels are enacted in other organ systems as well. The mediation of identical effects by distinct cytokines bound to unique receptors could conceivably be explained by receptor transmodulation or by overlapping signaling sequences. It is nevertheless also unclear how a single cytokine attached to a single receptor can accomplish varied and opposing effects, although divergent intracellular signaling mechanisms could account for some of these phenomena. Yet another enigma relates to how cells from one system can be properly influenced by a pleiotropic molecule such as LIF without significant "cross-effects" on other potentially responsive systems. Cytokine production that is restricted to certain developmental stages, or very localized distribution and spheres of influence within a microenvironment, could be explanatory. The findings of Rathjan and colleagues, i.e. that LIF exists as both a diffusible molecule and as a molecule incorporated into the extracellular matrix, is of special interest in relation to the above questions. Indeed, the distinctions between the roles of diffusible and immobilized signaling molecules could be crucial to the multiplicity of LIF's actions. Diffusible regulatory factors allow communication between spatially separated cells. Cellular responsiveness to such factors is dictated by the presence of appropriate receptors and postreceptor machinery.(ABSTRACT TRUNCATED AT 400 WORDS)     

Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate.

PURPOSE: To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. MATERIALS AND METHODS: Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. RESULTS: Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% +/- 1.4% (mean +/- standard error of the mean) to 60.7% +/- 1.4% after 1 week, 50.9% +/- 2.4% after 2 weeks, and returned to 66.5% +/- 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% +/- 3.0% versus 26.8% +/- 2.7% in responders versus nonresponders (P = .007). CONCLUSION: Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.     

Expression of c-abl in Philadelphia-positive acute myelogenous leukemia

The identical cytogenetic marker, t(9;22)(q34;q11) (Philadelphia [Ph] translocation), is found in approximately 90%, 20%, and 2% of adult patients with chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML), respectively. In CML, the molecular events resulting from the Ph translocation include a break within the bcr locus on chromosome 22, transfer of the c-abl protooncogene from chromosome 9 to 22, and formation of an aberrant 210- kD bcr-abl fusion protein (p210bcr-abl). Recently, the absence of bcr rearrangement and expression of a distinct aberrant 190-kd abl protein (p190c-abl) has been described in Ph-positive ALL, with the suggestion that the two abl variants may be pathogenetically associated with myeloid v lymphoid leukemogenesis. Here we report that the genomic configuration and translation product of Ph-positive AML can be similar to that of Ph-positive ALL: the break at 22q11 may occur outside the 5.8 kb bcr region and result in expression of a 190-kD abl protein lacking these bcr sequences. Phosphokinase enzymatic activity, a fundamental property of p210bcr-abl, was also associated with AML- derived p190c-abl. Our current observations indicate that p190c-abl can be found in cells of lymphoid or myeloid lineage and is therefore unlikely to play a specific role in the development of lymphoid leukemias. Formation of p190c-abl instead of p210bcr-abl appears to be a characteristic of the acute rather than the chronic Ph-positive leukemic state.     

Percentage of Philadelphia chromosome (Ph)-negative and Ph-positive cells found after autologous transplantation for chronic myelogenous leukemia depends on percentage of diploid cells induced by conventional- dose chemotherapy before collection of autologous cells

We collected peripheral blood mononuclear cells and bone marrow cells soon after recovery from conventional-dose chemotherapy-induced myelosuppression and transplanted these cells into advanced chronic myelogenous leukemia (CML) patients after treating these patients with 120 mg/kg cyclophosphamide, 750 mg/m2 VP-16, and 1,020 cGy of total body irradiation (TBI). Of the 10 late chronic-phase patients and the eight accelerated-phase CML patients evaluable posttransplant, 90% and 87%, respectively, remain alive posttransplant, whereas none of the three blast crisis CML patients given this therapy remain alive posttransplant. We measured the percentage of Philadelphia chromosome (Ph)-negative cells in the autologous cells collected after conventional-dose chemotherapy-induced myelosuppression before autologous transplant and in the marrow of these same CML patients after autologous transplantation of these cells into recipients treated with the cyclophosphamide, VP-16, and TBI. A direct correlation (correlation coefficient = 0.91) was observed between the level of Ph+ cells in the transplanted cells and the percentage of Ph+ marrow cells after transplant in 21 patients so transplanted. The data show that the chance of generating cytogenetic remissions post-transplant depends on the percentage of diploid cells in the preparations of autologous cells used for transplant and the stage of disease of the patients at the time of collection of the autologous cells.     

Clinical investigation of human alpha interferon in chronic myelogenous leukemia

Fifty-one patients with previously untreated or minimally treated chronic myelogenous leukemia in chronic phase received human alpha interferon 3 to 9 X 10(6) units intramuscularly (IM) daily until complete hematologic remission, then at doses ranging from 3 X 10(6) units every other day to 9 X 10(6) units daily. Forty-one (80%) patients achieved a hematologic response, 36 (71%) of them attaining a complete hematologic remission with normal peripheral WBC and differential counts. Responding patients showed continuous but slow normalization of several other blood and marrow parameters including platelet counts, serum lactic dehydrogenase and B12 levels, and marrow cellularity and maturation index. Suppression of the Philadelphia chromosome on serial cytogenetic studies of marrow metaphases was documented in 20 of the 36 patients who achieved complete hematologic remission (56%; 39% of total group), eight of whom (22%) had a decrease of the Philadelphia chromosome-positive metaphases to less than 35%. These changes were persistent for 6 months or longer in 18 patients, seven of whom had continuous suppression of the Philadelphia chromosome to less than 90% for a median of 30+ months (range 21+ to 39+ months). After a median follow-up period of 37 months, 25 patients remain in continued disease control with interferon therapy. The projected 3-year survival rate is 76%, with a yearly death rate of 6%, 9%, and 9% in the first 3 years. Response, Philadelphia chromosome suppression, and survival were significantly better among patients in the low-risk category compared to intermediate- and high-risk categories, as defined by a multivariate analysis-derived prognostic model. The projected 3- year survival rate was 94% for patients who achieved a complete hematologic remission on interferon therapy and 45% for those who did not. Thirteen patients have developed blastic crisis, six with lymphoid and three with undifferentiated morphology. We conclude that human leukocyte alpha interferon effectively controls chronic myeloid leukemia and allows reappearance of diploid hemopoietic cells in some patients.     

Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia

Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.     

Quantification of the breakpoint cluster region rearrangement for clinical monitoring in Philadelphia chromosome-positive chronic myeloid leukemia

The purpose of this report was to evaluate scintigraphy analysis of Southern blot hybridization as a method to quantify the breakpoint cluster region (BCR) rearrangement of Philadelphia chromosome (Ph)+ chronic myelogenous leukemia (CML). Cytogenetic and molecular studies performed simultaneously on 474 bone marrow and/or blood samples from 300 patients treated with alpha-interferon-based therapy were compared. Molecular results were expressed as the percentage of rearranged BCR bands versus the total scintigraphic signal. The percentage of Ph+ metaphases was calculated on 25 metaphases. The results of molecular studies obtained on both peripheral blood and bone marrow samples were identical. The rank correlation between the BCR quantification and the percentage of Ph positivity in 465 samples was excellent (r = .78). However, of 99 samples with a normal karyotype, 24% had a BCR rearrangement. Of 86 samples with no BCR rearrangement, 13% showed a Ph chromosome. Of 49 samples with partial cytogenetic remission (Ph+ metaphases, 1% to 34%), 23% had no BCR rearrangement. In samples with a minor or no cytogenetic response (Ph+ metaphases, > 34%), BCR analysis overestimated the degree of response in 73 of 326 samples (22%). Nevertheless, survival analysis by BCR quantification level showed statistically better outcome for patients in complete or partial molecular response (P < .01). Molecular quantification of BCR was useful in monitoring the course of Ph+ CML. This method, which can be used on peripheral blood, detected residual disease not shown by cytogenetic analysis and was prognostically relevant as a measure of disease suppression.