Chemotherapy of the blastic phase of chronic granulocytic leukemia: hypodiploidy and response to therapy.

Thirty-two patients in the blastic phase of Philadelphia chromosome-positive chronic granulocytic leukemia (CGL) were studied in a prospective randomized trial in which vincristine--prednisone (19 patients) was compared with cytosine arabinoside--6-thioguanine (13 patients). Seven remissions (37%), including two complete remissions, were achieved in the vincristine--prednisone group. Three of the five with predominant hypodiploid blast cell lines treated with vincristine--prednisone had complete or partial remissions. Both complete remitters presented with hypodiploidy consisting of 44 chromosomes. Four patients (30%) who were treated with cytosine arabinoside--6-thioguanine responded with one complete remission. The median survival of the responders was 8 mo, as compared to 1--2 mo for the nonresponders. Crossover to the opposite regimen as secondary therapy following refractoriness or resistance resulted in only 3 partial responses out of 21 treated. All three had previously responded to vincristine--prednisone. Of the 32 cases, 14 had an elective splenectomy during the chronic phase of the disease. Prior splenectomy did not influence the response to chemotherapy, as all three complete remitters occurred in the nonsplenectomized group. Similarly, survival in the blastic phase was not affected by prior splenectomy.     

Longitudinal study of serum ferritin concentrations in chronic granulocytic leukaemia

In 60 patients with Ph1-positive chronic granulocytic leukaemia (CGL) the serum ferritin concentration was measured as a part of the initial evaluation of the disease. The mean value (+SD) was 285 +/- 368.6 ng/ml, normal or slightly increased values being obtained in most cases. In 38 patients serum ferritin was again determined in clinical remission following busulphan treatment. Although the levels generally remained within the normal range, a significant decrease was observed with respect to the initial values (p = 0.0000004), suggesting that serum ferritin at presentation of CGL may be partially influenced by the disease activity. Finally, a further determination of serum ferritin concentration was made in a subgroup of 21 patients when they were diagnosed as being in the accelerated or blastic phases of CGL. Although no substantial increase was found with respect to the values obtained at presentation, a significant increase (p = 0.0008) was observed when accelerated-blastic phase ferritin levels were compared with those obtained in clinical remission. Although in patients in blast crisis no correlation was found between blast cell mass and serum ferritin, the differences observed between the different phases could indicate that in CGL serum ferritin concentrations roughly parallel the disease activity.     

The plicamycin and hydroxyurea combination chemotherapy for chronic granulocytic leukemia in myeloid transformation

Between 1987-1988 we treated, in a cooperative study, 13 patients in blast crisis of CGL according to Koller and Miller's regimen. We observed no return to the chronic phase of the disease, while some patients suffered major drug-induced side effects. Six patients in accelerated phase were treated with the same combination therapy. All of them responded with a return to the chronic phase for a median of 4.5 months. In our hands the combination of plicamycin and hydroxyurea was ineffective in patients with CGL in blast crisis. This regimen could deserve further evaluation in patients with CGL in acceleration.     

Treatment of the blastic transformation of chronic granulocytic leukemia using high dose BCNU chemotherapy and cryopreserved autologous peripheral blood stem cells

Seven nonsplenectomized patients with blastic CGL have received high dose BCNU chemotherapy followed by cryopreserved peripheral blood stem cells (PBSC). The PBSC obtained at diagnosis were stored in the vapor phase of liquid nitrogen in 10% dimethyl sulfoxide for 11-46 months prior to use. Patients received 2.9 X 10(8) (1.9-7.8) thawed washed mononuclear cells/kg over 30 minutes with minimal morbidity. One patient was not rendered pancytopenic and died with blastic leukemia at 4 months. One patient, previously treated with daily busulfan, died of progressive hepatic failure 2 months after high dose BCNU. Restoration of the chronic phase of CGL was observed in the remaining five patients. Peripheral blood counts returned to normal ranges after a median of 19 days. Median survival for all patients is 11 months. Cytogenetic studies revealed elimination of acquired aneuploid cell lines in four of seven patients with persistence of Ph1. We conclude that: 1) frozen PBSC retain their viability for up to 4 years after cryopreservation and 2) the use of autologous PBSC following ablative chemotherapy may be associated with both symptomatic and karyotypic improvement in patients with blastic CGL.     

The in vitro effects of vincristine on peripheral blood leukocyte progenitor cells (CFU-C) in patients in blast crisis of chronic granulocytic leukemia: Correlation with clinical response

The in vitro sensitivity of circulating progenitor cells (CFU-C) of 20 patients in blast crisis of chronic granulocytic leukemia (CGL) to vincristine was correlated with the clinical response to vincristine in vivo. Eleven patients who achieved either a good or partial clinical response displayed a reduction in the number of colonies or clusters formed by their peripheral blood leukocytes in a double layer agar culture assay following incubation with vincristine. The CFU-C of five of six patients who failed to respond clinically to vincristine and prednisone were not suppressed following incubation with up to 12 μM vincristine. Three additional patients were not evaluable due to early post-treatment deaths. In vitro assay of the effects of vincristine on CFU-C appears to have predictive value for in vivo response in blast crisis of CGL.     

Central Nervous System Blast Crisis in Chronic Myeloid Leukemia on Imatinib Mesylate Therapy: Report of Two Cases

Chronic myeloid leukaemia is a chronic myeloproliferative disorder characterised by a reciprocal translocation between chromosomes 9 and 22 and thereby formation of the Philadelphia chromosome. Imatinib mesylate (STI-571) is a potent and selective inhibitor of BCR-ABL tyrosine kinase and has emerged as a treatment of choice in chronic myeloid leukaemia (CML) patients in chronic phase. It has shown activity in CML patients in the chronic phase or blastic phase. However there is poor penetration of the central nervous system (CNS) by the drug or its active metabolites. Therefore the CNS acts as a sanctuary site for malignant cells for CML patients treated with Imatinib. We report cases of two CML patients on Imatinib therapy, who were in haematological remission but developed CNS disease.     

CNS blast crisis of chronic myelogenous leukemia in a patient with a major cytogenetic response in bone marrow associated with low levels of imatinib mesylate and its N-desmethylated metabolite in cerebral spinal fluid

Imatinib mesylate (STI571) is a very effective treatment option for Ph⁺ chronic myeloid leukemia (CML) in chronic phase. Secondary treatment failures have mostly been observed in patients with advanced stages of disease. We report the case of a patient who unexpectedly experienced blast crisis of the central nervous system although having achieved complete cytogenetic remission in the bone marrow. The levels of STI571 and its metabolite N-desmethyl STI were 40-fold lower in the cerebral spine fluid than in plasma. The risk of CNS disease has to be kept in mind when patients with CML in chronic phase who are at an increased risk for blastic transformation are treated with imatinib mesylate.     

Dibromomannitol in the treatment of chronic granulocytic leukemia: a prospective randomized comparison with busulfan

Dibromomannitol (DBM) is a new agent for the treatment of chronic granulocytic leukemia. A propsective evaluation of the drug was undertaken in a randomized comparison with busulfan. Forty previously untreated, Philadelphia chromosome-positive cases were treated, with 20 patients in each treatment group. The protocol provided for continuous maintenance therapy after remission induction, with a crossover to the opposite drug in patients who became refractory to the primary agent but are without evidence of blastic tranformation. There were 14 remissions in the DBM group and 15 in those treated with busulfan. The rate of decrease of the elevated leukocyte count was more rapid with DBM, but prolonged disease control off treatment occurred in only three of 14 cases as opposed to nine of fifteen busulfan-treated patients who required a median delay of 12 mo before maintenance could be initiated. Hypoplasia occurred in one DBM patient and two busulfan cases. Following recovery, crossover to the opposite drug in two cases again resulted in hypopllasia. Increased skin pigmentation, amenorrhea, pulmonary fibrosis, and cytologic dysplasia, commonly associated with busulfan adminstration, were also noted with DBM. The median duration of disease control with busulfan was 34 mo and 26 mo with DBM. There was no signigicant difference in the incidence of blastic transformation, and median survival for both groups was 44 mo. DBM appears to be as effective as busulfan in the treatment of the chronic phase of CGL but with a more predictable myelosuppressive action. The principal advantage of busulfan over DBM is the fact that more than half the busulfan-treated patients experienced prolonged disease control off treatment.     

Rearrangement and expression of p53 in the chronic phase and blast crisis of chronic myelogenous leukemia

We tested a population of over 60 patients with chronic myelogenous leukemia (CML) for changes in the structure and expression of the p53 gene, which is located on chromosome 17. Six of 27 (22%) blast crisis samples and 3 of 5 (60%) accelerated phase samples had rearrangements of chromosome 17, whereas only 3 of 42 (7%) chronic phase patients had cytogenetic changes in chromosome 17. There was no loss of heterozygosity during the transition to blastic crisis among seven individuals who were informative for polymorphic probes for regions in or around the p53 gene on 17p. One patient in the chronic phase and one patient in the blastic phase of the 61 CML patients studied exhibited rearrangements of the p53 gene that were detectable by Southern analysis. One p53 allele was rearranged in the chronic phase patient and both p53 alleles were rearranged in the blastic phase patient. The p53 messenger RNA (mRNA) was of normal size (2.8 kb) in chronic phase and blast crisis, and the expression of the p53 gene was at least as high or higher in blast crisis as in the chronic phase of CML. The high incidence of abnormalities of chromosome 17 in blast-crisis CML found in our studies and the discovery of rearrangements of the p53 gene in two CML patients studied suggest that further study with probes for the p53 gene and anonymous polymorphic sites in chromosome 17 should be conducted in CML.     

Extramedullary disease in Ph'-positive chronic myelogenous leukemia: frequency, clinical features and prognostic significance

Of 349 consecutive patients with Philadelphia-positive chronic myelogenous leukemia (Ph' + CML), 14 (4%) developed extramedullary disease (EMD) during their illness. The sites of EMD were: bone (57%), lymph nodes (29%), skin and soft tissues (21%), central nervous system (14%). The median time from diagnosis of CML to the occurrence of EMD was 48 months. At the time of diagnosis of EMD, 7 patients were hematologically in chronic phase, while 7 showed features of accelerated or blastic CML. For patients lacking medullary blastic transformation criteria, the median time from diagnosis of EMD to blast crisis was 4 months. The overall median survival from development of EMD was 5 months. In conclusion, EMD may occur during the course of CML either in the context of a frank blastic transformation, or as an isolated tumoral infiltrate which heralds an impending blast crisis. Its recognition requires a prompt change to acute-phase chemotherapy.     

Alkaline Phosphatase Activity in Immature Granulocytes

A positive reaction for alkaline phosphatase activity in granulocyte precursors (myelocytes, promyelocytes and even some blast cells) has been observed in three patients. Two of them had a blastic crisis of subacute or chronic myeloid leukaemia. In the third patient with a blastic crisis of a myeloproliferative syndrome, AP activity was unusually high in pseudo-Pelger forms of neutrophils from the myelocyte stage onwards. All other cytochemical reactions were normal and in accordance with the myeloid character of the blast cells. The nature of the cells involved and possible explanations of this unusual finding are discussed.     

Plasma fucosyltransferase as an indicator of imminent blastic crisis

Plasma fucosyltransferase activity was evaluated as an indicator of an impending blastic transformation in 25 patients with chronic granulocytic leukemia (CGL). Fifteen age-and sex-matched controls were also studied. The level of enzyme activity was significantly higher in the plasma of patients with blastic transformation (1,630 ± 570 units) compared with steady state chronic granulocytic leukemia (509 ± 110 units) and normal controls (354 ± 57 units). In three patients with CGL, a rise in fucosyltransferase activity preceded any other clinical or laboratory parameter of blastic transformation by 16–20 weeks.     

Chemotherapy and autografting for chronic granulocytic leukaemia in transformation: probable prolongation of survival for some patients

Between June 1977 and July 1983 51 patients with Ph1-positive chronic granulocytic leukaemia (CGL) in transformation were treated either by chemotherapy or by chemoradiotherapy followed by autografting with haemopoietic stem cells collected from their peripheral blood at the time of diagnosis. Forty-eight patients were restored to a second chronic phase. The median duration of survival after autografting was 26 weeks (range 2-152 weeks). Twenty-one patients with relatively long durations of second chronic phase were treated again by autografting as consolidation or when transformation recurred; this selected group of patients survived longer than the 30 patients treated by autografting only once (medians 52 v. 13 weeks respectively, P less than 0.01). There was no significant influence of the patients' age, splenectomy status, type of transformation, treatment pre-autograft or number of nucleated cells autografted on the duration of survival. Three patients treated in myeloid blastic transformation were restored to partially Ph1-negative haemopoiesis. We conclude that this approach to the management of CGL in transformation can offer benefit for a minority of patients and that further chemotherapy and autografting for patients still in second chronic phase may be valuable.     

Chronic granulocytic leukemia. Prolonged survival, muscle infiltration and sea-blue histiocytosis

Most patients with chronic granulocytic leukemia (CGL) survive from three to four years after diagnosis. We describe a patient with CGL who remained well for almost 13 years after the initiation of treatment. Shortly before death, when he was hematologically stable, the skin, subcutaneous tissue and muscle became infiltrated with leukemic cells. Many sea-blue histiocytes were found in his bone marrow. During the terminal phase of his disease, fever, basophilia, blast transformation, elevated leukocyte alkaline phosphatase activity and myelofibrosis were all present.     

Myelofibrosis in Chronic Granulocytic Leukaemia

Serial trephine biopsies were performed in 45 cases of chronic granulocytic leukaemia (CGL) in order to determine the frequency and significance of secondary myelofibrosis in the evolution of the disease. Histological changes were graded 1-5b, ranging from no increase in reticulin to dense osteomyelosclerosis. Many cases showed a progressive increase from Grade 1 to Grade 3, and accelerated disease, or blast crisis, often supervened when Grade 3 changes were present. However, a significant number of cases showed Grade 4 and 5 changes, which were indistinguishable histologically from those found in agnogenic myeloid metaplasia (AMM) (idiopathic myelofibrosis), at the time of diagnosis. These patients did not always show a rapidly fatal course and may be considered as an example of 'transitional myeloproliferative disorder', with features intermediate between CGL and AMM.     

Blastic phase of myeloproliferative syndrome coexisting with a malignant teratoma

A myeloproliferative condition in blastic phase is described in an 18-year-old male who was also found to have a mediastinal malignant teratoma. Myeloid metaplasia was found in the lymph nodes and spleen, and an infiltration of granulocytic blast cells was observed in the bone marrow and the lymph nodes. Aneuploidy with an extra chromosome (trisomy 8) was present in bone marrow cells. To our knowledge the combination of a myeloproliferative disorder and a malignant teratoma has not been earlier described.     

Hematologic and Cytogenetic Remission of Blastic Transformation in Chronic Granulocytic Leukemia

Thirty patients in the blastic phase ofchronic granulocytic leukemia weretreated with a combination of vincristine,2.0 mg/sq m weekly, and prednisone,60 mg/sq m orally each day. Remissionwas achieved in nine patients (30%), sixof whom had a complete remission, andthree had a good partial remission. Thesurvival of responding patients wassignificantly improved over the nonresponders. Cytogenetic studies wereperformed on all patients in thechronic phase of the disease, and in 28during the blastic phase. All were Philadelphia chromosome-positive throughouttheir course. Aneuploidy developed in68% of the patients entering the blasticphase. Complete hematologic remissionwas accompanied by disappearance ofaneuploid blast cell lines in the five patients in which they were detected, withreturn of the chromosomal constitution tothat which characterized the chronicphase of their disease. Hypodiploidy inblastic transformation of CGL appearedto predict for a favorable response tovincristine and prednisone. Subsequentrelapse of the disease in previously remitted patients was associated withfurther degrees of aneuploidy, suggestingclonal evolution of a resistant cell line.

Submitted on May 24, 1971 Revised on June 28, 1971 Accepted on June 30, 1971     

Atypical chronic myeloid leukaemia,a distinct clinical entitity related to the myelodysplastic syndrome?

The FAB group has recently published guidelines for distinguishing chronic granulocytic leukaemia (CGL) from chronic myelomonocytic leukaemia (CMML) and atypical chronic myeloid luekaemia (aCML). Whereas CGL is generally recognized to be a distinct entity, there is debate as to whether CMML and aCML are separate disorders or part of a spectrum of myeloproliferative disorders with dysplastic features. Data are presented on 10 cases who developed features of aCML during the course of their disease but who presented with a normal or low leucocyte count without a monocytosis and were diagnosed as refractory anaemia. This suggests that, at least in some cases, aCML represents an unusual evolution of MDS, and even though these patients have a uniformly poor prognosis it may be premature to regard aCML as a distinct clinical entity.     

Prognostic Significance of Cytogenetical Studies in Chronic Granulocytic Leukaemia

In a series of 121 patients with chronic granulocytic leukaemia (CGL) the frequence and prognostic significance of two cytogenetical features (absence of ph¹-chromosome and presence of ph¹-mosaicism) were studied. 13% of the patients were ph¹-negative, these patients showing a shorter survival than the ph¹-positive ones (P < 0.005). 23 instances of ph¹-mosaicism were found (22.5%). This feature was observed either at diagnosis or after treatment, and irrespective of the patient's being in chronic or blastic phase of CGL, but in no case later than 2 years from diagnosis of the disease. ph¹-mosaicism patients vs the remainder of the ph¹-positive group were compared for survival, and no difference was found. The lack of prognostic significance of ph¹-mosaicism was evident regardless of the latter feature being detected at diagnosis or after treatment.     

Antigenic determinants on myeloid leukaemia colony-forming cells resemble those of normal myeloid progenitor cells and differ from those of circulating blast cells

We studied the antigenic characteristics of leukaemic colony-forming cells (CFU-L) from the blood of patients with chronic granulocytic leukaemia (CGL) in blastic transformation (BT) and acute myeloid leukaemia (AML) by in vitro culture techniques after complement-mediated lysis with one anti-DR and 10 selected myeloid monoclonal antibodies (McAbs), all of which were cytotoxic in the presence of complement. At the same time we studied the antigenic characteristics of the circulating blast cells from the same patients using in addition one non-complement fixing antibody (BI.3C5) with standard immunofluorescence and immunoalkaline phosphatase techniques. We also used myeloid progenitor cell assays in conjunction with cytotoxic McAbs to investigate the antigenic determinants on Day 7 CFU-GM, Day 14 CFU-GM and BFU-E from the blood of patients with CGL in chronic phase (CP) and from normal bone marrow. We found that two of the McAbs, S4-7 and WGHS29.1, recognized a higher proportion of CFU-L from the blood of AML patients than from patients with CGL-BT. However, the patterns of reactivity for CFU-L from CGL-BT and AML patients with the other McAbs quite closely resembled those observed in CFU-GM and BFU-E from normal individuals and patients with CGL in CP. A McAb with DR specificity and one of the myeloid McAbs, 54/39, recognized both CFU-L from CGL-BT and AML and reacted also with circulating blast cells from the same patients. In contrast, six of the other myeloid McAbs that recognized CFU-L failed to label the corresponding blast cells. We conclude that the antigenic properties of CFU-L in CGL-BT and AML are very similar to, but perhaps not identical with, those of normal CFU-GM and BFU-E. There was a major discrepancy in the antigenic profiles of CFU-L and of the blast cells predominating in the blood.