A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1527-1535 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Antonio de Vivo ◽  
Francesca Bonifazi ◽  
Domenico Russo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Response Rate ◽  
Randomized Study ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Arabinosyl Cytosine

Interferon-α (IFN-α) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-α has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome–positive CML patients who were assigned at random to treatment with IFN-α2a alone or in combination with LDAC. The scheduled dose of IFN-α2a was 56IU/m2/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-α–plus–LDAC arm versus 55% in the IFN-α arm; P = .11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P = .003), and overall survival (5-year survival, 68% versus 65%; P = .77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-α versus IFN-α plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

scholarly journals Randomized Study on Hydroxyurea Alone Versus Hydroxyurea Combined With Low-Dose Interferon-α2b for Chronic Myeloid Leukemia

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2713-2721 ◽  
Author(s):  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Randomized Study ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Control Group ◽  
Interferon Α ◽  
Group A ◽  
And Control

Interferon-α (IFN-α) is considered the standard therapy for chronic myeloid leukemia (CML) patients not suitable for allogeneic stem cell transplantation. From 1987 through 1992, 195 patients in the Benelux with recent untreated CML were randomized between low-dose IFN-α2b (3 MIU, 5 days/wk) or hydroxyurea alone (control group). The white blood cell count had to be kept less than 10 × 109/L in both arms; to this end, the IFN group received additional hydroxyurea, if necessary. The complete hematologic responses at 6 months in the IFN group were 62%, versus 38% in the control group. In the IFN group, a complete hematologic response at 6 months predicted a better survival (P = .001), but such a tendency was also seen in the control group (P = .07). Cytogenetic responses in the IFN group yielded 9% complete responders, 7% partial responders (<35% Ph+), and 24% minor responders (36% to 95% Ph+). The quality of cytogenetic response within the first 24 months was highly predictive for survival (P = .002). Twenty-four patients discontinued IFN-α because of side effects, but they did this at a long median interval of 17.6 months; the remaining patients did not require dose adaptations. Although the hematologic and cytogenetic responses in the IFN group were higher than in the control group, the duration of chronic phase from randomization was not statistically different with 53 and 44 months in the IFN and control group, respectively. Also, no advantage for survival calculated from diagnosis was seen for the IFN group (median, 64 months) compared with the control group (median, 68 months).

Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1039-1043 ◽  
Author(s):  
Andreas Hochhaus ◽  
Brian Druker ◽  
Charles Sawyers ◽  
Francois Guilhot ◽  
Charles A. Schiffer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Imatinib Treatment ◽  
Serious Adverse Events ◽  
Response Level

Abstract Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.

Result of high-dose imatinib mesylate in patients with Philadelphia chromosome—positive chronic myeloid leukemia after failure of interferon-α

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Jorge Cortes ◽  
Francis Giles ◽  
Susan O'Brien ◽  
Deborah Thomas ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Rate ◽  
Interferon Α ◽  
High Dose ◽  
Molecular Remission

Abstract Imatinib at 400 mg daily is effective in chronic-phase chronic myeloid leukemia (CML) after interferon failure, although only a few patients achieve a molecular remission. We investigated whether higher doses of imatinib may be more effective. Thirty-six patients with chronic-phase CML after failure on interferon-α were treated with 400 mg imatinib twice daily. Median time from diagnosis was 25 months (range, 10-135 months); 4 patients (11%) had clonal evolution. All 11 patients with active disease achieved complete hematologic response. Excluding patients with fewer than 35% Ph-positive metaphases before the start of therapy, 19 (90%) of 21 evaluable patients achieved a major cytogenetic response. Of 27 evaluable patients, 24 (89%) achieved a complete cytogenetic response. Quantitative polymerase chain reaction was performed in bone marrow every 3 months. Of 32 evaluable patients, 18 (56%) showed BCR-ABL/ABL percentage ratios lower than 0.045%, including 13 (41%) with undetectable levels. With a median follow-up of 15 months, all patients were alive in chronic phase. Toxicities were similar to those reported with standard dose; 71% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induces complete cytogenetic responses in most patients with chronic-phase CML after interferon failure. This is accompanied by a high rate of molecular remission. (Blood. 2003;102:83-86)

Comparison Between Patients With Philadelphia-Positive Chronic Phase Chronic Myeloid Leukemia Who Obtained a Complete Cytogenetic Response Within 1 Year of Imatinib Therapy and Those Who Achieved Such a Response After 12 Months of Treatment

2006 ◽  
Vol 24 (3) ◽  
pp. 454-459 ◽  
Author(s):  
Ilaria Iacobucci ◽  
Gianantonio Rosti ◽  
Marilina Amabile ◽  
Angela Poerio ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Overall Survival Rates

Purpose Imatinib mesylate is a potent inhibitor of BCR-ABL, the constitutively active tyrosine kinase protein critical for the pathogenesis of chronic myeloid leukemia. Patients and Methods We reviewed 284 patients with late chronic-phase Philadelphia chromosome (Ph) –positive chronic myeloid leukemia treated with imatinib 400 mg daily after interferon-α failure. In a retrospective study, we evaluated the pattern and rapidity of the response to imatinib, comparing the cytogenetic and molecular responses, progression-free and overall survival rates in patients who obtained a complete cytogenetic response within 1 year of treatment (early responders), and in patients where a complete cytogenetic response was detected after 12 months (late responders). Results After 3 or 4 years of treatment, the molecular response of the late cytogenetic responders was similar to that of the early cytogenetic responders. At 36 months of treatment the amount of residual disease measured by standardized quantitative reverse-transcriptase polymerase chain reaction was 0.00047 in late responders versus 0.00022 in early responders, and at 48 months it was 0.00019 versus 0.00026 (median values, P value = nonsignificant). The estimated 4-year progression-free survival rate was 88% for early responders and 100% for late responders, while the estimated 4-year overall survival rates were 92% and 100% for early and late responders, respectively. Conclusion The sensitivity and the response (cytogenic and molecular) to imatinib may require 1 year or more. Long-term follow-up results continue to improve in terms of rates and durability of the complete cytogenetic response, major or complete molecular response, and progession-free and overall survival.

Nilotinib in Chronic Myeloid Leukemia Patients in Accelerated Phase (CML-AP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3229-3229 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Francis Giles ◽  
Andreas Hochhaus ◽  
Jane F. Apperley ◽  
Gert Ossenkoppele ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Time To Progression ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor, and binds to ABL with higher affinity and improved topological fit compared to imatinib. Nilotinib is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia pts in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-AP pts who are resistant or intolerant to imatinib. Nilotinib was dosed at 400 mg twice daily with the option to dose escalate to 600 mg twice daily for lack of response. The primary endpoint was confirmed hematologic response (HR). Complete hematologic response (CHR) was defined as meeting all of the following criteria: myeloblast count <5% in bone marrow, no myeloblast in peripheral blood, neutrophil count ≥1.5 × 109/L, platelet count ≥100×109/L, basophils <5%, no evidence of extramedullary involvement. Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival, and safety. Results: A total of 138 CML-AP pts (80% imatinib resistant; 20% imatinib intolerant) who received at least 1 dose of nilotinib were included in the analysis. Median age was 57 years (range, 22–82 years); median duration of prior imatinib treatment was 28 months. Seventy-nine percent of pts received prior imatinib doses ≥600 mg/day; overall, 45% received ≥800 mg/day imatinib. Median dose intensity of nilotinib was near planned dose at 775 mg/day with a median duration of exposure of 253 days (8.4 months). Of 134 pts with at least 6 months of follow-up included in the efficacy analysis, 56% had confirmed HR and 30% had CHR. Responses were rapid, with a median time to first HR of 1 month. Hematologic responses were durable at 1 year, with 78% of pts who achieved HR maintaining their response. MCyR and complete cytogenetic response (CCyR) occurred in 32% and 19% of pts, respectively. Cytogenetic responses were also durable, with 69% of pts maintaining MCyR at 18 months. Median time to progression was 16 months in this population of pts with advanced disease. Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. Estimated overall survival at 1 year is 82%. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (40%), neutropenia (40%), anemia (25%), elevated serum lipase (17%), and hypophosphatemia (12%). Grade 3/4 non-hematologic adverse events were uncommon (<1%) and included rash, nausea, fatigue, and diarrhea. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: The long-term follow-up results of this phase 2 study confirm that nilotinib induces rapid and durable responses in pts with CML-AP who failed prior imatinib therapy due to intolerance or resistance, with a favorable toxicity profile.

Long Term Outcomes Of Imatinib In Chronic Myeloid Leukemia In Saudi Population, Single Center Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5180-5180
Author(s):  
Enaam Mohammed Alsobhi ◽  
Mohammed m Abrar ◽  
Mohammed A Abdelaal ◽  
Ahmad S. Alsaeed ◽  
Ahmed Al-Absi ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Randomized Study ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Significant Difference

Abstract Background The introduction of Imatinib therapy has significantly changed the treatment of patients with newly diagnosed chronic myeloid leukemia (CML) and improved survival. Since the International Randomized Study of Interferon (IRIS), a number of studies were conducted involving diverse populations and showed significant variations in the treatment outcome. To date, there has been no published study on the effectiveness of imatinib in adult CML patients in Saudi Arabia. The aim of the present study was to present a single-institution experience in the treatment with imatinib of newly diagnosed patients with CML and compare it with results from international studies. Methods A total of 101 medical records of consecutive adult CML patients treated with imatinib as first line therapy at King Abdulaziz Medical City, Jeddah, Saudi Arabia between 2001 and 2012 were retrospectively reviewed. Survival and response rates were evaluated. Results The estimated overall survival (OS) rates at 5 and 10 years were 95%±2.3% when patients were stratified by cytogenetic type (stander vs.variant Ph positive chromosome) at presentations, significant difference in OS, EFS, and PFS were noted (P=0.001). Complete haematological response was achieved in 94 (93.1%) of our patients, cytogenetic response (CR) in 84 (83.2%) while complete and major cytogenetic response (MCR) were observed in 70 (69.3%) and 6 (5.9%) of the patients respectively. (MR), 62 patients (61.4%) achieved major molecular response (MMR) and 34 (33.7%) complete molecular response. Conclusion compared to other studies among different population, our results confirm the previously noted variation in the response to imatinib. Our study has shown that Ph variant has an impact on the outcome. Further study may be indicated. However second TKI generations as first line in treatment CML with Ph variants should be consider! Disclosures: No relevant conflicts of interest to declare.

Additional Chromosomal Abnormalities in Philadelphia Chromosome-Negative Metaphases Appearing during Therapy with Imatinib, Dasatinib, Nilotinib and Ponatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1577-1577 ◽  
Author(s):  
Ghayas C. Issa ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Banding Technique ◽  
First Year ◽  
Additional Chromosomal Abnormalities

Abstract Background Additional chromosomal abnormalities (ACAs) in the Philadelphia chromosome (Ph)-negative metaphases that emerge as patients with chronic myeloid leukemia (CML) are treated with tyrosine kinase inhibitors (TKIs) have been reported during treatment with imatinib. It has been suggested that these might be associated with an inferior outcome and in rare instances lead to the emergence of a new malignant clone resulting in myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Jabbour et. al, Blood 2007). This phenomenon has not been well characterized when other TKIs are used. We conducted a retrospective analysis of patients treated on imatinib, dasatinib, nilotinib, and ponatinib frontline trials to assess the frequency and prognostic impact of ACAs appearing during the treatment after achieving cytogenetic response. Patients and Methods A total of 524 patients with CML were evaluated with a median age at diagnosis of 48 years (range 15 to 86). These included 236 patients treated with imatinib, 125 with nilotinib, 118 with dasatinib and 45 with ponatinib. All the patients were treated in clinical trials approved by the institutional board review and signed an informed consent in accordance with institutional guidelines and in accordance with the declaration of Helsenki. Conventional cytogenetic analysis was done in bone marrow cells using standard G-banding technique at baseline, every 3 months during the first year, then every 6-12 months. Clonal ACAs were identified as abnormalities present in ≥2/20 metaphases or, if only one metaphase, present in ≥2 consecutive assessments. Results After a median follow-up of 83.8 months (range 0.3-176.6 months) 13% (72/524) patients had ACAs, of which 7% (41/524) were clonal. ACAs were seen in 11% (27/236) of patients on imatinib compared to 11% (13/118, p=0.9) on dasatinib, 19 % (24/125, p= 0.04) on nilotinib, and 17% (8/45, p=0.2) on ponatinib. Six patients had both clonal evolution (CE) and ACAs at different times. The median number of metaphases containing ACAs was 5/20 (range 1 to 20) with an average of 7/20. Most appeared within the first year of the start of the TKI (median 6 months, range 3-72 months); they first appeared after 12 months of therapy in 21 of the 72 (29%) patients. ACAs were transient and were detected in 2 or less time points in 52 of the 72 (72%) cases. The most common clonal ACAs were - Y (13/41) and +8 (4/41). The rates of cytogenetic and molecular responses were similar for patients with and without clonal ACAs (CCyR: 88% vs 91%; p=0.55) (MMR: 78% vs 86%, p=0.20). Having clonal ACAs did not affect the rate of deep molecular response either (MR4.5 71% vs 67%; p =0.65). There was no significant difference in EFS and OS (5y EFS 73% vs 86%; p=0.19) (5y OS 77% vs 93%; p=0.06) although there was a trend for lower rates for both. Responses and clinical outcomes were similar between different TKIs for patients with and without clonal ACAs. One patient with -7 treated with ponatinib developed MDS. Monosomy 7 appeared 9 months from the start of treatment in 9/20 metaphases and persisted. He was taken off ponatinib because of pancytopenia. He subsequently received bosutinib, achieved and maintained a CCyR. A high-risk MDS was documented approximately 1 year after appearance of the -7 clone. He was started on decitabine and achieved a partial cytogenetic response for MDS. Another patient in the imatinib cohort with -7 developed secondary AML (CCyR for CML) and died from a multiple organ failure after allogeneic stem cell transplant from a one antigen-mismatched unrelated donor. There was a third patient with -7 that later had CE and developed Ph+ CML blast phase. Conclusion ACAs are rare and mostly transient events that appear during the treatment of CML with TKIs. These changes do not affect responses or clinical outcomes, independent of what TKI is used. A small subset of patients with -7 may develop AML or MDS warranting close monitoring of patients with changes that are reminiscent of those diseases. Molecular analysis after appearance of ACAs could help identify mutations driving the Ph-clone into AML or MDS. Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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