Outcome with the Hyper-CVAD and Imatinib Mesylate Regimen in Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1830-1830 ◽  
Author(s):  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Jorge Cortes ◽  
Susan O’Brien ◽  
Francis Giles ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Single Agent ◽  
Disease Free Survival ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Cell Transplant

Abstract In Ph+ ALL, complete remission (CR) rates with intensive chemotherapy such hyper-CVAD is 90%, but most patients (pts) relapse within a median time of 16 months [Kantarjian et al, JCO18:547, 2000; Kantarjian et al, Cancer101:2788, 2004]. Single agent therapy with the tyrosine kinase inhibitor imatinib mesylate in relapsed or refractory Ph+ ALL or chronic myelogenous leukemia in lymphoid blast phase yielded CR rates of 20% with rapid disease recurrence. A phase II clinical trial of concurrent hyper-CVAD and imatinib was designed to improve these results, with the initial regimen of imatinib 400 mg orally daily days 1–14 of each course (fractionated cyclophosphamide, vincristine [VCR], doxorubicin and dexamethasone alternating with high dose methotrexate and cytarabine) followed by imatinib, VCR and prednisone maintenance with intensifications months 6 and 13. Allogeneic stem cell transplant (SCT) was performed in CR if feasible. Preliminary results of first 20 pts treated were encouraging [Thomas et al, Blood103:4396, 2004]. Recent modifications included increasing dosing of imatinib to 600 mg daily days 1–14 of course 1, then daily if tolerated with courses 2–8. Maintenance was extended to 24 months with imatinib indefinitely. To date, 43 pts with Ph+ ALL have been treated from April 2004 to July 2005. Thirty-six pts had active disease, either untreated (n=31) or refractory (n=1) to one induction course without imatinib; 7 pts were in CR after one induction course without imatinib. Of 35 evaluable pts, 33 (94%) achieved CR (1 induction death, 1 failed to meet platelet criteria for CR). Median days to response was 21 days. 13 pts underwent allogeneic SCT within a median of 3 months from start of therapy (range, 1–12). After a median follow-up of 3 yrs (range 1–48 months), 1 primary refractory pt relapsed at 12 months, 1 de novo pt had isolated CNS relapse, 2 pts relapsed after allogeneic SCT (no post SCT imatinib) and 2 pts changed therapy for persistent Ph+ metaphases (1 relapsing). Deaths in CR included 5 older pts without allogeneic SCT (1 osteomyelitis, 1 mucormycosis, 1 C. difficile colitis, 1 sudden death, 1 GNR sepsis) and 4 pts after allogeneic SCT (3 graft-versus-host disease, 1 GNR sepsis). Outcome with the hyper-CVAD and imatinib regimen continues to demonstrate favorable disease-free survival rates compared with hyper-CVAD alone, particularly for the de novo group. Use of higher dose imatinib concurrently appears to be feasible. Molecular response rates appear to be improved with the higher dose imatinib; additional accrual will be required to assess impact of modifications, including role of allogeneic SCT.

Outcome with the Hyper-CVAD and Imatinib Mesylate Regimen as Frontline Therapy for Adult Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 284-284 ◽  
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
Francis Giles ◽  
...  
Keyword(s):  
De Novo ◽  
Single Agent ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Molecular Response ◽  
Cell Transplant ◽  
Active Disease

Although complete remission (CR) rates with the hyper-CVAD regimen (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone alternating with high dose methotrexate, ara-C) in de novo adult Ph-ALL were 90% or better; remissions were brief with median CR duration of 16 months (mos) [Kantarjian et al, JCO18:547, 2000; Kantarjian et al, Cancer101:2788, 2004]. Single agent activity of imatinib in relapsed or refractory Ph-ALL or chronic myelogenous leukemia in lymphoid blast phase was 20% with rapid disease recurrence. A phase II trial of hyper-CVAD and imatinib was conducted in newly diagnosed Ph-ALL. Imatinib was initially given 400 mg days 1–14 of each of the 8 courses, followed by 12 mos of imatinib, VCR and prednisone maintenance interrupted by hyper-CVAD and imatinib intensifications mos 6 & 13. Allogeneic stem cell transplant (SCT) was performed in first CR if feasible. Preliminary results of the first 20 patients (pts) treated were encouraging [Thomas et al, Blood103:4396, 2004]. To exploit dose-response relationships, imatinib was increased to 600 mg days 1–14 of course 1, then daily with courses 2–8. Maintenance was extended to 24 mos followed by imatinib indefinitely. To date, 52 pts with imatinib-naïve de novo or minimally treated Ph-ALL received therapy from April 2001–July 2006. Forty-four pts had active disease, either untreated (n=37) or refractory (n=6) to 1 induction course; 9 pts were in CR. Median age was 51 years (range, 17–84); 52% were male. Five pts had CNS disease (10%). Of 43 evaluable pts with active disease at start (1 too early), 39 (91%) achieved CR (1 failed to meet platelet criteria for CR, 1 achieved partial response, 1 died early from sepsis). Multiparameter flow cytometry and quantitative RT-PCR for bcr-abl were monitored. Molecular response rate (negative nested PCR) without SCT was 58% in 33 evaluable pts. Fifteen pts underwent allogeneic SCT within a median of 5 months from start of therapy (range, 1–12); 3-yr survival rates were similar with or without SCT (60% vs 56%, p=0.8). After a median follow-up of 3 years (range, 1–60 mos), 7 relapses (14%) were observed. Five de novo pts relapsed at 8, 8, 11, 15 and 42 mos from start of therapy (2 after SCT without imatinib maintenance); 1 CR at start relapsed at 16 mos, and 1 primary refractory pt at 12 mos. Two other pts changed therapy either for persistent disease or intolerance and later relapsed at 6 and 10 mos. ABL mutation was identified at relapse in 1 (Q252H after SCT without imatinib) of 5 pts tested. Deaths in CR occurred in 12 pts (5 related to infections, 4 related to complications of allogeneic SCT, 1 pancreatitis, 1 intracranial hemorrhage, 1 unknown). Three-year remission and disease-free survival rates are favorable compared with hyper-CVAD alone (de novo group, 83% vs 24% and 55% vs 14%, respectively, p<0.001). Exploration of the newer tyrosine kinase inhibitors in combination with hyper-CVAD is planned.

Long-Term Follow-Up after Frontline Therapy with the Hyper-CVAD and Imatinib Mesylate Regimen in Adults with Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 9-9
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
De Novo ◽  
Survival Rates ◽  
Disease Recurrence ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Multiparameter Flow Cytometry ◽  
Molecular Response ◽  
Cell Transplant ◽  
Early Results

Historically, complete remission (CR) rates with hyper-CVAD (cyclophosphamide, vincristine [VCR], doxorubicin and dexamethasone alternating with methotrexate and cytarabine) in de novo adult Ph-ALL were 90% or better. There was no impact on survival since remissions were brief with median CR duration of 16 mos [Kantarjian, JCO18:547, 2000; Cancer101:2788, 2004]. CR rate of imatinib in relapsed/refractory Ph-ALL or chronic myelogenous leukemia in lymphoid blast phase was 20%, with rapid disease recurrence. A phase II trial of hyper-CVAD and imatinib for Ph-ALL was designed in 2001. Imatinib 400 mg was given days 1–14 of each course, followed by 12 months of continuous imatinib with monthly VCR and prednisone interrupted by 2 intensifications with hyper-CVAD and imatinib. Allogeneic stem cell transplant (SCT) was performed in first CR as feasible. Early results of 20 patients (pts) were encouraging and demonstrated feasibility [Thomas, Blood 103:4396, 2004]. Imatinib was then increased to 600 mg days 1–14 of course 1, continuously with courses 2–8, escalated to 800 mg during maintenance therapy (extended to 24 mos) then imatinib indefinitely. The study has completed accrual. Fifty-four pts with imatinib-naïve de novo or minimally treated Ph-ALL received therapy from April 2001 to September 2006. Forty-five pts had active disease, untreated (n=39) or refractory (n=6) to one induction course; 9 were in CR at start. Median age was 51 years (range, 17–84); 52% were male. Seven pts (13%) had CNS disease at presentation. Of 45 evaluable pts 42 (93%) achieved CR (1 CRp, 1 partial response, 1 died early from sepsis). Median days to response was 21. Molecular response rate (negative by nested PCR) was 52%. Allogeneic SCT was performed in 16 pts within a median of 5 mos from start of therapy (range, 1–13), and did not appear to improve survival (2-yr rates 63% vs 56% without SCT). After median follow-up of 4 years (range, 10–74 mos), eleven relapses (22%) were observed. Eight de novo pts relapsed at 8, 8, 10, 11, 11, 15, 16 and 42 mos from start of therapy (2 after SCT without imatinib maintenance); 2 CR at start at 16 and 19 months, and 1 primary refractory pt at 12 mos. Two pts changed therapy for persistent molecular disease or intolerance and relapsed at 6 and 10 mos. Relapse was preceeded by positive multiparameter flow cytometry with minimal increments in levels of quantitative RT-PCR for bcr-abl in a few cases. Non T315I ABL kinase domain (KD) mutations were identified at relapse in 3 of 8 pts tested. Deaths included 12 pts in CR (5 infections, 4 complications of allogeneic SCT, 1 pancreatitis, 1 intracranial hemorrhage, 1 unknown). The hyper-CVAD and imatinib regimen continues to demonstrate favorable 3-yr disease-free and overall survival rates for the de novo group compared with hyper-CVAD alone (66% vs 14% and 55% vs 15%, respectively, p<0.001). Development of ABL KD mutations was noted at disease recurrence in a few cases. Incorporation of the newer tyrosine kinase inhibitors into combination with therapy with hyper-CVAD is underway.

High-dose cytarabine and total body irradiation with or without cyclophosphamide as a preparative regimen for marrow transplantation for acute leukemia.

1988 ◽  
Vol 6 (4) ◽  
pp. 576-582 ◽  
Author(s):  
S Riddell ◽  
F R Appelbaum ◽  
C D Buckner ◽  
P Stewart ◽  
R Clift ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Total Body Irradiation ◽  
Disease Free Survival ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Severe Toxicity ◽  
Total Body ◽  
Disease Free

Twenty-nine patients were conditioned for allogeneic marrow transplant with cytarabine (ara-C) (3 g/m2 every 12 hours for 12 doses) and total body irradiation (TBI) (200 cGy daily for six days) with or without cyclophosphamide (CY) (60 mg/kg) to determine toxicity and efficacy. Four patients had chronic myelogenous leukemia (CML) in accelerated phase or blast crisis, and 25 patients had acute leukemia, 24 at stages later than first remission. Three patients (10%) had fatal regimen-related toxicity and another 10% experienced severe toxicity in at least one organ system. The addition of CY to the ara-C and TBI regimen was not associated with an increase in the frequency of severe toxicity. Twenty-five of 29 patients engrafted eight to 33 days posttransplant: three died early before engraftment, and one patient failed to engraft. Ten of 29 patients are alive without disease, and the actuarial probability of disease-free survival for the entire group at 3 years is 33%. Three of ten patients with acute nonlymphocytic leukemia (ANL), six of 15 with acute lymphocytic leukemia (ALL), and one of four with CML are alive and disease free 25 to 42 months (median, 30 months) after transplant. High-dose ara-C (HDara-C) and TBI with or without CY can be administered with approximately the same toxicity as CY plus TBI. Phase III studies appear warranted to determine if these newer regimens provide improved results compared with currently used regimens.

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

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2154-2154 ◽  
Author(s):  
Francois-Xavier Mahon ◽  
Francoise Huguet ◽  
Gabriel Etienne ◽  
Delphine Réa ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Molecular Remission

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

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

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 2873-2878 ◽  
Author(s):  
Hagop Kantarjian ◽  
Moshe Talpaz ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Complete Cytogenetic Response

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

Intensification of Chemotherapy Does Not Improve Prognosis of Standard Risk Patients Undergoing Therapy for Acute Myelogenous Leukemia: Results of the Pediatric Clinical Trial AML-BFM 98.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1793-1793
Author(s):  
Ursula Creutzig ◽  
Dirk Reinhardt ◽  
Joerg Ritter ◽  
Guenter Henze ◽  
Johannes Hermann ◽  
...  
Keyword(s):  
Clinical Trial ◽  
De Novo ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
Standard Risk ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract In order to further improve survival of children undergoing therapy for acute myeloid leukemia (AML), the multicenter clinical trial AML-BFM 98 intensified chemotherapy for standard risk (SR) patients (pts.). In addition, this randomized trial prospectively evaluated whether 2 short cycles of chemotherapy resulted in better prognosis than a 6-week consolidation. Patients and Methods: Between July 1998 and June 2003, 461 pts. < 18 years with de novo AML were enrolled in the trial AML-BFM 98. The SR group consisted of 170 (37%) pts. (FABM1/M2 with Auer rods or M4eo with ≤ 5 % blasts in the day 15 bone marrow; all pts. with FAB M3). All other pts. (n=291) were considered as high-risk (HR) pts.. In contrast to trial AML-BFM 93, a 2nd induction (HAM) was included in the treatment strategy for SR pts. (excluding FAB M3) which consisted of high-dose cytarabine (3g/m/12h x3 days) and mitoxantrone (10mg/m/d x2 days). Both SR and HR pts. were then randomly assigned to receive a 6-week consolidation or two short cycles of therapy. Compared to the 6-week consolidation, the short cycles contained higher doses of cytarabine, but the same cumulative dose of anthracylines. All other therapy elements [first induction (AIE; cytarabine, idarubicin and etoposide), intensification (HAE; high dose cytarabine, etoposide), and maintenance therapy] were identical in studies 93 and 98. Results: Overall, 407 out of 461 (88%) pts. achieved remission (CR). Five-year survival, event-free survival (EFS) and disease-free survival (DFS) were 59%±3%, 49%±3% and 55%±3%, respectively. Estimated survival and pEFS were similar to those of study 93 (58%±2% and 50%±2%, p logrank .09 and .80). Analysis of SR pts. (FAB M3 excluded) showed that the additional application of HAM did not improve the prognosis of SR pts. compared to AML-BFM 93 [CR rate 92% vs. 91%, p(chi)=.78; 5-year pEFS 58%±5% vs. 66%±4%; p logrank =.24]. However, when comparing HAM in study 98 and the 2nd chemotherapy cycle in study 93, significantly more severe infections (grade 3/4) occurred with HAM. Overall treatment related mortality in CR was 4% in both HR and SR pts., which was similar to trial AML-BFM 93. In addition, the outcome of pts. randomized for the 6-week consolidation was similar to that of the short cycles (p logrank .81). However, morbidity was lower in the short cycle arm (6 vs. 11 deaths in CCR, 2 vs. 4 in SR pts.). Conclusion: Our results indicate that in SR pts. with AML, a more intensive chemotherapy consisting of HAM does not result in improved survival. Therefore, new treatment options should be considered in this patient group. At the same time, optimizing treatment using the less toxic therapy with short cycles and improvement of supportive care strategies might help to reduce treatment related mortality and improve outcome in children with AML.

Update of the Hyper-CVAD and Imatinib Mesylate Regimen in Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2738-2738 ◽  
Author(s):  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Jorge Cortes ◽  
Susan O’Brien ◽  
Francis Giles ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Nested Pcr ◽  
Myelogenous Leukemia ◽  
Study Entry ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Rt Pcr ◽  
Active Disease

Abstract The intensive combination chemotherapy program hyper-CVAD in newly diagnosed Ph+ ALL yields complete remission (CR) rates of 90%, but remissions are brief with median CR duration of 16 months [Kantarjian et al, JCO 18:547, 2000]. The activity of the tyrosine kinase inhibitor imatinib given as a single agent in relapsed or refractory Ph+ ALL or chronic myelogenous leukemia in lymphoid blast phase was 20% [Druker et al, NEJM 344:1084, 2001]. A phase II trial of imatinib and hyper-CVAD was conducted in newly diagnosed Ph+ ALL. Imatinib was given 400 mg days 1–14 of each course of therapy (fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate and ara-C). Preliminary results were published in the first 20 patients (pts) treated, with CR rates of 100% in the de novo group, and improvement of disease-free survival (DFS) compared with hyper-CVAD alone [Thomas et al, Blood 103:4396, 2004]. To date, 32 pts with Ph+ ALL have been treated from April 2001 to February 2004. Twenty-six patients had active disease, either untreated (n=21) or refractory (n=5) to one induction course without imatinib. Six pts were in CR at study entry after one induction course without imatinib mesylate. Median age was 48 years (range, 17–75); 59% were male. Five had CNS disease (16%). Twenty-five of 26 pts (96%) with active disease at study entry achieved CR (1 failed to meet platelet criteria for CR). Median days to response was 21 days. Two of 26 pts (8%) required 2 courses to achieve CR. Allogeneic stem cell transplant (SCT) was performed in 13 pts in CR within a median of 3 months from start of therapy (range, 1–12). After a median follow-up of 2 years (range, 4–36 months), 1 primary refractory pt relapsed at 12 mos (bcr-abl/abl RT-PCR ratio <.05 at 9 mos), 1 pt relapsed day 149 after matched related SCT despite negative nested PCR for bcr-abl, and 2 pts changed therapy after 5 mos for persistent marrow Ph+ metaphases without overt leukemia relapse. Five pts died in CR, 3 older pts related to comorbid conditions (2 were negative for bcr-abl by nested PCR) and 2 related to complications of allogeneic SCT. Molecular response rate (negative bone marrow RT-PCR for bcr-abl confirmed by nested PCR) was approximately 50% in 19 pts who did not undergo allogeneic SCT. Outcome appears better with the hyper-CVAD and imatinib regimen with 2-year DFS rates of 87% (all pts) compared with 28% for hyper-CVAD alone or 12% for VAD (p<.001). Unexpected toxicities related to the addition of imatinib mesylate were not observed. The hyper-CVAD and imatinib regimen with or without allogeneic SCT continues to appear promising with additional accrual and longer follow-up.

High Dose Imatinib Is Effective In Children and Adolescents With Chronic Myelogenous Leukemia In Chronic Phase. The Italian Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1490-1490
Author(s):  
Fiorina Giona ◽  
Maria Caterina Putti ◽  
Giuseppe Menna ◽  
Concetta Micalizzi ◽  
Nicola Santoro ◽  
...  
Keyword(s):  
Side Effects ◽  
Median Time ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Effective Dosage ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Cell Transplant ◽  
Matched Sibling

Abstract Imatinib (IM) is an established first-line treatment for children with chronic myeloid leukemia (CML). However, the most effective dosage and duration of IM treatment are not well defined. This study was designed to evaluate the response to high-dose IM and long-term outcome in pediatric CML patients, previously untreated or resistant to IFN. Patients aged <18 years with a diagnosis of CML in chronic phase (CP) were treated with IM at a dosage of 340 mg/m2/day. Cytogenetic analysis was performed on bone marrow (BM) cells before and during IM therapy, at planned intervals; quantitative RT-PCR was assessed on peripheral blood (PB) monthly and on BM every 3 months, according to the European LeukemiaNet recommendations for minimal residual disease quantification. Major molecular response (MMR) is defined as <0.1% BCR-ABLIS, while complete MR (CMR) is considered as <0.01% BCR-ABLIS. From March 2001 to February 2013, 45 CML patients in CP (18 females, 27 males; median age: 119/12 years) were recorded from 9 Italian pediatric centers. Eight patients had previously received IFN. IM was started in all patients, including 16 with an HLA-matched sibling. The dosage was modulated according to hematologic toxicity and/or appearance of WHO >2 side- effects, mostly during the first 6 months of treatment (median administered dose: 309 mg/m2/day). Hematologic toxicity (medullary hypoplasia[n=1], neutropenia [n=11] and/or thrombocytopenia [n=6], anemia [n=1]) was observed in14/44 evaluable patients (32%); 13 patients (29.5%) experienced isolated or combined side effects: arthralgia/myalgia (n=10), nausea (n=1), vomiting (n=1), diarrhea (n=1), hepatitis (n=1), edema (n=1). After 3 months of IM treatment, 7/25 of tested patients (28%) obtained complete cytogenetic response (CCyR). Overall, 34/36 evaluable patients (94%) obtained a CCyR at a median time of 6 months. A molecular response (<0.1% BCR-ABLIS) was achieved in 21/26 tested patients (81%) on PB and in 30/33 evaluable patients (91%) on BM. Seventeen of 26 patients (65%), including 2 with a HLA-matched sibling, obtained a CMR on PB cells and 19/33 (55%) on BM cells at a median time of 15 and 19 months, respectively. With the aim of reducing the risk of longitudinal growth impairment or to improve treatment compliance, 9 patients with sustained CMR and 2 adolescents with MMR lasting >12 months received IM at the same daily dosage for 3 weeks a month (intermittent therapy). IM given without interruption was resumed in 3 of these 9 patients because of an increased BCR-ABL transcript. The growth rate showed a delay in height, which recovered over time, in 6 children who received IM prior to puberty. Overall, IM was stopped in 22/44 evaluable patients (50%) because of various reasons: stem cell transplant (SCT) in 8 patients (3 in CP, 1 in CCyR, 3 in MMR, 1 in CMR); hematologic (n=2) or extra-hematologic toxicity (n=2) (WHO grading >3) during the first 6 months in 4; recurrent disease in 6 (3 increased BCR-ABL transcript, 2 cytogenetic relapse,1 blast crisis [BC]); no response in 1; CMR ( <0.0032% BCR-ABL IS) lasting >88 months in 2 and pancreatitis in 1 patient in CMR for 75 months. Twelve patients underwent a SCT after a median time of 8 months: 8 from an identical siblings (5 responders to IM [1 CMR, 3 MMR, 1 CCyR]), 3 MUD (2 in CCyR and 1 in MMR) and 1 cord blood in CCyR after chemotherapy for CB. Three patients, transplanted from an identical sibling, had disease recurrence after 24 (molecular relapse), 36 (cytogenetic relapse) and 83 (BC) months, respectively. At the last follow-up, all patients are alive (CMR= 25; MMR=14; CCyR=3; minor CyR=2; too early=1) at a median of 52 months (range: 3-146). Of 42 patients evaluable for treatment, 23 are receiving IM at a dosage of 340 mg/m2 (4 intermittent IM); 11 are in CMR without any treatment (8 after SCT; 3 at 32, 33 and 50 months after IM discontinuation); 4 are in treatment with dasatinib, 3 with nilotinib and 1 with IFN. In our experience, higher dose IM is an effective treatment for childhood CP CML, associated with sustained responses. Moreover, IM can be safely discontinued in pediatric CML patients with a deep CMR lasting more than 7 years. For patients candidates to a SCT, IM provides a safe bridging option to transplant, at no increased risk. Since patients may lose their response, a close and regular monitoring should be performed, mostly for those who stop IM, as SCT and new TK inhibitors may be successfully employed in patients failing IM. Disclosures: Saglio: Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Immune Modulation of Minimal Residual Disease (MRD) in Patients (pts) with Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CP): A Randomized Trial of Frontline High-Dose (HS) Imatinib Mesylate (IM) with or without Pegylated-Interferon (PEG-IFN) and GM-CSF.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2207-2207 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
Residual Disease ◽  
Single Agent ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Myelogenous Leukemia ◽  
P Value ◽  
High Dose ◽  
Molecular Response ◽  
Gm Csf

Abstract Some studies suggest that HD IM renders higher molecular response rates than standard dose IM in CP CML. Yet, most patients have MRD detectable by PCR and in vitro studies suggest the CML stem cell is insensitive to IM. The efficacy of IFN in CML has been linked to its immunomodulatory properties and preclinical studies have shown synergy with IM. IFN may be used as adjunct for the management of MRD. IFN combined with GM-CSF is a potent dendritic cell stimulator. In this phase II study we investigated whether the addition of PEG-IFN to IM improves complete molecular response (CMR) rates and prolong remission duration in pts with early CP CML. Pts received IM 800 mg daily for 6 months (mo) before randomization to either continuing HD IM as single-agent or combined with PEG-IFN 0.5 mcg/kg/week and GM-CSF 125 mg/m2 three times weekly. Pts were monitored with real-time PCR and cytogenetics (CG) every 3 mo for 12 mo and every 6 mo thereafter. Ninety-four pts were randomized between Arm A (IM alone; 49 pts) and Arm B (IM+PEG-IFN+GM; 45 pts) and 91 (97%) were followed for at least 12 mo (2 pts in Arm A and 1 in Arm B did not start therapy). Ten pts randomized to Arm B did not start PEG-IFN (4 refused, 3 off study before 6 mo, 1 melanoma, 1 heart disease, 1 financial). The primary objective was to increase by 50% the rate of major molecular response (BCR-ABL/ABL ratio <0.05%) at 12 mo. Pt characteristics and response are shown in Table 1. Median follow-up for pts on study was 24 mo (range, 12 to 38) and 8 mo (range, 1 to 22) for those taken off-study. Toxicity in Arm A was similar to that reported in prior studies of HD IM. The most common grade 3–4 toxicities among 39 pts assessable in Arm B were fatigue (n=12, 31%), depression (n=3, 8%), pruritus (n=3, 8%), and headache (n=3, 8%) and were all significantly more frequent in Arm B than Arm A. PEG-IFN was discontinued in 43% of pts and GM-CSF in 45%, mainly due to fatigue, rash, and flu-like symptoms. Nine pts were taken off study in Arm A (3 resistant, 2 liver toxicity, 4 other) and 10 in Arm B (3 resistant, 2 financial, 1 liver toxicity, 4 other). Median IM dose intensity at 12 mo was 98% (range, 47% to 100%) in Arm A and 99% (range, 46% to 100%) in Arm B. By contrast, PEG-IFN dose intensity was only 45%, with 75% of pts receiving < 60% of the planned dose. We conclude that the combination of HD IM and PEG-IFN is associated with acceptable toxicity but does not impact significantly the achievement of molecular response after 12 mo of therapy at the dose schedule used in this study. The high drop-out rate observed in the PEG-IFN arm may have compromised any potential immunomodulatory benefit. Table 1 No. / No. evaluable (%) Overall IM alone IM+PEG-IFN+GM p value Median age (range), years 48 (19-79) 46 (19-73) 51 (19-79) Sokal (% low/int/high) 72/21/6 65/24/10 80/16/4 0.96 CG response at 12 mo partial 4/82 (4) 2/45 (4) 2/37 (5) 0.50 complete 76/82 (93) 41/45 (91) 35/37 (95) 0.09 Best molecular response         >0% - <0.05% 40/91 (45) 23/47 (49) 17/44 (39) 0.20         undetectable 15/91 (17) 8/47 (17) 7/44 (16) 0.29 Molecular response at 12 mo         >0% - <0.05% 23/91 (25) 10/47 (21) 13/44 (24) 1.00         undetectable 9/91 (10) 5/47 (11) 4/44 (9) 0.29

Outcomes of Patients (pts) with Myelodysplatic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML) Post Clofarabine Failure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1722-1722
Author(s):  
Hady Ghanem ◽  
Guillermo Garcia Manero ◽  
Stefan Faderl ◽  
Koichi Takahashi ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Median Duration ◽  
Salvage Therapy ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Cell Transplant ◽  
First Line ◽  
Platelet Recovery ◽  
Duration Of Response

Abstract Abstract 1722 Introduction: Clofarabine is a nucleoside analogue that has shown activity in pts with myeloid disorders. The outcome of pts with MDS and CMML post clofarabine is unknown. Aims: To evaluate the outcome of pts with MDS or CMML treated and failed clofarabine based chemotherapy as a first line or salvage regimen. Methods: We reviewed data of 89 pts with MDS and 21 patients with CMML treated with a clofarabine based chemotherapy at MDACC between 6/2001 and 5/2012. Thirty-nine pts (36%) received clofarabine as first line therapy and 71 pts (64%) received clofarabine as salvage therapy. Ninety-six pts (87%) received single agent clofarabine and 14 pts (13%) received a clofarabine containing combination. Response assessment followed standard criteria. Overall survival (OS) was measured from the time of therapy till the time of death or last follow-up. Results: One hundred and ten pts with a median age of 68 years (range, 42–88) were assessed. Sixty-five percent of the pts were older than 65 years. At the time of MDS diagnosis, 68 (61%) had a high or intermediate-2 risk International Prognostic System Score (IPSS). Thirty-one pts (27%) had complex cytogenetics. Sixty-one pts (55%) had failed therapy with a hypomethylating agent (HMA) before initiation of a clofarabine containing salvage therapy. Of the pts who received frontline clofarabine treatment, 15 (23%) achieved complete remission (CR) and 2 (3%) CR with incomplete platelet recovery (CRp), for an overall response rate (ORR) of 26%. Of the pts who received salvage clofarabine treatment, 4 (9%) achieved CR and 5 (11%) CRp, for an ORR of 20%. The median duration of response to clofarabine was 6 months. ORR was 14% among the 61 patients who had received a prior HMA. At time of clofarabine failure, 20 (18%) had progressed to acute myelogenous leukemia (AML). Fifty-eight patients received salvage therapy after clofarabine failure. Among these, 13 patients received allogeneic stem cell transplant, 17 patients received a high dose Ara-C containing regimen and 25 patients received only investigational treatments. Only 8 (14%) responded (median duration of response not reached) (range, 0–40 months). Within a median follow-up of 3 months from clofarabine failure, 13 pts (14%) remained alive. The median OS post clofarabine failure was 5.1 months and the 1-year survival rate of 25% (figure 1). Conclusion: Outcome of patients with MDS post clofarabine failure is poor, with a median survival of 5.1 months. These patients should be offered investigational strategies. Disclosures: Off Label Use: Use of clofarabine is investigational in MDS.

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