Significance of Rising Levels of Minimal Residual Disease in Patients with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+ CML) in Complete Cytogenetic Response (CGCR)

Abstract Background . Patients with Ph+ CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by quantitative polymerase chain reaction (QPCR) studies for minimal molecular disease. The clinical significance of rising levels of QPCR in CGCR is uncertain. Study Aims . To evaluate the relevance of increases of QPCR levels in patients with CML in CGCR on therapy. Study Group and Methods . Of 258 patients on imatinib therapy for newly diagnosed CML, 116 patients in durable CGCR on imatinib therapy for at least 18 months had significant QPCR increases (documented at least twice) as defined by literature reports. These were analyzed by the achievement of major molecular response (MMR; QPCR < 0.05%), and by the degree of QPCR increase. Results. The outcome of patients by disease status (still in MMR vs. loss of MMR vs. never in MMR) and by the QPCR level increase are shown in the Table. Only 13 of 116 patients (11%) with significant QPCR increases had CML progression; 11 of them were among 44 patients (25%) who either lost a MMR or never had a MMR, and had > 1 log increase of QPCR. The 5-year survival of all 116 patients was 92%, suggesting the minimal relevance of QPCR increases in patients in CGCR. Conclusion . Most patients with significant QPCR increases remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have > 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions. Allogeneic stem cell transplant should not be considered in view of the excellent survival. Outcome of Patients in CGCR by QPCR Increases Disease Status QPCR Log increase No. Patients CML Progression Median follow-up from QPCR increase in months (range) Persistent MMR Any 28 0 36 (3–62) Loss of MMR >0.5–1 12 0 34 (14–59) >1–2 25 3 31 (6–52) >2 11 4 45 (20–57) Not in MMR <1 32 2 35 (10–70) >1 8 4 25 (12–56)

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Significance of Increasing Levels of Minimal Residual Disease in Patients With Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia in Complete Cytogenetic Response

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.6999 ◽

2009 ◽

Vol 27 (22) ◽

pp. 3659-3663 ◽

Cited By ~ 43

Author(s):

Hagop M. Kantarjian ◽

Jianqin Shan ◽

Daniel Jones ◽

Susan O'Brien ◽

Mary Beth Rios ◽

...

Keyword(s):

Chronic Myelogenous Leukemia ◽

Kinase Inhibitors ◽

Residual Disease ◽

Quantitative Polymerase Chain Reaction ◽

Philadelphia Chromosome ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Therapeutic Interventions ◽

Molecular Response ◽

Complete Cytogenetic Response

Purpose The aim of this study was to evaluate the clinical relevance of increases in quantitative polymerase chain reaction (QPCR) levels in patients with chronic myelogenous leukemia (CML) who are in complete cytogenetic response (CGCR) on therapy. Patients with Philadelphia chromosome (Ph)–positive CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by QPCR studies for minimal molecular disease. The clinical significance of increasing levels of QPCR in patients in CGCR is uncertain. Patients and Methods One hundred sixteen patients in durable CGCR, and on imatinib therapy for at least 18 months, had increases in QPCR levels (documented at least twice consecutively) as defined by literature reports. These were further analyzed by the achievement of major molecular response (MMR) defined as QPCR ≤ 0.05%, as well as by the degree of increase in QPCR. Results Only 11 (9.5%) of 116 patients with increases in QPCR had CML progression; 10 of them were among 44 patients (23%) who either lost a MMR or never had a MMR, and had more than 1 log increase of QPCR. Conclusion Most patients with increases in QPCR remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have more than 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions.

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Detection of MRD may predict the outcome of patients with Philadelphia chromosome–positive ALL treated with tyrosine kinase inhibitors plus chemotherapy

Blood ◽

10.1182/blood-2012-11-466482 ◽

2013 ◽

Vol 122 (7) ◽

pp. 1214-1221 ◽

Cited By ~ 131

Author(s):

Farhad Ravandi ◽

Jeffrey L. Jorgensen ◽

Deborah A. Thomas ◽

Susan O’Brien ◽

Rebecca Garris ◽

...

Keyword(s):

Kinase Inhibitors ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Quantitative Polymerase Chain Reaction ◽

Philadelphia Chromosome ◽

Multiparameter Flow Cytometry ◽

Molecular Response ◽

Cell Transplant ◽

Treatment Intensification ◽

Philadelphia Chromosome Positive

Abstract From 2001 to 2011, 122 patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia were treated with chemotherapy + imatinib (n = 54) or + dasatinib (n = 68). One hundred fifteen (94%) achieved complete remission (CR) including 101 patients who achieved it with only 1 induction course and had at least 1 minimal residual disease (MRD) assessment; 25 patients underwent an allogeneic stem cell transplant in first CR and were excluded, leaving 76 patients as the subject of this report. MRD monitoring by multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (PCR) was performed at the end of induction and at ∼3-month intervals thereafter. Median age was 54 years (range, 21-84 years). There was no difference in survival by achievement of at least a major molecular response (MMR; BCR-ABL/ABL < 0.1%) at CR (P = .22). Patients achieving MMR at 3, 6, 9, and 12 months had a better survival (P = .02, .04, .05, and .01, respectively). Negative MFC at CR did not predict for improved survival (P = .2). At 3 and 12 months, negative MRD by MFC was associated with improved survival (P = .04 and .001). MRD monitoring by PCR and MFC identifies patients who benefit from treatment intensification in first CR.

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Prognostic Significance of the Lost of a Major Molecular Response In Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+CML).

Blood ◽

10.1182/blood.v116.21.3435.3435 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3435-3435

Author(s):

J. Valentin García-Gutiérrez ◽

Pilar Herrera ◽

Marta Jimenez-Rolando ◽

María Tenorio ◽

María Calbacho ◽

...

Keyword(s):

Kinase Inhibitors ◽

Conflicts Of Interest ◽

Residual Disease ◽

Prognostic Significance ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Major Molecular Response

Abstract Abstract 3435 Background: Albeit of well-known, dramatic improvements, there remain some questions to be solved around Ph+CML in treatment with tyrosine kinase inhibitors (TKI). Among these, the significance of the amount of minimal residual disease (MRD) measured by RT-PCR. For instance, loss of a so-called major molecular response (MMR) is claimed to be a Òsuboptimal responseÓ and following the ELN recommendations, a change in treatment should be considered in these patients. Aims: To evaluate the relevance of a loss of MMR in patients with complete cytogenetic response (CCR). Study Group and Methods: We have analized 81 patients treated with imatinib for CML in chronic phase with a median follow up of 66 months. 36 patients started imatinib after interferon failure and 45 as front line therapy. Major Molecular Response (MMR; BCR-ABL/ABL ratio<0.1% IS) at any time was achieved by 63 patients. Results: 22 patients (34%) lost MMR (documented al least twice). The risk of losing MMR was higher in late MMR (>18 months) compared with those cases whose MMR came much earlier (<18 months): 70% vs 18% (p=. 000). We have found no correlation among the lost of MMR and classical prognostic factors (Sokal-Index, mutations at the TK domain or imatinib plasma levels). Of these 22 patients, 7 (32 %) recovered MMR later with no therapy changes, 8 (36%) experienced fluctuations in the BCR-ABL transcript-levels without losing CCR, 4 (19%) did not attain a MMR but remained in stable CRR, and 3 (13%) lost CCR. These regained MMR after being treated on second generation TKI. The results show how the stability of the early MMR is greater than late MMR (table1). Conclusions: In our experience, one third of the patients who lost MMR recovered it later on the same treatment. And only 13% went on to treatment failure. Perhaps some similar cases (after first losing MMR) should be closely monitored before a change in treatment. Also of note is, of course regarding only our experience, that the risk of a loss of MMR seems to be maximal in patients who achieve a late MMR. Disclosures: No relevant conflicts of interest to declare.

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A Pilot Study Evaluating the Safety and Efficacy of Imatinib Given Early after Transplant for High-Risk Philadelphia Chromosome-Postive Leukemias.

Blood ◽

10.1182/blood.v106.11.1095.1095 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1095-1095

Author(s):

Paul A. Carpenter ◽

David S. Snyder ◽

Mary E. Flowers ◽

Jean E. Sanders ◽

Paul J. Martin ◽

...

Keyword(s):

Pilot Study ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Dose Intensity ◽

Antigen Expression ◽

Myelogenous Leukemia ◽

Imatinib Therapy ◽

Cell Transplant ◽

Hematopoietic Cell Transplant

Abstract Patients with Ph+ acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) in stages other than first chronic phase (CP1) frequently have recurrent malignancy after allogeneic hematopoietic cell transplant (HCT). Imatinib given after HCT for the treatment of hematological relapse has been of limited success in Ph+ALL but may induce more durable remissions in CML. Hypothesis: We postulated that imatinib might be most effective for preventing hematological relapse after myeloablative HCT if given immediately after engraftment to patients without detectable leukemia, or with leukemia that can be detected only at the molecular level. Study design: A pilot study is ongoing to evaluate the safety and preliminary efficacy of imatinib begun early after myeloablative HCT and continued until post-transplant day 365 (D+365). Study participants became eligible to start imatinib (adults 400 mg/day, children 260 mg/m2/day) if the residual marrow leukemia burden at the time of initial engraftment (ANC>500 on 2 consecutive days) did not exceed >1/20 Ph+ metaphases, >1% aberrant antigen expression on blasts by multidimensional flow, or presence of bcr/abl in >5% interphase nuclei by FISH. The primary endpoint of safety was defined by ability to tolerate imatinib (adults ≥200 mg/day, children ≥100 mg/day) for ≥ 6 days/week until D+90. An attempt was made to administer higher daily doses of imatinib after D+90. Patient characteristics: Ten patients with Ph+ALL (8 CR1, 2 CR2) and 6 patients with CML (2 AP, 2 CP2, 2 CP3) have been enrolled; 13/16 had leukemia detected by molecular or cytogenetic methods at the time of transplant. Median age at transplant was 40 y (range 5–62 y). Stem cell sources were cord blood (n=1), marrow (n=4) or G-mobilized peripheral blood (n=11). Donors were unrelated (n=10) or related (n=6). Results: Imatinib therapy began in 15 patients at a median of 29 days (range 24–39 days) after HCT and has been administered for a median of 299 days (range, 33–380 days). The median of average daily doses during this time period was 400 mg/day (range 389 to 510 mg/day) among adults and 304 mg/m2/day for the 2 children. All patients tolerated imatinib at the intended dose intensity within the first 90 days after HCT. Toxicities (NCI CTC v3.0) possibly attributed to imatinib included grade 1–2 nausea (n=3), grade 1 edema (n=3), grade 1–2 anemia (n=2), and grade 3 neutropenia (n=2). Per protocol, one patient with neutropenia received 2 doses of G-CSF at D+75 and continued imatinib without neutropenia. The second patient was not given G-CSF and imatinib was held for 2 weeks from D+160 until the ANC was >2000. All patients are surviving at a median of 333 days after HCT (range, 68–564), and 14/15 patients have no detectable bcr/abl transcripts in the blood or marrow. Seven patients (4 ALL, 3 CML) have completed imatinib therapy and survive at a median of 467 days after HCT (range, 410–564 days) and 6/7 have no detectable bcr/abl transcripts in blood or marrow. One patient (CML-CP3) with cytogenetic relapse at D+118 had a 4th remission after withdrawal of immunosuppression and continued imatinib but developed hematological relapse at D+429. Conclusions: We conclude that imatinib therapy can be safely prescribed early after myeloablative allogeneic HCT at a dose-intensity comparable to that used in general oncology. Preliminary efficacy data are encouraging and worthy of further study.

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Analysis of the Effectiveness of Maintenance Therapy By Imatinib in Patients with Pdgfra-Positive Neoplasm

Blood ◽

10.1182/blood-2018-99-116262 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1755-1755

Author(s):

Irina Nemchenko ◽

Nikolay Tsyba ◽

Ekaterina Chelysheva ◽

Oleg Shukhov ◽

Anna G Turkina

Keyword(s):

Dose Regimen ◽

Kinase Inhibitors ◽

Clinical Symptoms ◽

Myelogenous Leukemia ◽

Imatinib Therapy ◽

Response To Treatment ◽

Molecular Response ◽

Therapy Regimen ◽

Molecular Tests ◽

Complete Blood Counts

Abstract Introduction: The effective therapy of PDGFRA- and PDGFRB-myeloid/lymphoid neoplasms with eosinophilia in the era of tyrosine kinase inhibitors (TKI) allows to achieve a complete hematologic response (CHR) and a molecular response (MR). The long-term duration of the MR makes it reasonable to evaluate the eligibility of various TKI maintenance regimens by analogy with Ph'-positive chronic myelogenous leukemia. Objective: to evaluate the results of maintenance imatinib therapy in patients with PDGFRA-positive neoplasm. Patients and Methods: Between November 2003 and March 2018, imatinib was used in 42 patients with a PDGFRA-positive neoplasm (male:female=40:2, median age 39 years). The initial dose of imatinib was 100 mg per day. CHR was considered as normalization of complete blood counts and disappearance of clinical symptoms and complaints caused by to the disease. The MR was estimated by the qualitative RT-PCR method. The achievement of MR was noted in case of the absence of FIP1L1-PDGFRA transcript expression in bone marrow/peripheral blood cells. The preservation of stable CHR and stable MR was the indication for switching to a maintenance (supportive) regimen. The frequency of imatinib use during the maintenance regimen was reduced from 100 mg daily to 100 mg every other day or 100 mg twice a week. All patients receiving imatinib within a reduced dose regimen underwent regular clinical and laboratory monitoring. Results: CHR was obtained in 95% (40/42) of patients. The MR was evaluated in 37 patients. The MR achievement was obtained in 87% (32/37) patients. The reduction of the frequency of imatinib intake according to the above scheme was carried out in 1(53%) 7 out of 32 patients with stable CHR and MR at different time points after the therapy start. Patients who received imatinib in a supportive regimen were conditionally divided into 2 groups. The first group included 13(77%) patients in whom CHR was maintained; the repetitive molecular tests in 11 patients of this group confirmed the preservation of MR. The median follow-up of patients before transfer to a supportive regimen was 30 months (from 12 to 65 months). The median duration of the maintenance regimen at the time of presentation was 29 months (1.5 months to 99 months). The second group included 4(23%) of 17 patients with the loss of response to treatment during the maintenance regimen. The duration of imatinib therapy in the full-dose regimen prior to switch to a supportive regimen was 8, 13, 21 and 26 months and it was significantly less than in the first group of patients. The loss of MR and CHR was observed in 2 patients during the first 5 months after the change of the therapy regimen. Only a loss of MR without CHR loss was observed in the other 2 patients 3 and 11 months after the dose reduction of imatinib. Conclusions: Preserving a stable CHR and MR in patients with PDGFRA-positive neoplasm receiving imatinib makes it possible to transfer the patients to a maintenance regimen of imatinib 100 mg twice a week. We suggest that a continuous imatinib use in a dose 100 mg daily for at least 3 years is necessary in order to have a stable CHR and MR and to be eligible for switching to a supportive treatment regimen. Disclosures Chelysheva: Novartis: Other: provided consultations and performed lectures; Bristol Myers Squibb: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations . Shukhov:Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.

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Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukemia in Complete Molecular Remission: An Update Follow Up.

Blood ◽

10.1182/blood.v108.11.2154.2154 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2154-2154 ◽

Cited By ~ 1

Author(s):

Francois-Xavier Mahon ◽

Francoise Huguet ◽

Gabriel Etienne ◽

Delphine Réa ◽

Jean-Michel Cayuela ◽

...

Keyword(s):

Imatinib Mesylate ◽

Chronic Myelogenous Leukemia ◽

Kinase Inhibitor ◽

Residual Disease ◽

Quantitative Polymerase Chain Reaction ◽

Leukemic Cell ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Molecular Remission

Abstract The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) induces complete cytogenetic responses (CCR) in more than 85% of patients with chronic myelogenous leukemia (CML). However, patients in CCR relapse after imatinib interruption in case of detectable residual disease. In fact, less than 10% of patients achieve a molecular remission, defined by an undetectable residual disease using real time quantitative polymerase chain reaction (RTQ-PCR). We previously reported the outcome of CML patients in CCR after cessation of interferon-alpha during the pre-imatinib era. Seven (all with a negative PCR) out of 15 patients did not relapse (J Clin. Oncol.,20,2002:214–220). In the present study, we address the issue of the discontinuation of imatinib in CML with undetectable residual disease for more than 2 years in 15 patients. The median duration of RTQ-PCR negativity and imatinib therapy were respectively 32 months (24–46) and 45 months (32–56) before imatinib interruption. Eight patients displayed a molecular relapse with a detectable BCR-ABL transcript appearance between the first 6 months. Imatinib was then re-introduced and led to a novel molecular response in most patients. Seven other patients have still an undetectable level of BCR-ABL transcript after a median follow up of 20 months (9–24). With the assumption that the doubling time of a proliferative CML cell is 8 days, it will take a maximum of 6 months if only one leukemic cell persists and proliferates to reach 107 cells i.e corresponding to a residual disease detectable by RTQ-PCR. Relapses observed within 6 months may reflect the kinetic of undetectable dividing CML cells. Those cells may be eradicated or controlled in long term non relapsing patients described in our study.

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

Blood ◽

10.1182/blood.v85.10.2705.bloodjournal85102705 ◽

1995 ◽

Vol 85 (10) ◽

pp. 2705-2710 ◽

Cited By ~ 16

Author(s):

CF Verschraegen ◽

M Talpaz ◽

CF Hirsch-Ginsberg ◽

R Pherwani ◽

MB Rios ◽

...

Keyword(s):

Bone Marrow ◽

Peripheral Blood ◽

Residual Disease ◽

Philadelphia Chromosome ◽

Disease Suppression ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Breakpoint Cluster Region ◽

Cluster Region ◽

Molecular Studies

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.

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High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia

Blood ◽

10.1182/blood-2003-11-3800 ◽

2004 ◽

Vol 103 (8) ◽

pp. 2873-2878 ◽

Cited By ~ 283

Author(s):

Hagop Kantarjian ◽

Moshe Talpaz ◽

Susan O'Brien ◽

Guillermo Garcia-Manero ◽

Srdan Verstovsek ◽

...

Keyword(s):

Imatinib Mesylate ◽

Quantitative Polymerase Chain Reaction ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

High Dose ◽

Molecular Response ◽

Newly Diagnosed ◽

Complete Cytogenetic Response

Abstract Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] < 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P = .0005), major molecular response (QPRC < 0.05%; P = .00001), and complete molecular response (undetectable BCR-ABL; P = .001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML. (Blood. 2004; 103:2873-2878)

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An Unusual Case of Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia With Trisomy 19 Presenting With Megakaryoblastosis and Myelofibrosis

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2012-0151-cr ◽

2013 ◽

Vol 137 (8) ◽

pp. 1147-1151 ◽

Cited By ~ 2

Author(s):

Nika Aljinovic ◽

Agata M. Bogusz ◽

Sibel Kantarci ◽

Thomas P. Buck ◽

Rajan Dewar

Keyword(s):

Chronic Myelogenous Leukemia ◽

Kinase Inhibitors ◽

Blast Crisis ◽

Philadelphia Chromosome ◽

Myelogenous Leukemia ◽

Cell Transplant ◽

Life Saving ◽

Cytogenetic Studies ◽

Night Sweats ◽

Infectious Etiology

Initial identification of chronic myelogenous leukemia is very important since targeted therapy leads to life-saving remission. Rarely, chronic myelogenous leukemia presents with an unusual picture, making the diagnosis challenging. We describe such a case of chronic myelogenous leukemia in blast crisis in a previously healthy 61-year-old woman. The patient presented with fever, myalgias, and night sweats and was first worked up for an infectious etiology. Because of persistent anemia, a bone marrow biopsy was performed that revealed fibrosis with increased megakaryoblasts. Even though initial cytogenetic studies could not be performed because of “dry tap” aspirate, persistent efforts for cytogenetic studies were made, including a “squeeze preparation” from the core biopsy, which revealed t(9;22)(q34;q11.2) and trisomy 19. The patient was treated with tyrosine kinase inhibitors, chemotherapy, and subsequently an allogeneic stem cell transplant. She is in persistent remission. This case illustrates a complex presentation of chronic myelogenous leukemia and provides an overview of morphologic cues and the importance of performing cytogenetic studies that led to the diagnosis.

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Bosutinib (SKI-606) Demonstrates Clinical Activity and Is Well Tolerated among Patients with AP and BP CML and Ph+ ALL.

Blood ◽

10.1182/blood.v110.11.473.473 ◽

2007 ◽

Vol 110 (11) ◽

pp. 473-473 ◽

Cited By ~ 12

Author(s):

C. Gambacorti-Passerini ◽

H. Kantarjian ◽

T. Bruemmendorf ◽

G. Martinelli ◽

M. Baccarani ◽

...

Keyword(s):

Philadelphia Chromosome ◽

Fluid Retention ◽

Myelogenous Leukemia ◽

Clinical Activity ◽

Hematologic Toxicity ◽

Molecular Response ◽

Cell Transplant ◽

Major Molecular Response ◽

Wide Range ◽

Grade 3

Abstract Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor. Biochemical assays have shown it to be up to 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation. Unlike imatinib, bosutinib does not exhibit significant inhibition of c-kit or platelet-derived growth factor receptor (PDGFR), which may result in a relatively favorable safety profile. This is an ongoing open-label study in patients (pts) with Philadelphia chromosome positive (Ph+) accelerated phase (AP) and blast phase chronic myelogenous leukemia and (Ph+) ALL who failed prior imatinib therapy or other TKIs. Objectives are to assess safety and clinical activity of bosutinib. Pts receive bosutinib 500 mg/day. We report preliminary data for 57 pts, median age 54 yrs (range 22–83 yrs), 54% male. 23 pts (40%) were in AP, 15 (26%) in blast crisis (BC), 14 (25%) had Ph+ALL, and 5 (9%) were unclassified. Prior therapy included interferon (22 pts), imatinib (55 pts; data missing for 2 pts), dasatinib (17 pts), nilotinib (10 pts), stem cell transplant (5 pts). Overall median duration of bosutinib treatment was 2.7 mos (range 0.03–10.8 mos). Complete hematological response (CHR) was obtained in 7/25 evaluable pts (28%), including 4/14 (29%) pts with AP-CML, 2/8 (25%) pts with BC-CML, and 1/3 (33%) pts with Ph+ ALL. Among pts with no other TKI exposure, major cytogenetic responses (MCyR) were observed in 5/14 evaluable pts (36%), including 3/6 (50%) pts with AP-CML, 2/5 (40%) pts with BC-CML. Among pts with prior TKI exposure, 3/10 (30%) had MCyR, including 0/3 AP, 1/4 BP, and 2/3 ALL pts. Median time to MCyR was 8.9 weeks for pts previously exposed and 12 wks for unexposed to other TKIs. Duration of MCyR was 18 wks. 19 previously unexposed patients were evaluable for major molecular response. 4 (21%) had major molecular response, 3 (16%) of which were complete. Of 42 pts with samples tested for mutations, 13 different mutations were found in 20 pts (48%), including 5 cases of T315I. CHR occurred in 2/3 pts with P-loop mutations and 5/17 with non-P-loop mutations; MCyR occurred in 2/2 pts and 4/9 pts, respectively. Treatment was generally well tolerated in this cohort of heavily pretreated patients. The most common adverse events were gastrointestinal (diarrhea [56%], nausea [37%], vomiting [35%]) but these were usually grade 1–2, manageable and transient, reducing in frequency and severity after the first 3–4 weeks of therapy. Grade 3–4 hematologic laboratory abnormalities reported included thrombocytopenia in 31 pts (59%), neutropenia in 20 pts (38%), and anemia in 13 pt (25%). Grade 3–4 non-hematologic toxicities were diarrhea (9%) and vomiting (9%). Fluid retention was reported in 8 pts (14%), including 2 cases (3%) of pleural effusion (grade 2 and 3). Both were considered unrelated to treatment. Bosutinib is effective in imatinib-resistant pts with advanced CML. Responses were observed across a wide range of Bcr/Abl mutations. Bosutinib has a favorable toxicity profile with a small number of pts experiencing hematologic toxicity and fluid retention, possibly due to the lack of c-kit inhibition and PDGFR inhibition, respectively.

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