Sudden blast crisis in patients with Philadelphia chromosome-positive chronic myeloid leukemia who achieved complete cytogenetic remission after imatinib therapy

Authors


Abstract

BACKGROUND.

Most patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) in chronic phase (CP) who receive treatment with imatinib achieve complete cytogenetic remission (CCR), which is correlated tightly with long-term progression-free survival. In these patients, the occurrence of blastic crisis (BC) is rare, and its clinical biologic characteristics are not well known.

METHODS.

Among 164 patients who received imatinib and were followed for a median of 35 months, 11 patients (6.7%) developed a BC; this was sudden (i.e., it occurred within 3 months of a documented CCR) in 6 patients (54.5%). Those patients were analyzed with respect to their clinical and biologic features and were compared with previous reports.

RESULTS.

At the time of diagnosis, there were 3 low-risk patients and 3 intermediate-risk patients; 4 patients had received pretreatment with interferon, and 2 patients received only imatinib. The median CP was 18 months, and the median duration of imatinib therapy was 7 months. The median time to CCR was 3 months, and the median time from CCR to BC was 4 months. BC phenotype was lymphoid in 2 patients, myeloid in 3 patients (including 2 patients who had extramedullary localization), and biclonal in 1 patient. Karyotype evolution was detected in 4 patients, whereas a Ph-positive/Ph-negative mosaicism was evident in all 6 patients. One patient presented an M351T mutation. The overall median survival was 3 months.

CONCLUSIONS.

Sudden BC generally is an uncommon phenomenon that may be relatively frequent in patients with CML who receive imatinib. Clinical and biologic features also seem to characterize this peculiar type of abrupt disease evolution, which intervenes in patients' response to this drug. Close monitoring of disease markers and full disease eradication are warranted. Cancer 2006. © 2006 American Cancer Society.

The natural course of chronic myeloid leukemia (CML) typically is marked by an initial chronic phase and spontaneously evolves into a more advanced, accelerated phase, which proceeds into a terminal blast crisis (BC) of a few months' duration.1 Since the advent of imatinib, from 80% to 90% of patients with CML have been able to obtain a complete cytogenetic response (CCR), and from 50% to 70% have been able to achieve a major molecular response, and the rate and degree of responses have been used as surrogate markers for long-term disease-free survival.2, 3 The current follow-up data from approximately 5 years show that only a limited number of patients have developed blastic transformation, and it remains unclear whether their clinical and biologic characteristics differ somehow from those of patients who have developed BC under previous therapies, which consisted mostly of busulfan, hydroxyurea, and interferon (IFN)-based regimens or even bone marrow transplantation.4–9

In the past, the sudden onset of BC was defined as an acute transformation that occurred unexpectedly in patients who were in documented complete hematologic remission (CHR).4 Since the advent of imatinib, sudden BC was redefined suitably BC onset after a documented CCR in the immediately preceding bone marrow analysis.9 Herein, we report on our experience relating this event, which occurred in 6 patients in CCR during imatinib therapy.

MATERIALS AND METHODS

From January 2000 to December 2004, 200 patients with Philadelphia chromosome (Ph)-positive CML in chronic phase (CP) received imatinib at our institution. One hundred fifty patients were pretreated with IFN for a median of 24 months and then received imatinib for a median of 7 months, whereas 50 patients received imatinib as first-line therapy for a median of 15 months. After that treatment, all patients had cytogenetic examinations every 3 months until they achieved CCR; then, samples also were studied at the molecular level (reverse transcriptase-polymerase chain reaction [RT-PCR] analysis) for residual disease. Among 164 patients in CP who had available follow-up, 11 patients (6.7%) developed BC after a median of 35 months' observation. In 6 patients (54%), BC was sudden (defined as the abrupt onset of transformation occurring within 3 months of a documented CCR); the other 5 patients developed BC after previously demonstrating resistant disease.

BC was defined as the presence of ≥30% blasts in the bone marrow or peripheral blood or by extramedullary blastic disease. At the time of BC, morphologic, immunologic, and cytogenetic features were analyzed in all patients. Karyotypic study was performed and interpreted according to International System for Human Cytogenetic Nomenclature criteria (1985)10; fluorescence in situ hybridization (FISH) and RT-PCR molecular analyses were carried out as reported previously.11, 12 In 3 of the 6 patients, molecular analysis with the denaturing high-performance liquid chromatography (DHPLC) technique13 for rapid analysis of single-nucleotide polymorphisms was performed at the time of sudden BC to evaluate BCR/ABL kinase domain mutations.

RESULTS

Table 1 shows the clinical and biologic features of the 6 patients who had sudden BC. There were 5 males and 1 female, and the median age was 55 years (range, 40–74 years). At the time they were diagnosed with CML, 3 patients were low risk, and 3 patients were intermediate risk according to both the Sokal score14 and the Euro15 score.

Table 1. Clinical and Biologic Features of 6 Patients with Sudden Blast Crisis: Imatinib Therapy
             Karyotypic analysis  
PatientGenderAge, yearsSokal scoreEuro scoreBCR/ABL transciptPrior treatment, monthsDuration of CP, monthsImatinib therapy, monthsWeeks to CHRMonths to CCRMonths from CCR to BCType of BCSC (%)FISH (%)Therapy for BCFollow-up (Months from BC)
  1. CP indicates chronic phase; CHR, complete hematologic remission; CCR, complete cytogenetic remission; BC, blast crisis; SC, standard cytogenetics; FISH, fluorescence in situ hybridization; IFN, interferon-α; HU, hydroxyurea; Ph, Philadelphia chromosome; +, positive, −, negative; Int, intermediate; Flag, fludarabine, cytarabine, and granulocyte-colony stimulating factor; Ida: idarubicin; GO: gentuzumab ozogamicin; SCT: stem cell transplantation; Ly, lymphoid; VCR: vincristine; PDN: prednisone; My, myeloid; extra, extramedullary; ARA-C; cytosine arabinoside; DNR: daunorubicin; NR: not responding.

1Male40LowLowb3a2IFN + HU (12)186133Biclonal46, XY (98) 46, XY, Ph (2)Ph– (48) Ph+ (50) Ph, Ph (2)Flag/Ida + GO + SCTAlive (>36)
2Female66IntIntb2a2IFN + HU (106)1115232Ly46, XX (50) 46, XX, Ph (50)Ph– (7) Ph+ (93)VCR + PDNAlive (>30)
3Male44LowLowb3a216153312My46, XY (25) 47, XY, Ph, +8 (75)Ph– (45) Ph+ (55)Dead (0.5)
4Male74IntIntb3a2IFN + HU (30)388235Ly46, XY, Ph (100)Ph– (38) Ph+ (62)VCR + PDNDead (4, NR)
5Male40LowLowb3a218152312My + extra46, XY (94) 47, XY, Ph, Ph (6)failureARA-C + DNRDead (1.5, NR)
6Male70IntIntb3a2IFN + HU (6.5)125.5132.5My + extra47, XY, Ph, Ph (100)Ph– (2) Ph+ (96) Ph Ph (2)Dead (0.5)
All patients5 Males, 1 female Low (3), Int (3) b3a2 (5), b2a2 (1)4 IFN + HU (21; range, 6.5–106); – (2)-18 (Range, 12–111)7 (Range, 5–15)2 (Range, 1–3)34 (range, 2–12)3 My,2 Ly, 1 biclonal    

All patients displayed the classic t(9;22) Ph chromosome according to standard cytogenetics. Nested RT-PCR analysis performed on mononuclear bone marrow cells (according to BIOMED-1 Concerted Action12) produced positive results for the BCR/ABL b2a2 and b3a2 fusion transcripts in 1 patient and 5 patients, respectively.

Four patients were pretreated with IFN and hydroxyurea (2 patients were resistant, and 2 patients were intolerant), and the other 2 patients received imatinib as first-line therapy. The median duration of CP was 18 months (range, 12–111 months), and the median duration of imatinib therapy before sudden BC was 7 months (range, 5–15 months).

All patients attained a CHR between the first and the third week of imatinib therapy, and all achieved a CCR within the first 3 months. In 4 patients, CCR was confirmed at 6 months, whereas 2 patients developed sudden BC at 5 months and 5.5 months, respectively. The median time from CCR to BC was 4 months (range, 2–12 months). RT-PCR studies were performed only in the 2 patients who had longer CCR follow-up (Patients 3 and 5), and both patients showed persistence of the BCR/ABL transcript at the molecular level (data not shown).

Morphologic and flow cytometry characterization of BC revealed a myeloid (My) subtype in 3 patients, a lymphoid (Ly) subtype in 2 patients, and a biclonal My-Ly phenotype in 1 patient. In 2 of 3 patients who had My BC, an extrahematologic localization also was present at the time of disease progression and consisted of involvement of the cerebrospinal fluid in 1 patient and involvement of the pleura in the other patient.

Acute transformation was associated with a sudden drop in white blood cell counts in 4 patients and with hyperleukocytosis in 2 patients. No alterations in red blood cells or platelet counts were detected in any patient, and no organomegaly was detected. We observed clonal evolution, which consisted of a duplication of Ph chromosome in 3 patients and trisomy 8 in 1 patient. All 6 patients displayed a Ph-positive/Ph-negative mosaicism on metaphases according to standard cytogenetics and/or on interphase nuclei with FISH analysis, this latter indicated a greater percentage of Ph-positive cells versus Ph-negative cells (Table 1).

At the time of this report, with a follow-up of 36 months, 2 patients were alive (1 after a cord-blood transplantation and 1 after intensive chemotherapy), and 4 had died, for an overall median survival of 3 months. The DHPLC technique performed in 3 of the patients who had sudden BC revealed a BCR/ABL point mutation of catalytic domain (M351T) in 1 patient with mixed Ly-My phenotype (Patient 1).

DISCUSSION

To our knowledge, little is known regarding BC developing after patients receive imatinib, which has changed the natural history of CML substantially, and it is still of concern whether these transformations will manifest clinical and/or biologic peculiarities. Furthermore, a percentage of the patients reported to date had received IFN either alone or in combination prior to imatinib,4–9 whereas others had received imatinib as first-line therapy.5–7, 9 Thus, currently, the exact role of this drug in influencing BC features may be difficult to ascertain unequivocally.

The sudden onset of BC in patients in CHR4 has been reported as an uncommon event that occurs at a rate between 2.2% and 4% at 3 years after a variety of nontransplantation therapies, which often consist of IFN-based regimens.4, 11 It has been suggested that sudden BC arises mainly in low-risk patients, often after a short prior disease, and has a high frequency of the Ly phenotype, a higher response rate, and longer survival.4, 11

Recently, sudden blastic transformations have been observed in patients who received imatinib who were in documented CCR.5–9 After the first occasional reports, 4 episodes of sudden onset were observed by Jabbour et al.9 among 23 blast crises that developed in a series of 541 patients with CML (4%) at a follow-up of 46 months, and their incidence accounted for 17% of all BCs and 0.7% of all patients.

In our current series of 164 patients with CP-CML who received imatinib and were followed for 35 months, we observed 11 BCs, 6 of which were sudden transformations in patients who were in documented CCR. The incidence of this event corresponds to 54.5% of all BCs and to 3.6% of all patients, thus appearing higher compared with the values reported by Jabbour et al.9 However, differences in clinical and treatment characteristics in the 2 series of patients prevent any strict comparison of data. The real incidence of this disease evolution, thus, would be assessed better in patients who are treated homogeneously on prospective trials.

Two of our patients (33%) had the Ly phenotype, 3 patients (50%) had the My phenotype, and 1 patient had the biclonal My-Ly phenotype. Thus, altogether, the Ly component was present in 50% of patients (compared with an expected presence of approximately 30%).16

Clonal evolution was detected in 4 patients, whereas a mosaicism of Ph-positive/Ph-negative cells was observed in all 6 patients by standard cytogenetics and/or FISH analysis on bone marrow nuclei. The FISH analysis revealed a greater Ph-positive component, indicating greater mitotic activity by persisting normal cells compared with the abnormal BC clone.

Two patients who had My BC presented with an extrahematologic localization, indicating that clones resistant to imatinib can develop outside bone marrow, where the drug also may penetrate poorly, as suggested previously.6, 17 In a comparison of our data with those from previous reports4–9 (Table 2), similarities appear with regard to the lack of high-risk patients, short time to CCR (<4 months), and whole duration of CP (18 months vs. 20.5 months). Conversely, differences are evident in the rate of prior treatments (4 of 6 treatments vs. 1 of 7 treatments), duration of imatinib therapy (7 months vs. 18 months), and time elapsed from CCR to BC (4 months vs. 13.5 months), i.e., shorter in our patients, who mostly had a preimatinib phase. Altogether, these findings seem to suggest that more aggressive BC subclones may be present already at early or even at an initial disease phase and should follow their course to become evident irrespective of the type of treatment received.

Table 2. Patients with Sudden Blast Crisis from the Literature
PatientType of BCR/ABL transcriptGenderAge, yearsSokal risk (No.)Duration of CP, monthsPrior treatment, (No.)Months of imatinibMonths of CCR to BCMonths to CCR on imatinibCytology of BC (No.)KaryotypeReference
  1. CP indicates chronic phase; CCR, complete cytogenetic remission; BC, blast crisis; NR, no response; Ly, lymphoid; Ph, Philadelphia chromosome; +, positive; −, negative; My, myeloid; IFN, interferon; Int, intermediate.

1NRFemale65NR2322166Ly46, XY, Ph+ no point mutationAvery et al., 20037
2Ph–/Bcr+Male14Low141394Ly46, XY, t(2;17) Bcr/abl+Morimoto et al., 20045
3NRMale?NR?NRNR4MixedNRMatsuda et al., 20056
4NRFemale50Low55.9IFN18153Ly45, XX, −8, t(9;22), −20, +mar /46, XXJabbour, et al., 20059
5NRFemale54Low15.51293My48, XX, +8, t(8;21), t(9;22;19;10), +der (22) (20)Jabbour et al., 20059
6NRMale24Low18.118126Ly43-46, XY, −7, −8, i(9), t(9;22), −13, −17, −21 (13)/46, XY(1)Jabbour et al., 20059
7NRMale58Int2625223My47, XY, t(3;21), +8, t(9;22)(17)/46-48, XX, t(3;21), +8, t(9;22), +der(22) (3)Jabbour et al., 20059
All patients 4 Male, 3 females Low (4), Int (1), ? (2)20.5 (Range, 14–55.9)IFN (1)18 (Range, 12–25)13.5 (Range, 9–12)3.5 (Range, 3–6)My (2), Ly (4), mixed (1)4 clonal evolution 2 Ph+ (100)% 

The relatively high frequency of the Ly cytology observed in sudden BC is not surprising, because this type of evolution obviously should not be preceded by the intermediate phase that usually intervenes in the My cell component; the mutated Ly clone, thus, can emerge abruptly in the context of a stable Ph-positive or even normal cell population. Similarly, the high rate of patients in the low-risk category is not surprising, because the prognostic scores are based mainly on the proliferative expression of the My cell compartment. This evidence is supported further by the characteristics of our patients with gradual BC, who had prevalence of My cytology and intermediate-to-high risk scores.

Thus, although it is unclear whether imatinib can have a causative role in the occurrence of sudden BC, current data seem to suggest that this drug may have mainly an indirect effect by leaving a “window of opportunity” for more aggressive subclones to emerge in the context of restored normal cell population. The existence of resistant and/or mutated subclones, even in low-risk, responding patients, always must be considered during imatinib therapy. Continued, rigorous monitoring of molecular disease markers and a search for new therapeutic strategies to detect and eradicate leukemic residual cells are warranted.

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