scholarly journals Impact of frontline treatment approach on outcomes of myeloid blast phase CML

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kapil Saxena ◽  
Elias Jabbour ◽  
Ghayas Issa ◽  
Koji Sasaki ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Kinase Inhibitors ◽  
Treatment Approach ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Cell Transplant ◽  
Blast Phase ◽  
Frontline Treatment ◽  
The Impact

Abstract Background The natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach. Methods We retrospectively analyzed the response rates and survival outcomes of 104 consecutive patients with myeloid blast phase CML (CML-MBP) treated from 2000 to 2019 based on 4 different frontline treatment approaches: intensive chemotherapy (IC) + TKI (n = 20), hypomethylating agent (HMA) + TKI (n = 20), TKI alone (n = 56), or IC alone (n = 8). We also evaluated the impact of TKI selection and subsequent allogeneic stem cell transplant (ASCT) on patient outcomes. Results Response rates were similar between patients treated with IC + TKI and HMA + TKI. Compared to treatment with TKI alone, treatment with IC/HMA + TKI resulted in a higher rate of complete remission (CR) or CR with incomplete count recovery (CRi) (57.5% vs 33.9%, p < 0.05), a higher complete cytogenetic response rate (45% vs 10.7%, p < 0.001), and more patients proceeding to ASCT (32.5% vs 10.7%, p < 0.01). With a median follow-up of 6.7 years, long-term outcomes were similar between the IC + TKI and HMA + TKI groups. Combination therapy with IC/HMA + TKI was superior to therapy with TKI alone, including when analysis was limited to those treated with a 2nd/3rd-generation TKI. When using a 2nd/3rd-generation TKI, IC/HMA + TKI led to lower 5-year cumulative incidence of relapse (CIR; 44% vs 86%, p < 0.05) and superior 5-year event-free survival (EFS; 28% vs 0%, p < 0.05) and overall survival (OS; 34% vs 8%, p = 0.23) compared to TKI alone. Among patients who received IC/HMA + TKI, EFS and OS was superior for patients who received a 2nd/3rd generation TKI compared to those who received imatinib-based therapy. In a landmark analysis, 5-year OS was higher for patients who proceeded to ASCT (58% vs 22%, p = 0.12). Conclusions Compared to patients treated with TKI alone for CML-MBP, treatment with IC + TKI or HMA + TKI led to improved response rates, CIR, EFS, and OS, particularly for patients who received a 2nd/3rd-generation TKI. Combination therapy with IC + TKI or HMA + TKI, rather than a TKI alone, should be considered the optimal treatment strategy for patients with CML-MBP.

Superior Outcomes Associated with Complete Response: Analysis of the Phase III VISTA Study of Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2778-2778 ◽  
Author(s):  
Jean-Luc Harousseau ◽  
Antonio Palumbo ◽  
Paul Richardson ◽  
Rudolf Schlag ◽  
Meletios A Dimopoulos ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Response Rates ◽  
Complete Response ◽  
Phase Iii ◽  
Maximal Response ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Long Term Outcomes ◽  
The Impact

Abstract Complete response (CR) has been shown to be prognostic for improved long-term outcomes, including progression-free survival and overall survival (OS), in previously untreated multiple myeloma (MM) patients receiving high-dose therapy and stem cell transplant (SCT; Harousseau et al, IMW 2007; van de Velde et al, Haematologica 2007). However, there is limited evidence of such a correlation in the non-transplant setting. In the large, international phase III VISTA study in previously untreated MM patients ineligible for SCT, bortezomib plus melphalan–prednisone (VMP) demonstrated superiority to MP across all efficacy end points, including response rates, time to progression (TTP), and OS. Here, we assess the differential prognostic impact of best response on time-to-event parameters in VISTA, and evaluate the impact of timing of CR on outcome in patients receiving VMP. A total of 682 patients (median age 71 years) were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, and days 1, 8, 22, 29, cycles 5–9, plus melphalan 9 mg/m2 and prednisone 60 mg/m2, days 1–4, cycles 1–9) or MP (N=338). The primary end point was TTP. Response and progression were determined using European Group for Blood and Marrow Transplantation (EBMT) criteria; in a post-hoc analysis, response was determined using International Myeloma Working Group (IMWG) uniform criteria. Associations between long-term outcomes and response were examined in the intent-to-treat population by multivariate Cox regression analysis with time-dependent covariates, adjusted for stratification factors (baseline β2-microglobulin and albumin; region), with age, sex, race, MM type, baseline Karnofsky Performance Status, and number of bone lesions as covariates. Among evaluable patients, response rates to VMP vs MP were 71% vs 35%, including 30% vs 4% CR, by EBMT criteria, and 74% vs 39%, including 33% vs 4% CR and 8% vs 4% VGPR, by IMWG criteria. Median TTP was 24.0 vs 16.6 months. CR by EBMT criteria was associated with significantly longer TTP (hazard ratio [HR] 0.45, p=0.004; Figure), time to next therapy (TNT; HR 0.44, p=0.014), and treatment-free interval (TFI; HR 0.37, p=0.004) vs PR, plus improved OS (medians not reached; clear separation between the curves; HR=0.59, p=0.265; statistical significance not seen likely due to a small number of deaths). Significant benefit was seen for CR and PR vs no response by EBMT criteria for all four parameters, including OS. Findings were similar for CR vs VGPR+PR vs no response by IMWG criteria. Importantly, CR was associated with significantly longer TTP (HR 0.45, p=0.019) and TFI (HR 0.39, p=0.026) vs VGPR, with a trend towards longer TNT (HR 0.54, p=0.126); no significant differences for these parameters were seen for VGPR vs PR. However, these findings should be interpreted with caution due to the small number of patients achieving VGPR. Among patients achieving CR (EBMT criteria) with VMP, there were no clear differences in clinical benefit associated with achieving CR early (cycles 1–4, within 24 weeks) vs later (cycle 5 onwards, after 24 weeks), although TTP and overall duration of response appeared slightly longer with later CRs, possibly due to the inherent slightly longer duration of therapy (mean 7.4 vs 8.5 cycles). In conclusion, this analysis demonstrates the prognostic significance of CR on long-term outcomes in the setting of non-intensive therapy. The data show that CR is associated with improved outcomes vs VGPR by IMWG criteria, and indicate that the clinical benefit of CR with VMP is similar regardless of time to achieve CR, supporting continuation of therapy to achieve maximal response. Figure: TTP in patients achieving CR vs PR (EBMT criteria) with VMP Figure:. TTP in patients achieving CR vs PR (EBMT criteria) with VMP

Allogeneic Hematopoietic Stem Cell Transplantation Cures CLL: A Retrospective Analysis from the SFGM-TC Registry.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2991-2991
Author(s):  
Mauricette Michallet ◽  
Quoc-Hung Lê ◽  
Jean-Paul Vernant ◽  
Franck E. Nicolini ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Autologous Transplantation ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Cord Blood Cell ◽  
The Status ◽  
The Impact ◽  
Long Term Survivors

Abstract This retrospective study concerned 471 B-CLL patients registered in the SFGM-TC registry from Apr 1,984 to Feb 2,005, who underwent either autologous transplantation (n=313, 138 F and 175 M, median age = 54, 236 PBSC and 77 BM) or allogeneic transplantation (n=158, 78 F and 80 M, median age = 49, 76 PBSC, 81 BM and 1 cord blood cell transplant from 17 related and 141 unrelated donors). Among alloT patients, 50 were ABO incompatible and 70 sex-mismatched. The median interval diagnosis-transplantation was 32 months for autoT and 51 months for alloT. Just before conditioning 302 autoT and 143 alloT were evaluated for the disease status: 100 and 26 patients were in CR, 170 and 55 were in PR, 4 and 13 in stable disease (SD), 28 and 49 in progressive disease (PD) for autoT and alloT respectively. Among alloT patients, 73 received reduced intensity conditioning (RIC) and 85 standard conditioning (72 Cyt+TBI, 33 Fluda+TBI, 23 Fluda+Bu+ATG, 8 Cyt+Bu and 21 other). Before autoT the conditioning consisted of 224 Cyt+TBI, 45 BEAM and 44 other. After alloT, 71 patients developed an aGVHD ≥ grade II and 60 developed a cGVHD (25 limited and 35 extensive). The non-relapse mortality at 1 year was 29%. With a mean follow-up of 28 months for autoT and 40 months for alloT, the probabilities of 3-year, 5-year and 8-year overall survival were 80%, 66%, 45.5% after autoT and 52%, 48% and 35% after alloT respectively. An analysis aimed to determine the percentage of long-term survivors, or patients censored on the final plateau of survival curves was performed on alloT and autoT groups. A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The percentage of long-term survivors for the autoT group was 1.2%, with a mean survival length for uncured population of 160 months. Fig A shows that both curves were close and consequently shows good adequacy and the absence of a final plateau. The percentage of long-term survivors for alloT was 34.03% (figure1). Fig B shows rather good adequacy. The study of the impact of usual prognosis factors (age, time diagnosis-transplant, sex match, HLA match, CMV status, type of conditioning, BM or PBSC, ABO compatibility and disease status before transplantation) on the percentage of long-term survivors showed that only the status of disease at transplant had a significant impact: (CR vs SD or PD, HR: 0.11 [0.02–0.5] p=0.01 and PR vs SD or PD, HR: 0.30 [0.09–0.96] p=0.04). This study pointed out the possibility of curing B-CLL patients who responded to conventional chemotherapy with allogeneic transplantation rather than with autologous transplantation. Figure Figure Figure Figure

Combination Therapy with Tyrosine Kinase Inhibitors and Agents with Different Mechnisms of Actions Is Effective in a Patient with Chronic Myeloid Leukemia Harboring the T315l BCR - ABL1 Mutation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4282-4282
Author(s):  
Fabio P S Santos ◽  
Jorge Cortes ◽  
Charles Koller ◽  
Elias Jabbour
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Combination Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Specific Inhibitor ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
T315i Mutation

Abstract Abstract 4282 Mutations of BCR-ABL1 have been observed in 50% of patients with chronic myeloid leukemia (CML) who develop resistance to imatinib. The gate-keeper mutation T315I is one of the mutations with universal resistance to imatinib and to the second-generation tyrosine kinase inhibitors (TKI) that are approved for the treatment of patients with imatinib failure. The use of new kinase inhibitors with in vitro activity against T315I mutation as well as other agents with different mechanisms of actions is being evaluated in clinical trials. We report the case of a 57-year old man that was diagnosed with CML in 2003. Patient received initial therapy with standard-dose imatinib that was subsequently increased to 800 mg daily. He did achieve a complete cytogenetic response (CCyR) 9 months post dose escalation. He was followed by RT-PCR for BCR-ABL1.. In May, 2007, the patient BCR-ABL1/ABL1 ratio increased to 16.38 but the patient remained in CCyR. BCR-ABL1 sequencing revealed the T315I mutation in 100% of cells (Figure 1). One month later the patient lost CCyR (5% Philadelphia-positive [Ph+] cells) and the BCR-ABL1/ABL1 ratio was 5.08. The patient was started on the T315I specific inhibitor KW-2449 (100 mg orally twice daily for 14 days, every 3 weeks). Patient had a progressive decline in percentage of cells with the T315I mutation (Figure 1). However, at the same time he had an increase in percentage of Ph+ cells. In September, 2007, three months after starting therapy with KW-2449, patient had no cytogenetic response (80% Ph+ cells, PCR for BCR-ABL1 ratio > 100) and the T315I mutation was undetectable. At that time, a new ABL1 sequencing revealed the F359I mutation (no quantification was done). Patient was maintained on KW-2449 for the next 6 months, without significant improvement in cytogenetic response nor BCR-ABL1 ratio, but the clone with the T315I mutation did not reappear. In February, 2008, the patient lost hematologic response and presented with an elevated white blood cell count of 22×109/L. The F359I mutation was still present. Therapy with KW-2449 was stopped and the patient started dasatinib 100 mg/day and Interferon-a 3,000,000 units. Three months later, the patient acheived CCyR with a BCR-ABL1/ABL1 ratio of 0.05. At the last evaluation, 16 months after the start of dasatinib and interferon combination, the patient was maintaining CCyR and major molecular response. In conclusion, this case illustrates the benefit of the use of combination therapy, mainly TKI and agent with different mechanism of action either sequentially (TKI followed by KW-2449) or concomitantly (TKI + interferon) in eradicating resistant disease with T315I clone. Figure 1 Serial Monitoring of Ph+ Cells, T315I Cells and BCR-ABL1/ABL1 Ratio Figure 1. Serial Monitoring of Ph+ Cells, T315I Cells and BCR-ABL1/ABL1 Ratio Disclosures: Cortes: Novartis: Research Funding. Jabbour:Novartis: Speakers Bureau; Bristol Myers Squibb : Speakers Bureau.

Causes of Death for Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Imatinib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4279-4279
Author(s):  
Andrea Renata Dean ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Mary Beth Rios ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Causes Of Death ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Cardiac Complications ◽  
Time Of Death ◽  
Lost To Follow Up

Abstract Abstract 4279 Background Imatinib is the current standard initial therapy for patients with CML in CP. Over 80% of patients achieve a complete cytogenetic remission (CCyR), and the projected overall survival at 7 years is 89%. This survival probability is significantly better than the historical pre-imatinib era (approximately 50% at 5 years). Understanding the causes of death among patients treated with imatinib is needed to further improve the long-term results. Aim To determine cause of death in patients treated with imatinib as initial therapy for CP Philadelphia-chromosome positive CML. Methods We reviewed the records of all patients with CML in CP treated with imatinib (standard or high-dose) as initial therapy since 2000. Results A total of 281 patients were treated. The overall rate of major cytogenetic response (MCyR) was 94% and CCyR 89%. At 6 years the projected event-free survival was 83% and overall survival 91%. After a median follow-up of 5.6 years, 29 (10%) patients have died. The median age at diagnosis was 56 years (range, 20 to 84 years) and at the time of death 60 years (23 to 91 years). The median time from start of therapy to death was 3.9 years (6 months to 8 years). Initial imatinib dose was 400mg for 13 patients (out of 281, 26% treated at that dose) and 800mg for 16 patients (out of 281, 74% treated at 800mg). All patients had achieved a complete hematological response. Among those that eventually died, 24 (82%) pts achieved a MCyR with imatinib: 19 (65%) achieved CCyR and 5 (17%) partial cytogenetic response (PCyR). Two patients achieved a minor cytogenetic response and 2 had no cytogenetic response; one patient was lost to follow up soon after starting treatment. Causes of death included the following: CML (8), transplant-related complications (4), cardiac complications (3), cerebral vascular accident (2), motor vehicle accident (2), acute myeloid leukemia (1), suicide (1), sudden cardiac death (1), metastatic melanoma (1), metastatic renal cell carcinoma (1), and bowel obstruction (1). Four patients were lost to follow up and cause of death could not be determined. All eight patients that died from CML had lost their hematological response to imatinib; 7 transformed to blast phase. Three of these patients received treatment with second generation tyrosine kinase inhibitors and one achieved a transient MCyR. The four patients that died from transplant-related complications ranged in age from 20 to 48 years at diagnosis. Patients underwent transplant (2 in CP, 2 in 2nd CP) after failing treatment with imatinib and other therapies. Three patients where in CCyR at time of death and 1 had unknown cytogenetic response. Among the other 17 pts, 9 (53%) were in CCyR at the time of death. The 3 patients that died from cardiac complications had past medical histories of heart disease and all were in CP at time of death: 2 with CCyR and 1 with PCyR. These patients died from congestive heart failure, myocardial ischemia, or arrthymia, respectively. The 2 patients that died from cerebral vascular accidents had prior histories of stroke. Both patients were in CP: 1 in CCyR and 1 with PCyR. The 2 patients who died of car accidents were in CP at the time of death: 1 in CCyR and 1 with PCyR. The patients that died of acute myeloid leukemia, suicide, sudden cardiac death, metastatic renal cell carcinoma and bowel obstruction were all in CCyR prior to death. The patient who died from metastatic melanoma had unknown cytogenetics prior to death. Among the patients that died for reasons other than CML or transplant-related complications, all except three were treated with imatinib only. Two of the 4 patients lost to follow up underwent bone marrow transplants at other facilities and status at time of death is unknown. The other 2 patients lost to follow up discontinued imatinib due to side effects long before their death. Discussion The survival probability of CML CP patients treated with imatinib is excellent. Less than half of the deaths are related to CML or stem cell transplant. These deaths might be preventable if 2nd generation tyrosine kinase inhibitors are more effective as initial therapy. Other deaths result from co-morbidities, with no deaths attributed to the treatment with imatinib. Close monitoring of patients with predisposing factors for these events could improve their long-term outcome. Disclosures: Rios: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau. Jabbour:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Cortes:Novartis: Research Funding.

Impact of Cytogenetics and Cytogenetic Response On Outcome in MDS Treated with Azacitidine (AZA).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2807-2807 ◽  
Author(s):  
Marie Sebert ◽  
Valérie Vidal ◽  
Virginie Eclache ◽  
Sylvain Thepot ◽  
Thorsten Braun ◽  
...  
Keyword(s):  
Research Funding ◽  
Response Rates ◽  
Risk Groups ◽  
Cytogenetic Response ◽  
Risk Category ◽  
Complex Karyotype ◽  
Cytogenetic Abnormalities ◽  
Hematological Response ◽  
Number Of Patients ◽  
The Impact

Abstract Abstract 2807 Background: hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the prognostic value of baseline cytogenetics on response to AZA, and the impact of cytogenetic response (CyR) on outcome in responders remain uncertain. Methods: Between Jan 2005 and Nov 2011, we treated at our center155 consecutive MDS patients (pts), including FAB RAEB-T / WHO AML with 20–30% blasts, with AZA (75 mg/m2/d x7 d every 4 weeks, for a median of 6 cycles). Karyotype at onset of AZA was evaluable in 143 pts, and abnormal in 95 (66%) pts. Median age was 74 years and IPSS high: 51, int2: 58, int 1: 14, NA: 20. 65 (42%) pts achieved hematological IWG 2006 response, including 28 (18%) CR, 8 (5%) PR, 13 (8%) Marrow CR, 16 (10%) stable with HI. With a median follow up of 28 months, median OS was 16 months. Results: Of the 95 pts with abnormal karyotype, 47 had −7/del(7q) including 9 isolated −7/del (7q), 37 had del(5q)/-5 including only 3 isolated del(5q)/-5,26 had +8 including 9 isolated +8, 9 had abnormalities leading to del (17p)(6 of them had complex karyotype), 16 had del (20q)and 44 had complex karyotype (>= 3 abnormalities). Response and OS according to cytogenetics are summarized in table 1. None of the cytogenetic abnormalities studied (complex, normal, del20q, 17p, del5q/-5,7/del (7q) or +8) had a significant impact on response to AZA. Presence of del (17p) (median 7 vs 18 mo, p= 0.0001), del5q/-5 (12.5 vs 20 mo, p= 0.0008), −7/del (7q) (9.7 vs 20 mo, p=0.02) or complex karyotype (12 v 20 mo, p=0.002) was associated with significantly shorter OS. Among pts with complex karyotype, there was a trend for shorter OS for pts when 17p abn (median 6.7 vs 12.5 mo, p=0.12) del (5q)/-5 (9 v 21 mo, p=0.16) or −7/del (7q) (7 v 17 mo, p=0.06) abnormality was part of the complex karyotype. By contrast, isolated −7/del (7q) (21 vs 16 mo, p=0.3) and +8 (all+8:20 vs 14 mo, p=0.48; isolated +8:23 vs 16 mo, p=0.92) had no significant impact on OS. According to IPSS cytogenetic risk, response rates and CR rates were similar across the 3 groups, but OS was significantly longer in the good risk category (p=0.04) (table 1). Cytogenetics could be reclassified using new IPSS-R cytogenetic groups in 138 pts (Shanz, JCO, 2011) in 1 very good, 52 (38%) good, 24 (17%) int, 30 (22%) poor and 31 (23%) very poor. According to this IPSS-R cytogenetic classification, response rates and CR rates were similar across the 4 main groups. Median OS was 20.6 mo, 23 mo, 14 mo and 12 mo in the good, int, poor and very poor risk groups respectively (p= 0.037). 66 of the pts with baseline cytogenetic abnormalities had cytogenetic analysis at treatment evaluation, after 4 to 6 cycles of AZA, of whom 32 had achieved hematological response. In those 32 pts, 34% achieved complete CyR(CCyR), none partial CyR, 37% had stable cytogenetics (and the remaining pts had cytogenetic failure). In those 32 pts, achievement of CCyR had no significant impact on OS (p=0.36) but the number of pts was relatively small. In a landmark analysis performed at D100 in pts with baseline cytogenetic abn, achieving CCyR was not associated with an OS advantage compared to stable cytogenetics (median 22 vs 17 mo, p=0.82). Of note, only 1 patient with baseline cytogenetic abn (+8) who did not achieve hematological response achieved CCyR, of 6 months duration, before disease progression. Conclusion: Baseline cytogenetic findings were strong predictors of survival in patients with MDS treated with AZA, while impact on response was limited. In hematological responders with baseline cytogenetic abnormalities, achieving cytogenetic response was not was associated with an OS advantage, butthe number of patients analyzed may have been insufficient to conclude. Disclosures: Gardin: celgene: Honoraria. Fenaux:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Central nervous system (CNS) leukemia after imatinib mesylate therapy for chronic myelogenous leukemia (CML)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7042-7042
Author(s):  
M. M. Solh ◽  
H. Kantarjian ◽  
S. O'Brien ◽  
F. Giles ◽  
S. Faderl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Blast Transformation ◽  
Blast Phase ◽  
Cns Disease

7042 Background: Imatinib is the standard first line treatment for CML. Imatinib penetrates the CSF poorly. We examined the incidence and outcome of CNS disease in pts with CML treated with imatinib at our institution. Methods: The clinical data for pts with early or late chronic phase and accelerated phase CML treated with imatinib between 1999 and 2006 were reviewed. Pts who were started on imatinib elsewhere and progressed to blast phase were also included. CNS disease was defined as a pathologically proven enhancing lesion (leptomeningeal or parenchymal) or presence of CSF leukemic cells. Results: Nine hundred and ten pts with chronic or accelerated phase CML were treated with imatinib. Fifty five developed blast crisis while on imatinib; another 28 pts had blast transformation while receiving imatinib elsewhere, making up a total of 83 pts. At diagnosis, their median age was 51 yrs, median Hgb, WBC and PLT counts were 10.6 g/dl, 59.7×109/L and 307×109/L, respectively. Median time from diagnosis to starting imatinib was 45.4 mts and the median duration of imatinib therapy was 17.9 mts. Fifteen pts had achieved a complete cytogenetic response and 47 had a complete hematologic response before progressing to blast phase. Their median overall survival from diagnosis was 73.2 mts. Thirty pts developed extramedullary disease; they had similar baseline characteristics as the rest with a median survival of 68.3 mts. Fifteen pts developed CNS disease (5 leptomenigeal, 5 CSF, 3 parenchymal, and 2 spinal cord); 14 had concomitant medullary blast crisis. They had a statistically significant younger age at diagnosis (41.9 vs 52.4 yrs), lower platelet counts (186 vs 334×109/L), and shorter overall survival (66.7 vs 73.2 mts) compared to the other pts with blast phase. Conclusions: CNS disease occurs infrequently in pts receiving imatinib for CML but should be suspected in pts with relevant symptoms. Pts developing CNS leukemia had a worse prognosis; this may be secondary to an inherently worse disease, poor CSF penetration of imatinib, and subsequent difficulty in eradicating CNS disease using available therapies. More potent tyrosine kinase inhibitors, such as nilotinib and dasatinib, and new agents with the ability to cross the blood-brain barrier should be evaluated in this setting. No significant financial relationships to disclose.

scholarly journals Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5058-5063 ◽  
Author(s):  
Carmen Fava ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
Nitin Jain ◽  
...  
Keyword(s):  
Survival Rate ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Blast Phase ◽  
Complete Hematologic Response

Abstract Second-generation tyrosine kinase inhibitors are effective in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). Occasionally, patients with Ph+ ALL, or accelerated phase (AP) or blast phase (BP) CML achieve a major cytogenetic response (MCyR) but not a complete hematologic response (CHR). We analyzed 126 patients with CML in AP or BP, or with Ph+ ALL treated with dasatinib or nilotinib after imatinib failure. Twenty patients received sequential treatment with both dasatinib and nilotinib for a total of 146 instances. CHR and MCyR rates were 54% and 37%, respectively in AP, 17% and 39% in BP, and 33% and 50% in Ph+ ALL. Failure to achieve a CHR at the time of achievement of a MCyR was associated with an inferior outcome, similar to that of patients without a MCyR (2-year survival rate, 37% and 35%, respectively). In contrast, patients with MCyR and concomitant CHR had a 77% 2-year survival rate. Twelve of 29 patients with MCyR without concomitant CHR later achieved a CHR; the 2-year survival rate for these patients was 55% compared with 22% for those who never achieved a CHR. These results suggest that achievement of a MCyR without concomitant CHR is associated with poor outcome.

scholarly journals Narcotic Use in Multiple Myeloma Patients at the Time of ASCT and One-Year Follow up

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4726-4726
Author(s):  
Matthew Danish ◽  
Tabitha Copeland ◽  
Joseph Ho ◽  
Mansi Shah ◽  
Dennis Cooper
Keyword(s):  
Multiple Myeloma ◽  
Clinical Response ◽  
Bone Pain ◽  
Novel Agents ◽  
Cell Transplant ◽  
Post Transplant ◽  
Opiate Use ◽  
The Impact

Background: Bone pain is one of the most common presentations of multiple myeloma and nearly all patients have skeletal involvement in the course of disease. Consequently, many patients require narcotics for symptom management at the time of diagnosis but the long term impact of MM treatment on pain control remains uncertain. With the advent of combination therapy for MM with novel agents followed by transplant and then maintenance therapy, clinical response is nearly universal and greater than 30% of patients achieve a serologic complete response. Therefore, we examined the impact of modern myeloma-directed therapy and high response rates on the use of narcotics up to 1 year after transplant in this group of patients. Methods: A retrospective review of data collected from the Rutgers-CINJ database was conducted. All patients who received induction inducing therapy (e.g. bortezomib, lenalidomide and dexamethasone or cyclophosphamide, bortezomib and dexamethasone) followed by high dose melphalan and autologous stem cell transplant (ASCT) and who had adequate post-transplant follow up (at least 100 days) were included. Morphine use was assessed at the time of transplant and at follow-up visits. All opiates (e.g. oxycodone, fentanyl, MS contin, etc.) where converted to morphine equivalents/day (ME/day) and recorded. Treatment responses were determined based on the International Myeloma Working Group Response Criteria. We compared the incidence and amount of narcotic use over time using one-way analysis of variance (ANOVA) and Dunn's multiple-comparison test. Results: 189 patients were included in the analysis. 38% were using opiates at the time of transplant. At 100 days post-transplant 35.5% were using opiates and at 1 year post transplant 30.9% were using opiates (p=0.04) . Average opiate use was 74.1 ME/day (95% CI: 55.2 to 92.9), 69.45 ME/day (95% CI: 50.5 to 88.3), and 70.78 ME/day (95% CI: 43.5 to 98) for each of the aforementioned time points (p=0.088) (Figure 1). For example, 74 ME/day would be equal to approximately 50 mg of Oxycodone daily. 74 patients were active opiate users at the time of transplant (Table 1). Response to myeloma treatment (remission, progression, relapse) was not different in opiate-using patients at the time of transplant or at 100 days and 1 year after transplant (Table 2). Conclusion : Early studies from the 1960's reported on the rapid reduction of bone pain in treatment responsive patients with MM (Hogstrata et al.). Recently, treatment modalities for MM have significantly improved, leading to markedly increased remission rates (>90%), progression-free and overall survival. With dramatically increased serologic responses, one would hypothesize that there would be a decline in pain and a subsequent decrease in opiate use. However, in this retrospective chart review we found that 30% of multiple myeloma patients continued to use opiates following transplant and that ongoing use of opiates appeared to be independent of clinical response. Interestingly, at the time of transplant active opiate users had a CR of 27.2% while the non-opiate using patients had a CR of 13.3%. Although there was a slight decline in the number of opiate users at the 1 year follow up, 33% of opiate users continued at their original level of opiate use and 22% increased their opiate use at 1 year post ASCT. Persistent long term use of opiates is of particular concern given that the survival of patients with MM has significantly improved with the use of novel agents and autologous transplant with an increasing number of patients surviving 10 years or more. In patients who have achieved an excellent response (e.g. serologic CR and negative PET scan), ongoing narcotic use should be addressed at each visit and other advanced pain management techniques should be considered. Disclosures No relevant conflicts of interest to declare.

scholarly journals Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance

Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2232-2235 ◽  
Author(s):  
Dushyant Verma ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Rajyalakshmi Luthra ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Blast Phase ◽  
Complete Hematologic Response ◽  
Risk Patients

Abstract The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Of the CP, 4 achieved complete hematologic response (CHR); 2, complete cytogenetic response (CCyR); 2, partial cytogenetic response (PCyR), and 1 did not respond to imatinib. Five patients progressed to myeloid BP (3), lymphoid BP (1), or AP (1). The AP patient received various TKIs sequentially and achieved only CHR. BP patients received hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) plus imatinib/dasatinib or idarubicin plus cytarabine (Ara-C); 2 did not respond, 1 had CCyR, and 1 short-lasting complete molecular response (CMR). Overall, cytogenetic responses lasted 3 to 18 months; only 2 achieved major molecular response (MMR) on TKI. P190BCR-ABL CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients.

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