Optimizing Patient Care in Chronic Phase Chronic Myelogenous Leukemia: A Multidisciplinary Approach

Abstract Cytogenetic studies were performed on nine patients with acute promyelocytic leukemia. Every patient had an identical translocation (15;17) or, in one case, a variant three-way rearrangement between chromosomes 7, 15, and 17. Another patient with chronic myelogenous leukemia was examined at the time of blastic crisis when the patient's bone marrow was infiltrated by hypergranular promyelocytes and blasts. Bone marrow cells contained a t(15;17) as well as a Ph1 chromosome. Only the latter abnormality was observed in the chronic phase of the disease. The translocation (15;17) was detected in all ten patients when bone marrow or peripheral blood cells were cultured for 24 hours prior to making chromosome preparations. However, the t(15;17) was not seen in three of these same cases when bone marrow cells were processed directly. These findings indicate that the t(15;17) is closely associated with acute proliferation of leukemic promyelocytes and that detection of this karyotypic defect may be influenced by the particular cytogenetic processing method used in different laboratories. An analysis of the banding pattern in the variant translocation provided additional evidence favoring chromosomal breakpoints at or very near the junction between bands 17q12 and 17q21 and at 15q22.

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Use of alpha interferon for the treatment of relapse of chronic myelogenous leukemia in chronic phase after allogeneic bone marrow transplantation

Blood ◽

10.1182/blood.v80.6.1437.bloodjournal8061437 ◽

1992 ◽

Vol 80 (6) ◽

pp. 1437-1442 ◽

Cited By ~ 1

Author(s):

CS Higano ◽

WH Raskind ◽

JW Singer

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Chronic Myelogenous Leukemia ◽

Marrow Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Chronic Phase ◽

Allogeneic Bone Marrow ◽

Myelogenous Leukemia ◽

Allogeneic Bone ◽

Sex Marker

Eighteen patients with relapse of chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation (BMT) were treated with recombinant human alpha 2a interferon (IFN). Relapse was defined as greater than 90% metaphases containing the Philadelphia chromosome (Ph) and hematologic abnormalities consistent with chronic-phase (CP) CML. There were 11 males and seven females, with a median age of 38 years (range, 3 to 55). Three patients relapsed after second BMT. Only one patient had received T-cell-depleted marrow initially. The initial IFN dose of 3 x 10(6) U/m2/d was escalated to the maximum tolerated dose or to a maximum of 6 x 10(6) U/m2/d. IFN controlled the white blood cell (WBC) counts in 14 of 16 patients who had abnormal counts, and in all six patients with an elevated platelet count. Six patients (33%) have had a complete disappearance of the Ph and two have had a partial response (less than 35% Ph+ metaphases). One patient has a decrease in Ph+ metaphases after 9 months of IFN. Five patients had no significant cytogenetic response after 9 to 12 months, and four developed clinical accelerated phase or blast crisis after 3 to 6 months on therapy. Of four patients with a sex marker, the Ph- population was of donor origin in three and of host origin in one. Clonal cytogenetic abnormalities other than Ph were present in 13 patients and did not predict for lack of response to IFN. IFN is effective in suppressing the Ph clone in some patients who relapse with CML after allogeneic BMT and controls the blood counts in the majority.

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Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia [see comments]

Blood ◽

10.1182/blood.v83.12.3449.3449 ◽

1994 ◽

Vol 83 (12) ◽

pp. 3449-3456 ◽

Cited By ~ 90

Author(s):

C Wada ◽

S Shionoya ◽

Y Fujino ◽

H Tokuhiro ◽

T Akahoshi ◽

...

Keyword(s):

Genomic Instability ◽

Chronic Myelogenous Leukemia ◽

Blast Crisis ◽

Chronic Phase ◽

Genetic Alterations ◽

Myelogenous Leukemia ◽

Leukemic Cells ◽

Genetic Event ◽

Familial Predisposition ◽

Somatic Instability

Abstract Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor-suppressor genes. Investigation of genomic instability of microsatellites has indicated a new mechanism for human carcinogenesis in hereditary nonpolyposis colorectal cancer and sporadic cancer and this instability has been shown to be related to inherited predisposition to cancer. This study was conducted to determine whether such microsatellite instability is associated with the evolution of chronic myelogenous leukemia (CML) to the blast crisis. Nineteen CML patients clinically progressing from the chronic phase to accelerated phase or blast crisis and 20 other patients in the CML chronic phase were studied. By polymerase chain reaction assay, DNAs for genomic instability in five separate microsatellites in chromosome arms 5q (Mfd27), 17p (Mfd41), 18q (DCC), 3p (CI3–9), and 8p (LPL) were examined. Differences in unrelated microsatellites of chronic and blastic phase DNAs in 14 of 19 patients (73.7%) were demonstrated. Somatic instability in five microsatellites, Mfd27, Mfd41, DCC, CI3–9, and LPL, was detected in 2 of 19 (10.5%), 8 of 19 (42.1%), 11 of 19 (57.9%), 4 of 17 (23.5%), and 4 of 17 (23.5%) cases. In 10 of 19 cases (52.6%), genetic instability in at least two of five microsatellites was observed and was categorized as replication error (RER+) phenotype. CML evolution cases with myeloid, lymphoid, and mixed phenotypes and the blast crisis and accelerated phase showed somatic instability in a number of microsatellites. No alterations in leukemic cells at the chronic phase could be detected in any microsatellites. These data indicate instability of microsatellites (RER+) but not familial predisposition to possibly be a late genetic event in the evolution of CML to blast crisis. In the microsatellite of the DCC gene, complicated alterations in band patterns caused by instability as well as loss of heterozygosity (LOH) were observed in 13 of 19 cases (68.4%): instability in 9 cases, instability plus LOH in 2 cases, and only LOH in 2 cases. These highly frequent alterations in microsatellites, including instability and LOH, suggesting that secondary events due possibly to loss of fidelity in replication and repair machinery may be significantly associated with CML evolution.

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Mutations of the N-ras gene in juvenile chronic myelogenous leukemia

Blood ◽

10.1182/blood.v83.8.2248.bloodjournal8382248 ◽

1994 ◽

Vol 83 (8) ◽

pp. 2248-2254 ◽

Cited By ~ 5

Author(s):

J Miyauchi ◽

M Asada ◽

M Sasaki ◽

Y Tsunematsu ◽

S Kojima ◽

...

Keyword(s):

Sequence Analysis ◽

Chronic Myelogenous Leukemia ◽

Blast Crisis ◽

Gene Mutations ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Disease Stage ◽

Nucleotide Sequence Analysis ◽

Age Group ◽

Ras Gene

Juvenile chronic myelogenous leukemia (JCML), a myeloproliferative disorder of childhood, is distinct from adult-type chronic myelogenous leukemia (CML) and bears resemblance to chronic myelomonocytic leukemia (CMMoL). Since mutations in the N-ras gene have been found at high frequencies in CMMoL, but only rarely in CML, we analyzed mutations activating the N-ras gene in 20 patients with JCML. We used the strategy for analysis of gene mutations based on in vitro DNA amplification by polymerase chain reaction (PCR) followed by single- strand conformation polymorphism (SSCP) analysis and/or direct sequence analysis. Nucleotide sequence analysis showed single nucleotide substitutions involving codons 12, 13, or 61 in six of 20 patients (30%). Four of six patients with mutations were in chronic phase and the other two in blast crisis, indicating no apparent correlation with disease stage. Most of the patients with mutations were in the older age group with poor prognosis, although one patient in the younger age group also harbored the mutation. These data suggest that N-ras gene mutations may be involved in the pathogenesis and/or prognosis of JCML and provide further evidence that JCML is an entity distinct from CML.

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How I Treat Chronic Phase Chronic Myelogenous Leukemia

Blood ◽

10.1182/blood.2021011722 ◽

2021 ◽

Author(s):

Ellin Berman

Keyword(s):

Chronic Myelogenous Leukemia ◽

Clinical Care ◽

Treatment Algorithm ◽

Safety Data ◽

Specific Treatment ◽

Chronic Phase ◽

The United States ◽

Myelogenous Leukemia ◽

Individual Response ◽

Number Of Patients

When imatinib, the first tyrosine kinase inhibitor (TKI) developed for use in chronic myelogenous leukemia (CML) was approved in 2001, the treatment of this disease was forever changed. Significant reductions in the molecular burden of disease were seen with the first generation TKI imatinib and with the addition of dasatinib (2006), nilotinib (2007), bosutinib (2012) and ponatinib (2013), deeper and more rapid reductions were noted. Physicians could begin to tailor TKI therapy to individual patients, and patients who did not respond to or could not tolerate first line therapy now had options. Importantly, the number of patients who developed accelerated or blast phase disease decreased dramatically. Research in CML continues to evolve and by presenting illustrative cases, this article will review some of the newer aspects of clinical care in this disease. Updated information regarding bosutinib and asciminib, the latter currently in clinical trials, will be presented; bosutinib is of particular interest as the drug's transit through the United States Food and Drug Administration (FDA) highlights the question of what is considered optimal response to TKI therapy. The challenge of understanding the cardiac safety data of ponatinib and the unique dosing schedule based on individual response will be discussed. Lastly, two cases will focus on features of TKI treatment that -remarkably- have become part of the treatment algorithm: family planning for women with CML and stopping therapy after meeting a specific treatment milestone.

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Interferon- Before Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia Does Not Affect Outcome Adversely, Provided It Is Discontinued at Least 90 Days Before the Procedure

Blood ◽

10.1182/blood.v94.11.3668 ◽

1999 ◽

Vol 94 (11) ◽

pp. 3668-3677 ◽

Cited By ~ 79

Author(s):

Rüdiger Hehlmann ◽

Andreas Hochhaus ◽

Hans-Jochem Kolb ◽

Jörg Hasford ◽

Alois Gratwohl ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Chronic Myelogenous Leukemia ◽

Marrow Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Chronic Phase ◽

Observation Time ◽

Allogeneic Bone Marrow ◽

Myelogenous Leukemia ◽

Allogeneic Bone

Abstract The influence of interferon- (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN ± chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl–positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P = .0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.

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Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits.

Journal of Clinical Oncology ◽

10.1200/jco.1992.10.5.779 ◽

1992 ◽

Vol 10 (5) ◽

pp. 779-789 ◽

Cited By ~ 28

Author(s):

J E Wagner ◽

M Zahurak ◽

S Piantadosi ◽

R B Geller ◽

G B Vogelsang ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Chronic Myelogenous Leukemia ◽

Marrow Transplantation ◽

Univariate Analysis ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Allogeneic Bone ◽

Term Survival ◽

Gvhd Prophylaxis

PURPOSE Allogeneic bone marrow transplantation (BMT) is an option for some patients with chronic myelogenous leukemia (CML). We retrospectively evaluated the effect of various risk factors observed at diagnosis and at transplantation on survival, event-free survival (EFS), and relapse after BMT. PATIENTS AND METHODS Seventy-nine patients with CML in chronic phase (CP) were treated with cyclophosphamide and total body irradiation followed by BMT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) in most instances or CsA plus the use of lymphocyte-depleted bone marrow (BM). RESULTS Survival at 4.5 years was 52%. Stratified by age and GVHD prophylaxis, the actuarial survival was 65% (95% confidence interval [CI], 47% to 78%) in patients aged less than 30 years receiving unmanipulated BM, 33% (95% CI, 12% to 56%) in patients greater than or equal to 30 years old receiving unmanipulated BM, and 38% (95% CI, 14% to 63%) in patients greater than or equal to 30 years old receiving lymphocyte-depleted BM. In univariate analysis, patient age (greater than or equal to 30 years) and the use of lymphocyte-depleted BM negatively influenced EFS. When stratified by age and GVHD prophylaxis, however, ABO incompatibility, cytomegalovirus (CMV) seropositivity, and chronic GVHD significantly reduced the probability of EFS. Factors that have been associated with early death in nontransplanted patients (ie, sex, spleen size, blast and platelet counts at presentation) were not predictive of long-term survival outcome after BMT. CONCLUSIONS The data suggest that (1) BMT should be offered early after diagnosis to all patients with CML in CP who have compatible sibling donors regardless of prognostic factors at presentation, (2) GVHD remains the principal cause of mortality after BMT in patients receiving CsA, and (3) T-cell depletion by the physical separation method of counterflow elutriation (CE) is associated with a significant risk of relapse.

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Fas-Mediated Modulation of Bcr/Abl in Chronic Myelogenous Leukemia Results in Differential Effects on Apoptosis

Blood ◽

10.1182/blood.v92.3.981 ◽

1998 ◽

Vol 92 (3) ◽

pp. 981-989 ◽

Cited By ~ 29

Author(s):

Carmine Selleri ◽

Jaroslaw P. Maciejewski ◽

Fabrizio Pane ◽

Luigia Luciano ◽

Anna Maria Raiola ◽

...

Keyword(s):

Chronic Myelogenous Leukemia ◽

Chronic Phase ◽

Poor Response ◽

Inhibitory Response ◽

Myelogenous Leukemia ◽

Poor Responders ◽

Cd34 Cells ◽

In Cells

Abstract Fas-R is expressed constitutively in CD34+ cells of patients with chronic myelogenous leukemia (CML); Fas-R triggering results in decreased proliferation rate due to apoptosis of clonogenic cells. We have already shown that α-interferon (IFN-α) enhances Fas-R expression on CML progenitor cells, thus increasing their sensitivity to Fas-R agonists. Although it appears that IFN-α can prime CML cells for the effects of Fas, the response to IFN-α in vivo is not a constant feature in CML patients. We studied the mechanisms of Fas-mediated apoptosis in 11 patients suffering from CML in chronic phase and tried to see whether there was a correlation between in vitro inducibility of apoptosis in CD34+ CML cells after Fas-R triggering and the clinical response to IFN-α. After priming with IFN-α, Fas triggering resulted in in vitro suppression of hematopoietic cell growth in seven of eight patients who had optimal hematologic response to IFN-α; in the same conditions, no inhibitory response to Fas-R agonist was observed in cells from three of three patients who proved to be poor responders to IFN-α. In responders to IFN-α, Fas-R agonist induced dose-dependent apoptosis of CD34+ cells; this effect was associated with a decrease in the bcr/abl protein level. In cells derived from patients with a poor response to IFN-α, the rate of apoptosis in culture remained unchanged in the presence of Fas-R agonist and nobcr/abl downmodulation was observed. Finally, we measuredbcr/abl mRNA by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and found that decreased bcr/ablprotein after Fas triggering was not associated with decreased amounts of specific mRNA, a finding which is consistent with a posttranscriptional regulation of the bcr/abl protein expression. It appears that Fas-mediated downmodulation of p210bcr/abl restores susceptibility to apoptosis of CML cells; in addition, in vitro studies on CML cells may predict response to IFN-α treatment. © 1998 by The American Society of Hematology.

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BCR Rearrangement–Negative Chronic Myelogenous Leukemia Revisited

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.11.2915 ◽

2001 ◽

Vol 19 (11) ◽

pp. 2915-2926 ◽

Cited By ~ 62

Author(s):

Razelle Kurzrock ◽

Carlos E. Bueso-Ramos ◽

Hagop Kantarjian ◽

Emil Freireich ◽

Susan L. Tucker ◽

...

Keyword(s):

Chronic Myelogenous Leukemia ◽

Blast Crisis ◽

Chronic Phase ◽

Interferon Alfa ◽

Myelogenous Leukemia ◽

Disease Evolution ◽

Number Of Patients ◽

Significant Difference ◽

Atypical Cml ◽

Peripheral Blood Smears

PURPOSE: To document the characteristics of patients with major breakpoint cluster region (M-bcr) rearrangement–negative chronic myelogenous leukemia (CML). PATIENTS AND METHODS: The hematopathologist, who was blinded to patients’ molecular status, reviewed the referral bone marrows and peripheral-blood smears from 26 patients with Philadelphia (Ph) translocation–negative CML who lacked Bcr rearrangement (and other evidence of a Bcr-Abl anomaly) and 14 patients (controls) with chronic-phase Ph-positive CML. Clinical data was ascertained by chart review. RESULTS: Among the 26 M-bcr rearrangement–negative CML patients, three pathologic subtypes emerged: (1) patients indistinguishable from classic CML (n = 9), (2) patients with atypical CML (n = 8), and (3) patients with chronic neutrophilic leukemia (n = 9). Among the 14 patients with Ph-positive CML who were included in the blinded review, 13 were classified as classic CML, and one was classified as atypical CML. The only statistically significant difference between M-bcr rearrangement–negative subgroups was in the proportion of patients having karyotypic abnormalities, an observation common only in patients with atypical CML (P = 0.008). However, the small number of patients in each subgroup limited our ability to differentiate between them. Interferon alfa induced complete hematologic remission in five of 14 patients; four of these remissions lasted more than 5 years. Only one of 26 patients developed blast crisis. The median survival of the 26 patients was 37 months. CONCLUSION: Patients with M-bcr rearrangement–negative CML fall into three morphologic subgroups. Disease evolution does not generally involve blastic transformation. Instead, patients show progressive organomegaly, leukocytosis, anemia, and thrombocytosis. Some patients in each subgroup can respond to interferon alfa.

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