"Secondary Chronic Myeloid Leukemia": Comparison between Patients Previously Exposed or Not to Chemo and/or Radiotherapy

Abstract Introduction. Haematological malignancies related to previous chemo and/or radio-therapy for neoplasia have been well investigated. This subgroup was defined as therapy-related myeloid neoplasms by ELN. In the field of chronic myeloid leukaemia (CML) the diagnosis of a secondary neoplasia after CML diagnosis has been studied but the presence of 'secondary CML' has not been completely defined. In clinical practice we collected patients with a CML diagnosis who had a previous history of malignancy. Aim and methods. We reviewed our databases to collect the cases of 'secondary CML' in 4 hematological Italian centres. Results. We found 51 patients who were diagnosed with previous malignancies out of 617 CML patients (8.3%). We conducted the analysis on 48 patients, removing the other three patients who were diagnosed before the era of tirosine-kinase inhibitors (TKIs). We then subdivided patients in two groups according to the treatment they received for the previous neoplasia: patients treated by surgery (group A: 27 patients) and patients treated by chemotherapy and/or radiotherapy (group B: 21 patients). Clinical characteristics at diagnosis of the patients of the two groups were summarized in Table 1. The majority of the patients showed bcr-abl b3a2 (59% in group A and 62% in group B), no one showed additional cytogenetic abnormalities. The median time between the diagnosis of the primary neoplasia and CML were not different: 78 months (range 1-276) in the group A and 75 months (range 1-371) in the group B. Upfront treatment was Imatinib in 55.6% of the patients in group A and 81% in group B; the remaining patients were treated with Dasatinib in 22.2% and 14% of the patients, respectively, and Nilotinib 22.2% and 5% of the patients, respectively. All patients achieved haematological response after 1 month, 24 out of 27 patients (89%) of the group A achieved complete cytogenetic response after a median time of 3 months (range 3-28) and 20 out of 21 patients (95%) of the group B achieved complete cytogenetic response after a median time of 3 months (range 3-12). The median time of major molecular response was 9 months in 20 out of 27 patients (74%) of group A and in 19 out of 21 patients (90%) of group B. Patients in group A showed a higher number of events who determined a change in the treatment: 9 patients (33.3%) in group A changed TKI due to resistance (3 patients: 2 primary resistance and 1 secondary resistance) or intolerance (6 patients) versus 4 patients (19%) of the group B because of resistance (3 patients: 2 primary resistance and 1 secondary resistance) or intolerance (1 patient). We recorded 3 deaths: 2 in the group A not related to CML and 1 in the group B due to CML. The median overall survival was 53 months (range 8-228) in the first group and 51 months (range 4-196) in the second group. Unexpectedly we found a 12.5% of patients with a previous diagnosis of lymphoma in patients developing CML and this reached statistical significance (p=0.004) when compared to patients in A group. We also detected 3 out of 48 CML patients (6%) with a previous history of 2 neoplasia and all of them were treated with chemo and/or radiotherapy. Conclusion. Our research found that "secondary CML" occurred in 8.3% of newly diagnosed CML patients. Patients were comparable in terms of bcr-abl transcript, risk assessment, clinical and laboratory presentation. Cytogenetic and molecular response to TKIs as well as survival was similar to CML standard population. A significant fraction of patients with "secondary CML" received prior chemo and /or radiotherapy for an haematological malignancies and poses new questions in terms of either genetic predisposition and/or exposure to anticancer treatment. Disclosures No relevant conflicts of interest to declare.

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Randomized study of imatinib for chronic myeloid leukemia: comparing standard dose escalation with aggressive escalation

Blood Advances ◽

10.1182/bloodadvances.2018025981 ◽

2019 ◽

Vol 3 (3) ◽

pp. 312-319 ◽

Cited By ~ 3

Author(s):

Koichi Miyamura ◽

Kazunori Ohnishi ◽

Shigeki Ohtake ◽

Noriko Usui ◽

Chiaki Nakaseko ◽

...

Keyword(s):

Dose Escalation ◽

Standard Dose ◽

Randomized Study ◽

Early Time ◽

Cytogenetic Response ◽

Molecular Response ◽

Inadequate Response ◽

Number Of Patients ◽

Group A ◽

Group B

AbstractIn 2007, we conducted a prospective randomized study to compare an aggressive dose escalation (group B, n = 123) with the standard dose escalation proposed by European LeukemiaNet (group A, n = 122). In group B, if patients did not achieve a complete cytogenetic response (CCyR) at 3 months or did not achieve a major molecular response (MR3) at 6 months, imatinib was increased to 600 mg. At 6 months CCyR was achieved in 69.4% and 78.7% of patients in groups A and B, respectively. The rate of MR3 at 12 months and 24 months were similar in group A (52.1% and 70.0%) and group B (58.7% and 68.3%). The cumulative incidence of withdrawal by failure without accelerated/blast phase was higher in group A than in group B (9.2% vs 2.5% at 24 months). At 3 and 6 months, the protocol called for the imatinib dose to increase to 600 mg in 90 patients (74.4%) in group B. Among the 42 patients who received increased dose according to the protocol, 25 (60.0%) achieved MR3 at 12 months, whereas only 14 (35.0%) of 40 patients who did not receive an increased dose achieved MR3 (P < .05). The number of patients who withdrew from this study was similar (group A, 20%; group B, 21%). The early aggressive dose escalation failed to produce a better molecular response at 12 months. However, for patients who tolerate imatinib well, but show inadequate response at an early time point, aggressive dose escalation may contribute to achieving a better outcome. This study was registered at http://www.umin.ac.jp/ctr/ as #R000000965.

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For CML Patients in Chronic Phase Who Achieve a Cytogenetic Response to Imatinib the Finding of a BCR-ABL Mutation Predicts for Progression to Advanced Phase but It Has No Such Significance in Primary Resistance.

Blood ◽

10.1182/blood.v110.11.323.323 ◽

2007 ◽

Vol 110 (11) ◽

pp. 323-323

Author(s):

Hugues de Lavallade ◽

Jamshid S. Khorashad ◽

Dragana Milojkovic ◽

Simon Wagner ◽

Jaspal Kaeda ◽

...

Keyword(s):

Adverse Effect ◽

Genomic Instability ◽

Direct Sequencing ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Primary Resistance ◽

Secondary Resistance ◽

Advanced Phase

Abstract We analysed outcome for 211 CML patients treated with imatinib in chronic phase (CP) (99 newly diagnosed and 112 late chronic phase) who were screened for BCR-ABL kinase domain (KD) mutations using direct sequencing regardless of the response status. When a mutation was found all available previous cDNA samples were analysed by pyrosequencing to establish the date of its first occurrence and subsequent kinetics. The median age of patients was 47.4 years. The Sokal risk score was ‘low’ in 57 patients, ‘intermediate’ in 82 and ‘high’ in 72. The median follow up from starting imatinib was 45 months (rage 6 to 89 months). A mutation was detected in 34 of the 211 patients (16%) at a median time of 27 months from starting imatinib. Twenty-two different mutations were identified, the most frequent being M244V (n=6) and F359V (n=3). When studied serially by pyrosequencing the size of the mutant subclone never exceeded 50% of total BCR-ABL transcripts in 8 patients, while in 17 patients it exceeded 90% on at least one occasion. 48 patients discontinued imatinib while still in CP and received either dasatinib, nilotinib or an allograft. The overall progression-free survival (absence of advanced phase) at 5 years was 73%. Major (MCyR) and complete (CCyR) cytogenetic responses were achieved by 153 and 123 patients respectively; 56 patients achieved major molecular response. 24% of the patient with up front cytogenetic resistance had a mutation while 40% of the patients with acquired cytogenetic resistance develop a mutation. In an-intention-to-treat analysis, patients harboring a mutant clone had a poorer PFS at 4 years (78% versus 57%, p=0.0014). The various mutations had no differential effects based on their known imatinib IC50. By multivariate analysis, factors associated with worse PFS were the presence of a KD mutation and failure to achieve CCyR (relative risks for PFS 2.6 and 8.7 respectively, p=0.002). Interestingly, the adverse effect of the presence of a KD mutation was restricted to the patients who achieved a MCyR (PFS 91% versus 62% at 5 years, p = 0.0006); it had no adverse impact on patients who failed to achieve a MCyR (PFS 42% and 49%, p=0.73). Similar results were found when the analysis was repeated according to the achievement of CCyR (data not shown). Surprisingly patients with a continuously low percentage (≤50%) of mutated vs wild type (>50%) clones fared worse than patients in whom the mutated clone became the predominant population (PFS 14% vs 69% respectively, p=0.0005). Comparable results were obtained when the patients were censored at the point of discontinuing imatinib, correcting for the effects of subsequent treatment, ie allografting (data not shown). The fact that the adverse effect of a mutation seems to be restricted to patients who had achieved cytogenetic response, the fact that mutations present at low level seemed to have a remarkable adverse effect and the fact that the in-vitro level of resistance to imatinib of the specific mutation did not affect the PFS could all be explained if the development of a mutation is only a reflection of the genomic instability of the disease that leads to secondary resistance to imatinib and eventually to transformation. Thus genomic instability may be less important in explaining primary resistance to imatinib and eventual transformation in patients with up-front resistance.

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Predictive factors for developing acute cholangitis and cholecystitis in patients undergoing delayed cholecystectomy: a retrospective study

10.21203/rs.2.15258/v1 ◽

2019 ◽

Author(s):

Takashi Miyata ◽

Daisuke Matsui ◽

Yuta Fujiwara ◽

Hiroto Saito ◽

Yoshinao Ohbatake ◽

...

Keyword(s):

Risk Factor ◽

Surgical Outcomes ◽

Intraoperative Complications ◽

Acute Cholangitis ◽

Previous History ◽

Cell Counts ◽

Number Of Patients ◽

History Of ◽

Group A ◽

Group B

Abstract Background We evaluated the risk of acute cholangitis and cholecystitis while waiting for cholecystectomy for gallstones. Methods We retrospectively enrolled 168 patients who underwent cholecystectomy for gallstones after a waiting period and conservative therapy between April 2014 and March 2018 at our hospital. We compared the clinical data from 20 patients who developed acute cholangitis and cholecystitis while waiting for cholecystectomy (group A) with data from 148 patients who did not develop cholangitis and cholecystitis (group B). The risk factors for developing acute cholangitis and cholecystitis and all patients' surgical outcomes were investigated. Results Preoperatively, significant differences in age (68.6 years vs 60.7 years; p= 0.004) and the number of patients with a previous history of acute grade II or III cholecystitis (55.0% vs 10.8%; p< 0.001) and biliary drainage (20.0% vs 2.0%; p= 0.004) were observed between group A and group B, respectively. Preoperative white blood cell counts (13500/µL vs 8155/µL; p< 0.001) and serum C-reactive protein levels (12.6 mg/dL vs 5.1 mg/dL; p< 0.001) were significantly increased, and serum albumin levels (3.2 g/dL vs 4.0 g/dL; p< 0.001) were significantly decreased in group A vs group B, respectively. Gallbladder wall thickening (≥ 5 mm) (45.0% vs 18.9%; p= 0.018), incarcerated gallbladder neck stones (55.0% vs 22.3%; p= 0.005), and abscess around the gallbladder (20.0% vs 1.4%; p= 0.002) were seen significantly more frequently during imaging in group A vs group B, respectively. Furthermore, investigating patients' surgical outcomes revealed a higher conversion rate to open surgery (20.0% vs 2.0%; p= 0.004), longer operation time (137 min vs 102 min; p< 0.001), and a higher incidence of intraoperative complications (10.0% vs 0%; p= 0.014) in group A vs group B, respectively. Conclusions Our results suggest that a history of severe cholecystitis is a risk factor for developing acute cholangitis and cholecystitis in patients waiting for surgery, and a risk factor for increased surgical difficulty.

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Clinical Characteristics and Outcome of Patients (pts) with V299L BCRABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽

10.1182/blood.v112.11.1105.1105 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1105-1105

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Dan Jones ◽

Elizabeth Burton ◽

Jorge Cortes

Keyword(s):

Kinase Inhibitors ◽

Mutation Detection ◽

Lymphoblastic Leukemia ◽

Point Mutations ◽

Cytogenetic Response ◽

Experimental Models ◽

Molecular Response ◽

Primary Resistance ◽

Secondary Resistance

Abstract Background. Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. Aims. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML and Ph+ ALL at our institution, and the response following change of therapy. Results. V299L mutation was detected in 14 pts (12 CML, 2 Ph+ ALL): 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 47 pts (19%) who developed mutations on dasatinib therapy, and 4 among 18 pts (22%) who developed mutations on bosutinib therapy (p<0.001); none of the 49 pts who developed mutations on nilotinib therapy acquired V299L. Median age was 55 years (range, 26–82 years). Seven pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). Nine pts developed V299L after being on dasatinib for a median of 14 mos (range, 1–30 mos); 7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib. In 4 pts V299L appeared after receiving bosutinib as 3rd TKI after imatinib and dasatinib failure, for a median of 5 mos (range, 2–8 mos). None of the 11 evaluable pts treated with 2nd generation TKIs had V299L at start of therapy. The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 4 bosutinib) was complete hematologic response only in 5 (36%, 4 dasatinib, 1 bosutinib), minor cytogenetic response in 2 (14%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (29%; 3 dasatinib, 1 bosutinib); no response in 3 pts (1 dasatinib, 2 bosutinib). The median duration of response was 14 mos. V299L was associated with primary resistance in 3 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 4 pts were in chronic (CP), 7 in accelerated (AP), 1 in blast phase (BP), and 2 with Ph+ ALL. 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 responded (major molecular response sustained for 16+ mos). One pt received INNO406 and did not respond. One pt with Ph+ ALL was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 8 mos (range, 3–29 mos), from the time V299L was detected, 4 died (1 CP, 1 BP, 2 ALL). The estimated 2-year survival from mutation detection was 74%. Conclusion. V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation.

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ABCG2 and SLC22A1 Expression Are Associated with Imatinib Response in Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v118.21.1422.1422 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1422-1422

Author(s):

Douglas Vivona ◽

Luciene Terezina Lima ◽

Carolina Tosin Bueno ◽

Rosario D C Hirata ◽

Mario H Hirata ◽

...

Keyword(s):

Conflicts Of Interest ◽

Philadelphia Chromosome ◽

Cytogenetic Response ◽

Response To Treatment ◽

Molecular Response ◽

Major Molecular Response ◽

Primary Resistance ◽

Secondary Resistance ◽

Altered Expression ◽

Complete Cytogenetic Response

Abstract Abstract 1422 Background: Imatinib Mesylate (IM) used in the treatment of CML, interacts with membrane efflux transporters such as ABCB1 and ABCG2, whereas the active uptake of IM into the cells is mediated by SLC22A1. The predictive value of these markers is still controversial. The altered expression of these genes could impact on intracellular concentration of IM and contribute to resistance. Aims: The aim of this study was to investigate ABCB1, ABCG2 and SLC22A1 gene expression as potential sources of resistance to imatinib in patients with CML Methods: One hundred and eighteen patients in chronic phase of CML, both genders with age range 18 to 80 were studied. All patients were initially treated with a standard dose of IM (400 mg/day) and divided in two groups according to response. The responder group comprised 70 patients who had a complete cytogenetic response within 18 months of treatment. The non-responder group comprised 48 patients who did not have a complete cytogenetic response with the initial dose (400 mg/day) of IM or who relapsed during treatment and were submitted to higher doses of 600 or 800 mg/day. Criteria of failed response to treatment were established by European LeukemiaNet. Patients with cytogenetic patterns other than the Philadelphia chromosome and patients with mutations in the BCR-ABL1 gene were excluded from this study. Major molecular response (MMR) was defined as a reduction of BCR-ABL1 transcripts levels to ≤ 0.1% in the peripheral blood standardized on the International scale. Complete molecular response (CMR) was defined as a reduction ≤ 0.032% BCR-ABL1 transcripts levels. Primary resistance and secondary resistance also were evaluated. Real-Time PCR was performed to evaluate the ABCB1, ABCG2 and SLC22A1 mRNA relative expression to control gene GAPDH. Results: Expression of ABCG2 in the non-responder group was higher than in the responder group (P=0.028). This result was influenced by patients with primary resistance (n= 34 p=0.029) but not secondary resistance (n=14 p=0.249) when compared with responders (n=70). ABCB1 and SLC22A1 expression were similar between responder and non-responder groups. Higher levels of SLC22A1 mRNA were found in patients who achieved MMR in the responder group (p=0.009). The elevated ABCG2 expression was also found in those who did not achieve MMR (p=0.027) when all patients were analyzed. None of studied genes was associated with CMR. Conclusions: The high expression of ABCG2 is related to primary resistance and SLC22A1 is positively associated with major molecular response to treatment with IM. Our data suggests that ABCG2 may be a mediator of IM resistance, whereas SLC22A1 could be a good predictor of response to IM therapy. Financing: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2009/54184-0). Disclosures: No relevant conflicts of interest to declare.

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Characteristics and Outcome of Patients (pts) with V299L BCR-ABL Kinase Domain (KD) Mutation After Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽

10.1182/blood.v116.21.3428.3428 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3428-3428

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Dan Jones ◽

Yin Cameron ◽

Elizabeth Burton ◽

...

Keyword(s):

Research Funding ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Cytogenetic Response ◽

Experimental Models ◽

Molecular Response ◽

Primary Resistance ◽

Secondary Resistance ◽

Abl Kinase

Abstract Abstract 3428 Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML at our institution, and the response following change of therapy. V299L mutation was detected in 15 pts with CML: 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 69 of the 170 evaluable (i.e., had abl sequencing) pts (13%) who developed mutations on dasatinib, and 5 among 19 of the 72 evaluable pts (26%) who developed mutations on bosutinib (p<0.001); none of the 51 pts who developed mutations on nilotinib (among 125 tested) acquired V299L. Median age for pts with V299L was 56 years (range, 26–82 years). Eight pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). The median time to development of V299L was 14 mos (range, 1–30 mos) for those treated with dasatinib (7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib), and 13 mos (range, 2–48 mos) for those treated with bosutinib (after imatinib failure in 1, and as 3rd TKI after imatinib and dasatinib failure). The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 5 bosutinib) was complete hematologic response only in 6 (40%, 4 dasatinib, 2 bosutinib), minor cytogenetic response in 2 (13%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (27%; 3 dasatinib, 1 bosutinib); no response in 3 pts (20%; 1 dasatinib, 2 bosutinib). The median duration of response was 17 mos. V299L was associated with primary resistance in 4 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 5 pts were in chronic (CP), 7 in accelerated (AP), and 3 in blast phase (BP). 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 in CPresponded (major molecular response sustained for 40+ mos). One pt received INNO406 and did not respond. One pt in BP was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 23 mos (range, 3–48 mos), from the time V299L was detected, 8 died (4 CP and 4 BP). In conclusion, V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation if treated in chronic phase, but more data is need to evaluate the long-term benefit of this approach. Disclosures: Jabbour: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.

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Phase III Randomized Study of Imatinib Therapy in Chronic Phase Chronic Myeloid Leukemia Comparing Standard Dose-Escalation with Progressive Dose-Escalation (JALSG CML207 study)

Blood ◽

10.1182/blood.v128.22.941.941 ◽

2016 ◽

Vol 128 (22) ◽

pp. 941-941

Author(s):

Koichi Miyamura ◽

Shigeki Ohtake ◽

Kazunori Ohnishi ◽

Noriko Usui ◽

Chiaki Nakaseko ◽

...

Keyword(s):

Dose Escalation ◽

Research Funding ◽

Standard Dose ◽

Randomized Study ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

Group A ◽

Group B

Abstract Imatinib mesylate (IM) given orally at a daily dose of 400 mg was the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in the chronic phase (CML-CP), before 2ndTKI era. Treatment guidelines by European Leukemia Net (ENL) propose dose escalation based on clinical assessments of disease response in 2006. Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. However, randomized study to compare high-dose IM (800 mg) with the standard dose (400 mg) as front-line in all CML high-risk patients did not support the extensive use of high-dose IM. To improve the results of CML therapy, another alternative strategy is a dose-escalation based on more aggressive clinical assessments of disease response in comparison with the standard ELN proposed. In 2007, we conducted a prospective randomized study to compare different dose escalation programs; the standard-dose escalation program proposed by ENL (Group A) and the aggressive dose escalation program (Group B) among newly diagnosed patients with CML-CP. The aggressive dose escalation program consisted of the following interventions. If the patients do not obtained a complete cytogenetic response at 3 months or do not reach a major molecular response (MR3, IS=0.1%), IM is increased from standard dose of 400mg daily to 600 mg daily. The primary endpoint is the rate of major molecular response at 12 months, which is a surrogate for long-term progression-free survival (PFS). It is also a surrogate for complete molecular response, which is pointed out recently to be the condition for treatment free survival. Total 248 patients entered to this study between June 16 2007 and June 15, 2011. Median age was 49 years old (range 15-69); 86 were female and 162 were male. Sokal score index was high-risk in 46 patients, intermediate-risk in 77 and low-risk in the remaining. White blood cell count at diagnosis was 43X10^9/L in median (10-881 in range). There was no significant difference between Group A (N=126) and Group B (N=127) according to these factors. Overall survival was 100%, 98% and 98% at 1, 2 and 3 years after treatment, respectively. Three patients developed blast crisis during 3 years (day 177, 272, 481) and all received hematopoietic stem cell transplantation (HSCT). Two other patients who had no cytogenetic response also received HSCT. Eleven patients (4.5%, Group A, N=8, Group B, N=3) failed to achieve complete hematological remission. The overall complete cytogenetic response (CCR) rate at 6 months after the treatment was better in Group B (89%) than in Group A (79%) with borderline significance (p=0.05, Fisher's exact test). However, the overall CCR rate at 12 months was 92% in both groups. At 12 months, MR3 was achieved in 61% and 64% of patients in Group A and Group B, respectively (p=0.69). Also, at 24 months, MR3 was achieved in 91% and 87% of patients in Group A and Group B, respectively. At 3 months, plans called for 8 and 45 patients to increase the dose of IM to 600 mg in Group A and B, respectively; however, only 4 and 27 patients followed the protocol. At 6 months, 10 and 55 patients were to increase the dose of IM to 600 mg in Group A and B, respectively; however, only 2 and 24 patients followed this protocol. The main reason was intolerance of IM. Among the patients who were to increase the dose at 3 and 6 months, 53% of those who could do according to the protocol achieved MR3 at 12 months, while only 16% of patients failed to increase (p=0.08). Eighty patients experienced drug discontinuation during 1 year. The incidence of discontinuation was 37% in Group B, whereas it was 29% in Group B (p=0.18). A substantial part of patients withdrew from this study; however, there was no difference between Groups (A 20%, B 21%). This is the first randomized study to compare two different dose escalation programs. The aggressive dose escalation program showed a better early cytogenetic response than the standard-dose escalation program, but, failed to evidence a better molecular response in a later period. Higher efficacy of high dose IM might be cancelled by the more frequently discontinuation of IM in this group. This study concluded that aggressive dose escalation is not recommended and careful management of drug dose according to patients' condition (residual leukemia, adverse effect, emotion) might be the best way for better outcome, which is applicable to new generation TKIs. Disclosures Miyamura: Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria. Usui:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding. Nakaseko:BMS: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; NOVARTIS: Honoraria. Fujita:Chugai Pharmaceutical Co.,LTD: Honoraria. Okumura:Novartis Pharma: Honoraria. Hatta:Novartis Pharma: Honoraria. Naoe:Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Celgene K.K.: Honoraria, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding.

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Acute Myeloid Leukemia in the Context of Previous History of Cancer with or without Exposure to Chemotherapy or Radiotherapy

Blood ◽

10.1182/blood-2021-145745 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3368-3368

Author(s):

Kebede H. Begna ◽

Mithun V. Shah ◽

Naseema Gangat ◽

Hassan B. Alkhateeb ◽

Mrinal M. Patnaik ◽

...

Keyword(s):

Research Funding ◽

Previous History ◽

Cell Transplant ◽

Advisory Committees ◽

Free Survival ◽

Allogenic Stem Cell Transplant ◽

History Of ◽

Group A ◽

Group B ◽

History Of Cancer

Abstract Background: Therapy-related acute myeloid leukemia (AML) is a well-described entity and known to carry a worse prognosis, compared to de novo AML. In the current study, we sought to describe the presenting features and outcome of patients with AML, in the setting of previous history of cancer with or without exposure to chemotherapy or radiotherapy. Methods: A Mayo Clinic database of patients with AML was queried to identify patients with a previous history of cancer, both hematologic and solid tumors. A comparative analysis of presenting features, treatment details and survival were performed between patients with therapy-related AML (Group A) and those with AML and a history of cancer that had been managed with surgery alone (Group B). Results: A total of 250 patients (median age 68 years, range 19-90; 60% males) with AML and a previous history of cancer (both hematologic and solid) were identified; 182 (73%) cases were determined to be therapy-related AML (Group A) while the remaining 68 (27%) did not receive chemotherapy or radiotherapy for their antecedent cancer (Group B) (Table). Among group A patients 106 (58%) were exposed to chemotherapy, 37 (20%) to radiotherapy and 39 (22%) to combination chemotherapy and radiotherapy for their cancer. At the time of AML diagnosis, adverse karyotype was noted in 91 (51%) group A and 12 (19%) group B patients (p<0.0001); the incidence of adverse karyotype in patients exposed to chemotherapy vs radiotherapy alone vs combined chemoradiotherapy was 54% (57/106), 30% (11/37), and 59% (23/39) respectively (p=0.04). Group A patients, compared to those in group B, included more females (46% vs 24%; p=0.001), and more preceding hematologic malignancies (p=<0.0001). Next generation sequencing was performed in 74 patients and the results showed no significant difference between groups A and B (Table). Treatment and outcome in Groups A and B: Intensive and less intensive AML-directed chemotherapy were given to 100 (55%) and 44 (24%) patients in group A and 38 (56%) and 14 (21%) patients in group B (P=0.8). 79 (65%) remissions (complete remission (CR) 42 (29%) and CR with incomplete count recovery (CRi) 37 (26%) were documented in Group A and 37 (71%) remissions (CR: 21 (40%) and CRi=16 (31%) in Group B (P=0.2). After a median follow-up of 8.4 months (range: 0.9-217), 184 deaths were documented: 132 (72.5%) in Group A and 52 (76.5%) in Group B (P=0.5). 52 (36%) patients from Group A and 25 (48%) from Group B relapsed (P=0.1). The median (range) overall survival (OS) rates of patients from Group A was 13 (9-17) months and that of Group B was 14 (10-35) months (P=0.6). The 1-, 3- and 5-year OS rates were 52%, 28%, and 24% in Group A; and 62%, 33%, and 24% in Group B patients (Fig 1). Multivariable analysis identified relapse (HR 2.8, 95% CI 1.7-4.7) and failure to achieve CR/CRi (HR 2.8 95% CI 1.9-4.7) as risk factors for inferior survival (Fig 2a and 2b). The median (range) relapse free survival of patients in Group A was 28 (17 -81) and that of Group B was 27 (14 - 76) months (P=0.9) (Fig 2c). 28 patients underwent allogenic stem-cell transplant (25 in CR1 and 3 in CR2), 23 in Group A and 5 in Group B; the 1-, 3-, and 5-year OS of patients who underwent allogenic stem cell transplant were 88%, 72%, and 72% regardless of the group (Fig 2d). Conclusion: The current study did not find significant differences between AML patients with previous history of cancer with or without exposure to chemo/radiotherapy, in terms of either response to AML-directed therapy or overall or relapse-free survival, despite a higher prevalence of adverse karyotype in therapy-related AML. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee.

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CML and Imatinib Mesylate: Response Related to Karyotype.

Blood ◽

10.1182/blood.v106.11.4866.4866 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4866-4866

Author(s):

Araceli Rubio-Martinez ◽

Valle Recasens ◽

Maria D. Odero ◽

Daniel Rubio-Felix ◽

Maria J. Calasanz ◽

...

Keyword(s):

Imatinib Mesylate ◽

Cytogenetic Study ◽

Specific Inhibitor ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Rt Pcr ◽

Group A ◽

Group B ◽

Mean Time

Abstract Background: Imatinib mesylate (STI571), as a specific inhibitor for tyrosine kinase product of oncoprotein Bcr/Abl. Efficacy of Imatinib is questioned when other cytogenetics abnormalities associated to t(9;22) are present. We describe our experience in CML patients treated with Imatinib in one centre, evaluating hematological (HR) and cytogenetic response (CR) related to kariotype. Patients and methods: 28 patients diagnosed as having CML, 1990–2005, Imatinib 400–800 mg/d, were stratified according to cytogenetic abnormalities: Group A: t(9;22) typical in 19 patients, Group B: patients with t(9;22) and different genomic rearrangement associated: 9. At diagnosis were classified in stages Kantarjian score and the cytogenetic study (kariotype, % metaphases Ph, FISH and PCR/RT-PCR in bone marrow (BM) and peripheral blood (PB)). HR was evaluated monthly and CR in BM every 3–6 months. In patient with complete cytogenetic response (CCR) we performed follow-up in PB by RT-PCR every 3 months and a cytogenetic study in BM once a year. Cytogenetic response (CR) was quantified by n° metaphases Ph in BM: 0% CCR, 1–35% partial (PCR), 36–95% minor (MCR) and > 95% failure (F). Molecular response (MR): normal kariotype (Bcr/Abl negative and RT-PCR<5 copies). Statistical analysis: Chi-cuadrado and Kaplan-Meier survival test. Results: 18 M /10 F (2 died by blast crisis), mean age 50 (range 30–72), Kantarjian score: A group (4: 2pts, 3: 5pts, 2: 5pts, 1: 7 pts). Mean time on therapy: 26.46 m (1–51 ). Previous therapy: α-interferon 7, α-interferon/pegilated 1, α-interferon/α-interferon+citarabine 3, α-interferon+citarabine 6. Imatinib as first line: 11. When Imatinib started: accelerated phase 3, chronic phase 23 and chronic phase post-blast crisis2. The results of therapy are in table I. We have not observed statistically significant differences (s.s.d) in MR (p=.577) and in OS (p=.581) between group A and B with the same doses. Two patients that had started therapy with Imatinib 800 mg/day (group A) reached MR three months later. In group B one patient 12 months after got MR surprisingly developed a ALL Ph’, he received chemotherapy plus Imatinib 800 mg/day and 6 months later he is in CCR. Conclusions: Three months after Imatinib therapy HR was 100% in both groups. One year undergoing therapy CR response was higher in A group (81% vs 50%). Nevertheless the n° of MR obtained in patients with complex karyotypes receiving Imatinib 400 mg/day has been high (33.3%) and without s.s.d.with those with classical translocation. Hematological and Cytogenetic response to Imatinib Months N.E.P. A Group (19) N.E.P. B Group (9) 1 19 HR : 100% 9 HR :78% 3 10 HR:100%. CR 7 (70%): 4CCR(2MR), 2PRC, 1MRC, 3F. 3 HR: 100%. CR 2 (67%): 2MCR, 1F 6 16 HR: 94%. CR: 12 (75%), 7CCR (3MR), 3PRC, 2MCR, 4F 6 HR: 86%. CR 4 (67%): 3CCR, 1MCR, 2F 12 16 HR: 94%. CR 13 (81%): 11CCR (6MR), 2PRC, 3 F 4 HR: 100%. CR 2 (50%): 2CCR (1MR), 2F 18 13 HR: 100%. CR 12 (92%): 10CCR (6MR), 2PRC, 1F 5 HR: 80%. CR 3(60%): 3CCR (2 MR), 2F 24 13 HR: 93%. CR 12 (92%): 10CCR (7MR), 2PRC, 1F 6 HR: 83%. CR : 4 (67%): 3CCR (3 MR*), 1PRC, 2F 36 4 HR: 100%. CR 3 (75%): 2CCR (1MR), 1PRC, 1F 5 HR: 60%. CR 2 (40%): 2CCR (2MR), 3F 48 2 HR: 100%. CR 1 (50%): 1 PRC,1F 0 MR:N 10 (52,6%). Mean time : 12 m (3–24 m). Imatinib : 488,88 mg/d, Months in MR : mean 15.8 (9–21m) 3 (33.3%). Mean time : 18 months (12–26 m). Imatinib : 400 mg/day. Months in MR : mean 18 (12–26 m)

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Gestational diabetes mellitus: does treatment modality predict the obstetric and neonatal outcome?

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20175858 ◽

2017 ◽

Vol 7 (1) ◽

pp. 262

Author(s):

Lopamudra B. John ◽

Reddi Rani P. ◽

Seetesh Ghose

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Neonatal Outcome ◽

Previous History ◽

Treatment Modalities ◽

History Of ◽

Group A ◽

Group B ◽

The Impact

Background: Gestational diabetes mellitus (GDM) may be controlled with dietary modifications alone or may require insulin treatment. This study aims to find out the impact of these two treatment modalities on the maternal and neonatal outcomes.Methods: This retrospective observational study divided the GDM patients into two groups, A and B, treated with diet and insulin therapy respectively and the maternal and neonatal outcome parameters were compared.Results: 299 (6.7%) GDM patients over a period of two years were divided into group A (n=222) and group B (n=77). Need for induction of labour was significantly higher in group B (p=0.02). More number of history of previous abortions were seen in group A (p=0.1) and higher number of emergency Caesarean sections were observed in group B (p=0.1). Previous history of intrauterine deaths, gestational hypertension and hypothyroidism in the present pregnancy, meconium stained liquor, large for gestational age babies and need for neonatal intensive care were comparable in the two groups.Conclusions: There are no significant differences in the pregnancy outcomes of GDM treated with diet therapy alone or insulin except for a higher number of induced labours in the insulin treated group.

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