Received Imatinib Mesylate Research Articles

Outcome of Patients Age 60 and Over with Acute Lymphoblastic Leukemia (ALL) Treated with a Modified Pediatric Protocol

Acute lymphoblastic leukemia (ALL) in patients over age 60 years is a poor prognosis disease with complete remission rate of 50–60% and median overall survival of less than a year. Between July 2004 and June 2007, we treated 17 elderly patients with newly diagnosed ALL with a modified pediatric protocol that included a remission induction phase, a CNS prophylaxis phase with intrathecal chemotherapy × 4, a 21-week intensification phase (7 cycles × 3 weeks each), and a 72-week maintenance phase. Induction chemotherapy consisted of vincristine 2 mg weekly × 3, doxorubicin 30mg/m2 × 2 doses, methotrexate 40mg/m2 × 1, asparaginase 12,000/m2 U × 1, and dexamethasone 40mg/day × 8 doses; BCR-ABL+ patients received imatinib mesylate 400 mg daily × 16 days instead of asparaginase. The intensification phase consisted of vincristine 2 mg × 7 doses, doxorubicin 30mg/m2 × 7 doses, asparaginase 6000 U/m2 weekly × 21 doses, 6-mercaptopurine 14/21 days, and dexamethasone 6 mg BID × 5/21 days. BCR-ABL+ patients received imatinib 400 mg daily × 14/21 days instead of asparaginase. Maintenance was the same as intensification except that no asparaginase was given. The median age was 66 years (range 60–78 years). Seven patients (41%) were BCR-ABL+ and four (24%) were pre-B with WBC > 30. Major side effects during the induction phase included infection (71%), hyperglycemia requiring insulin (24%), and cardiac toxicity (18%). The complete remission (CR) rate was 71% with an induction mortality of 29%. Of the five induction deaths, four were due to bacterial sepsis or pneumonia, and one was due to tumor lysis syndrome. CNS prophylaxis was well-tolerated except in one patient who required IV hydration for nausea/vomiting. Eleven patients proceeded to intensification. Major side effects during the intensification phase included infections (64%), peripheral neuropathy (64%), thrombosis (27%), and grade 3 nausea/vomiting (27%). Two patients required hospitalization during the intensification phase; there was one myocardial infarction and one acute pancreatitis. Eleven patients proceeded to the maintenance phase; major side effects during maintenance included infections (36%) and grade 3 peripheral neuropathy (18%). Two patients (17%) have relapsed, both during early maintenance phase; both had had a number of dose modifications and delays during intensification. The one year overall survival (OS) was 71% and the median OS has not been reached. After a median follow-up duration of 17 months (range 9–40 months), the median relapse-free survival (RFS) of the CR patients has not been reached; the one year RFS was 82%. These results show that administering a modified pediatric protocol to patients over age 60 years with ALL is feasible with an improved CR rate than generally reported. The OS and RFS also compare favorably to previously reported results, although further follow-up is required. However, induction mortality was high, and infectious complications persisted throughout the entire course of induction and intensification, though much diminished during the maintenance phase. Accrual to the protocol is continuing.

Efficacy of Imatinib Mesylate in the Treatment of Refractory Sclerodermatous Chronic Graft-Versus-Host Disease.

Outcomes in the treatment of sclerodermatous chronic graft-versus-host disease (cGVHD) are generally disappointing. Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) pathways. Recently, the drug's effects on fibroblasts have been reported in both in vitro and in vivo studies. Inhibiting fibroblast growth (and thus decreasing collagen production in dermal fibroblasts) is thus a logical therapeutic approach. Here, we report on our experience with 12 patients who received imatinib mesylate for refractory sclerodermatous cGVHD following allogeneic stem cell transplantation (allo-SCT). The patients' characteristics were as follows: median age, 35 years (range: 15–59); 7 male recipients, 6 female donors; 4 cases of CML, 4 MDS, 2 ALL and 2 Hodgkin's lymphoma. The patients had received either myelo-ablative conditioning with standard GVHD prophylaxis based on cyclosporine and short-course MTX (n=9) or nonmyelo-ablative conditioning with cyclosporine and MMF. Seven patients received a marrow graft and 5 received a peripheral blood graft. All displayed refractory, chronic, sclerodermatous GHVD with at least 3 lines (range 3–6) of prior immunosuppressive therapy. The modified Rodnan skin score was used to assess the extent of skin damage. Glivec was initiated at a dose of 400 mg/day between 16 and 119 months post-transplantation (median: 44). Despite an imatinib dose reduction and the administration of various symptomatic treatments, 4 patients (33%) had to discontinue their treatment soon after its initiation (range: 16–64 days) because of intolerance (especially muscle cramps) and were not evaluable in terms of the efficacy criterion. Other side effects reported were parenthesis, diarrhea and edema. In the remaining patients, the scleroderma symptoms improved within three months of treatment initiation. At the time of this report, all patients were alive and those who tolerated imatinib mesylate have experienced a complete or near-complete response (n=4) or partial response (n=4). All responders (except for one who discontinued the drug 157 days after initiation, due to cramps) were still on the treatment, after a median time period of 216 days (range: 80–2053). This retrospective report shows that when imatinib mesylate is well tolerated, it is effective in patients with refractory sclerodermatous cGVHD and is thus a promising candidate for the treatment of this complication. This study should provide useful background information for building prospective, multicenter studies.

Hyalinized collagen in a dermatofibrosarcoma protuberans after treatment with imatinib mesylate

We report a novel histological finding in a dermatofibrosarcoma protuberans (DFSP) after treatment with imatinib mesylate: copious amounts of hyalinized collagen. A 57-year-old female was referred for evaluation and treatment of a 7 x 8 x 10 cm tumor on the right anterior shoulder. Histological evaluation of the incisional biopsy showed a highly cellular dermal neoplasm composed of spindle cells arranged in a storiform pattern with minimal collagen. A CD34 immunohistochemical stain was strongly positive, highlighting atypical spindle cells in the dermis. A diagnosis of DFSP was made and the patient was enrolled in the Southwest Oncology Group trial. She received imatinib mesylate 400 mg per day for 1 year. At the end of therapy, the DFSP decreased in size to 5.5 x 4 x 4 cm. The tumor was excised. Histological evaluation showed a residual dermal neoplasm composed of atypical spindle cells and a copious amount of hyalinized collagen. Areas of necrosis were not seen. A CD34 stain confirmed the presence of residual DFSP, highlighting atypical spindle cells. A procollagen I stain was strongly positive, confirming the presence of abundant collagen in the dermis. A similar finding has been reported in gastrointestinal stromal tumor, which shows deposition of myxohyaline stroma after treatment with imatinib mesylate.

Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD

Treatment of sclerodermatous chronic GVHD (cGVHD) remains disappointing. Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFbeta) and PDGF pathways. Recently, the drug's effects on fibroblasts have been reported in both in vitro and in vivo studies. The inhibition of fibroblast growth and decreased collagen production in dermal fibroblasts is thus a logical therapeutic approach. Two patients who developed refractory sclerodermatous cGVHD following allo-SCT received imatinib mesylate at the dose of 400 mg/day. In both patients, the scleroderma symptoms disappeared within 3 months of initiation of the treatment. At the time of this report, the two patients were both alive and had a very good skin response. This report shows that imatinib is effective in patients with refractory sclerodermatous cGVHD. Considering its well-documented clinical profile in other diseases, imatinib is a promising candidate for the treatment of sclerodermatous cGVHD.

Molecular and cytogenetic response of chronic myelogenous leukemia treated with imatinib mesylate: one institutional experience in Japan

We retrospectively analyzed the clinical outcome of chronic myelogenous leukemia (CML) patients who received imatinib mesylate (IM) as initial therapy at Tokyo University Hospital. In all patients, molecular response as well as hematological and cytogenetic response was measured routinely. Our cohort showed respectable outcome with complete cytogenetic response (CR) of 82% in 1 year, and 97% in 5 years. The estimated progression free survival of 29 patients who were in chronic phase at diagnosis was 97% and the estimated OS was 92.4% at 5 years. Although IM interruption due to side effects was observed in about half of the cases, the discontinuation was only temporary in all cases. However, patients who showed persistent intolerance with adequate dose of IM (300 mg/day or more) showed poor molecular response.

Trisomy 6 in a CML patient receiving imatinib mesylate therapy

The emergence of chromosome abnormalities in Philadelphia-negative cells in chronic myelogenous leukemia patients during imatinib therapy have been described by several authors. While these abnormalities are frequently transient, in rare instances they may be presented on repeated occasions suggesting the possibility of the development of a new malignant clone. We describe a patient with Philadelphia chromosome-positive chronic myelogenous leukemia diagnosed in 1998, in whom multiple clonal abnormalities were identified in Ph-negative cells while on imatinib therapy. The patient developed lymphoid blast crisis associated with an additional Ph chromosome and trisomy 6 in Ph-negative cells. Our results further reinforce the importance of serial chromosomal studies in patients receiving new therapies which may ultimately lead to alternative therapies.

Pathologic complete response confirmed by surgical resection for liver metastases of gastrointestinal stromal tumor after treatment with imatinib mesylate

A 39-year-old male underwent distal gastrectomy for a high grade gastrointestinal stromal tumor (GIST). Computed tomography (CT) and magnetic resonance imaging (MRI) 107 mo after the operation, revealed a cystic mass (14 cm in diameter) and a solid mass (9 cm in diameter) in the right and left lobes of the liver, respectively. A biopsy specimen of the solid mass showed a liver metastasis of GIST. The patient received imatinib mesylate (IM) treatment, 400 mg/day orally. Following the IM treatment for a period of 35 mo, the patient underwent partial hepatectomy (S4 + S5). The effect of IM on the metastatic lesions was interpreted as pathologic complete response (CR). Pathologically verified cases showing therapeutic efficacy of IM have been rarely reported.

Imatinib Mesylate Reduces Plexiform Neurofibromas by Targeting the Hematopoietic Microenvironment.

Von Recklinghausen's neurofibromatosis type 1 (NF1) is the most common genetic disease in man with a predisposition to cancer, a disorder caused by mutations of the NF1 tumor suppressor gene that functions as a GTPase for p21ras. Affected individuals are predisposed to plexiform neurofibromas, congenital tumors that arise from cranial and peripheral nerves for which no effective therapies are available. We have recently utilized a genetically engineered murine model to demonstrate that mast cells and the c-kit/kitL pathway have a key role in plexiform neurofibroma formation. In the present study, we utilized this model to determine whether imatinib mesylate, an FDA approved drug that targets the c-kit ligand in mast cells and other cell lineages in the tumor microenvironment in inducing tumor regression. Krox20; Nf1flox/−mice begin to develop plexiform neurofibromas by 6 months of age, especially in the dorsal root ganglia involving the sciatic nerve. Fluoridinated PET/CT images were utilized to verify that experimental mice had developed plexiform neurofibromas and to evaluate tumor progression. Following a 12 week treatment, Krox20; Nf1flox/−mice who received the vehicle had an increase in FDG uptake in the tumor growth area. In contrast, mice received imatinib mesylate had a dramatic reduction in the FDG uptake. At autopsy, the spinal cords were examined and sections were prepared for histologic examination. Grossly, tumors from the vehicle control treated mice were consistent with plexiform neurofibromas, as previously described (Zhu, Science 2002). In contrast, dissection of the spinal cords from Gleevec treated mice revealed that the mean volume of the tumor was significantly reduced. In addition, though there is still hyperplasia observed in the dorsal root ganglia from imatinib mesylate treated mice, the overall architecture of the nerve is improved as compared to the hematoxylin and eosin stained sections from the placebo treated control. Serial sections from 10 tumors isolated from placebo treated mice and serial sections from all dorsal root ganglia in the FDG positive affected regions of imatinib mesylate treated sections were scored. There is variability in the number of mast cells from the placebo treated tumors. However, there is a consistent, significant reduction in the number of mast cells scored in the dorsal root ganglia from the imatinib mesylate treated mice, suggesting that imatinib mesylate is inhibiting the c-kit receptor kinase and thus reducing mast cell numbers in the neurofibroma. Finally, since there are anatomic reductions in tumor size of imatinib mesylate treated mice as compared to placebo control treated animals, we hypothesized that the FDG affected regions would have an increase in apoptosis as compared to the amount of apoptosis observed in tumors from placebo treated mice. While only rare TUNEL positive cells were observed in tumors treated with the placebo, up to 10% of cells were TUNEL positive in tumors received imatinib mesylate. Collectively, these studies provide direct evidence that targeting the microenvironment induces regression of a plexiform neurofibromas and provides the basis for conducting clinical trials for a tumor that affects approximately 10–15 thousand patients in the US alone.

Stem Cell Transplantation (SCT) Improves Survival in Acute Biphenotypic (ABL) and Acute Undifferentiated Leukemia (AUL): A Single Centre Experience.

Background: ABL and AUL are associated with an unfavourable outcome for patients (pts) treated with standard-dose therapy alone. Although high-dose therapy has been used successfully in this population, the optimal management of pts with ABL/AUL remains unclear. Methods: A retrospective review was performed involving 24 adult pts with ABL or AUL who were treated in Vancouver between 1984 and 2006. Kaplan-Meier estimates were utilized for event-free survival (EFS) and overall survival (OAS) and a multivariate analysis was performed to determine factors predictive of outcome. Characteristics: Utilizing the WHO criteria, 18 pts had ABL and 6 pts had AUL. There were 17 males and 7 females with a median age of 37 (range 22–75) years. Median white cell count (WCC) at presentation was 10.1 × 109(range: 0.9–196 × 109)/L. Seven pts had poor-risk karyotypes (3 pts complex, 3 pts with t(9,22), 2 pts with11q23 rearrangement, and 1 pt with monosomy 7),12 pts had standard-risk karyotypes, and 5 pts had an unknown karyotype. Induction chemotherapy consisted of Cytosine arabinoside (3–6/m2/day), Daunorubicin, Vincristine and Prednisone with one pt with t(9,22) also having received Imatinib Mesylate. Thirteen pts went on to receive high-dose therapy and SCT. Stem cell source was autologous in 3 pts (all with AUL) or a related (6 pts) or an unrelated donor (4 pts). Eight of 10 pts were in complete remission at the time of SCT, one was in relapse and one had primary refractory ABL. Conditioning was TBI-based in 10 pts and Busulfan-based in 3 pts. Results: EFS and OAS estimates for all 24 patients at 3 years were 25% (95% CI 13%–50%) and 32% (95% CI 17%–58%), respectively. The non-relapse mortality (NRM) for the whole group at 3 years was 43% (95%CI 15%–61%). On multivariate analysis, when compared to pts receiving only standard-dose chemotherapy, pts who underwent high-dose therapy had significantly improved EFS [39% (95% CI 19%–77%) vs. 9% (95% CI 1%–59%), p=.03] and OAS [46% (95% CI 26%–83%) vs.14% (95% CI 3–74%), p=0.01], respectively. Age, WCC at presentation and cytogenetic risk group were not found to significantly influence outcome. Conclusion: Although patient numbers are limited, this experience would suggest that patients with ABL/AUL who achieve complete remission with standard chemotherapy should be considered for high-dose therapy and stem cell transplantation. This approach provides them with the greatest probability of long-term event- free and overall survival.

Cytogenetic Remissions Induced by Interferon α and Imatinib Mesylate are Immunologically Distinct in Chronic Myeloid Leukemia

We compared immunologic parameters of chronic myeloid leukemia (CML) patients in cytogenetic remission receiving imatinib mesylate (STI) treatment, CML patients receiving interferon alpha (IFN-alpha), and healthy volunteers. Each group comprised 14 subjects. Median treatment dosages and durations were 6 x 10(6) IU/week and 174 months, respectively, for IFN-alpha and 400 mg/day and 54 months for STI. The numbers of T-cells were significantly lower in the 2 patient groups (P = .0006), whereas the 3 groups were comparable with respect to the numbers of natural killer cells. Not only the absolute numbers of monocytes and B-cells but also serum immunoglobulin G (IgG) and IgA titers were significantly lower in the STI group than in the IFN-alpha group (P < .0001). For T-cell subsets, the ratio of CD4 T-cells to CD8 T-cells was significantly lower in the IFN-alpha group than in the STI group, but the proportion of CD26(high)CD4+ T-cells among CD4+ cells was significantly higher. Collectively, the 2 therapeutic agents induce a distinct immunologic status in CML patients whose hematopoiesis has returned to normal levels.

Rare incidence of congestive heart failure (CHF) in gastrointestinal stromal tumor (GIST) and other sarcoma patients (pts) receiving imatinib mesylate (IM) therapy

10026 Background: Potential IM cardiotoxicity has not been evaluated in patients with GIST or other sarcomas. CHF has been reported in leukemia pts on IM. Objectives: To determine the incidence of CHF in GIST and other sarcoma pts receiving IM. Methods: From our clinical trial database we reviewed all Grade III/IV potential cardiac adverse events (PCAEs) including dyspnea, dyspnea on exertion, chest pain, edema, pleural effusion, ascites, cardiac ischemia, and arrhythmia. Results: 219 pts were enrolled on clinical trials with IM from Dec 27, 2000 to May 11, 2006. 18 pts (8.22%) were identified as having PCAEs. The median age was 65.5 yrs (range, 21 to 88 yrs) and 7 were women. Their diagnoses were advanced GIST (13 of 125 pts, 10.40 %), primary GIST (4 of 48 pts, 8.33 %), or osteosarcoma (1 of 46 sarcoma pts, 2.17%). The osteosarcoma pt had received prior anthracycline therapy. The median time from start of IM to a PCAE was 173.5 days (11 to 1,568 days). IM dose at the time of the PCAE was 400 mg/d in 10 pts, 600 mg/d in 4 pts, and 800 mg/d in 4 pts. 13 pts had a past medical history of risk factors for coronary artery disease (CAD) or established heart disease: diabetes (4 pts, 22.22%), hypertension (9 pts, 50%), CAD (2 pts, 11.11%), hypertrophic obstructive cardiomyopathy (1 pt, 5.56%), peripheral vascular disease (2 pts, 11.11%), hyperlipidemia (3 pts, 16.67%) or arrhythmia (1 pts, 5.56%). None of these patients had evidence of pulmonary vascular congestion by chest film. 8 pts had an ECHO or MUGA scan at the time of the PCAE, and 1 of them had documented low ejection fraction; in only 2 of these 8 pts was there an ECHO prior to IM (LVEF &gt;50% in both). The single pt with LVEF&lt;50% at the time of the PCAE had prior a history of hypertension, multi-vessel CAD and coronary artery bypass grafting 12 years prior to the PCAE. All of the pts continued IM therapy with dose adjustments and toxicity-specific management with no further complications. Conclusions: Pts who develop PCAEs on IM should be treated with diuretics, ACE-inhibitors, and beta-blockers with continuation of IM as clinically indicated. CHF in sarcoma patients treated with IM is rare and was observed in only one elderly patient with known prior cardiac disease. No significant financial relationships to disclose.

Gastric GIST: A single institutional retrospective experience with surgical treatment for primary disease

Aims Because gastric GISTs show variable clinical behavior, we reviewed our experience with primary gastric GISTs after surgical treatment and imatinib mesylate treatment for advanced disease. Methods Between December 1995 and December 2005, 111 patients who underwent surgical treatment for primary gastric GISTs were enrolled in this study. Patients were grouped according to the risk assessment classification, and clinicopathological features, tumor recurrence and patient survival were assessed. Results One patient was included in the very low risk group, 35 in the low risk group, 31 in the intermediate risk group and 44 in the high-risk group. All patients with very low, low and intermediate risk GISTs and 70% of patients with high risk GISTs underwent R0 resection. While there was no recurrence or metastasis in patients with very low, low and intermediate risk GISTs, 23% of those with high risk GISTs showed a distant metastasis at diagnosis and 35% of these patients had a recurrence after R0 resection. The overall 5-year survival rate of the high risk patients was 77.1%. Nineteen patients received imatinib mesylate therapy due to an incomplete resection or recurrence; 7 with no measurable lesion at the CT scan by a local tumor control showed no tumor progression after imatinib mesylate therapy, however, 12 patients with measurable lesions showed variable clinical courses after treatment. The overall 5-year survival rate of 19 patients with imatinib mesylate treatment was 80.0%. Conclusions The clinical outcome of the very low, low and intermediate risk gastric GISTs was excellent, while high risk gastric GISTs had a high rate of recurrence and therefore a less favorable outcome. A complete resection is the most important treatment for cure; however imatinib mesylate treatment may improve the clinical outcome of the patients with metastatic or recurrent gastric GISTs.

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas

Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate

Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate

Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate

Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate

Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate

Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate

Imatinib mesylate in the treatment of advanced gastrointestinal stromal tumors

To evaluate the efficacy and safety of imatinib mesylate in the treatment of patients as preoperative supplement, or used alone for unresectable and/or metastatic gastrointestinal stromal tumors (GIST). A total of 51 cases with advanced GIST were proved pathologically. Among them, CD117 was detected positive in 47 patients and negative in 4 patients; 4 patients received imatinib mesylate before operation and 47 patients with unresectable and (or) metastatic GIST received oral imatinib mesylate daily at dose of 300-800 mg. One patient was lost in follow-up and the objective effect was evaluated in 50 patients. 3 of the 50 patients (6.0%) achieved complete response (CR), 34 (68%) had partial response (PR), 5 (10.0%) had stable disease (SD) and 8 (20.0%) had progression disease (PD). The median time to progression (mTTP) was 16 months during which most of the patients experienced benefit. 32 patients had been followed up for more then 1 year. The 1-year and 2-year survival rate were 95.3%, 89% respectively. 50 patients were valuable for the toxicity assessment according to the WHO standard. The main toxicity included grade I-II edema of periorbital area and lower limb in 72.0% (36/50) patients, leukopenia was present in 46% (23/50) and intratumoral bleeding in 4.0% (2/50). Other toxicities included mild fatigue (28.0%), abdominal pain (14.0%), efflorescence (18.0%), nausea and vomiting (18.0%). As an inhibitor of tyrosine kinase, imatinib mesylate is generally well tolerated and has been proved to be effective and safe during prolonged treatment of patients with advanced gastrointestinal stromal tumors. Its toxicity is acceptable.

Outcomes of Children with First Marrow Relapse: Results from Children's Oncology Group (COG) Study AALL01P2.

Treatment of relapsed acute lymphoblastic leukemia (ALL) remains a significant challenge. Objectives of the COG AALL01P2 study were: a) to define a clinically acceptable re-induction platform to which novel agents might be added and b) to track response and minimal residual disease (MRD) through 4 months of treatment. The initial regimen consisted of 3, 35-day blocks of chemotherapy (block 1: vincristine, dexamethasone, PEG-asparaginase, idarubicin, and intrathecal cytarabine and methotrexate (CNS-negative), or triple intrathecal therapy (CNS-positive); block 2: etoposide, cyclophosphamide, 5 g/m2 methotrexate and intrathecal methotrexate (CNS-negative), or triple intrathecal therapy (CNS-positive); block 3: high dose cytarabine and L-asparaginase). Patients with Philadelphia chromosome positive (Ph+) ALL received imatinib mesylate in combination with all 3 blocks of chemotherapy. AALL01P2 opened in January 2003. The study was suspended in May 2003, however, due to unacceptable toxicity among the first 21 patients. Block 1 therapy was subsequently modified substituting doxorubicin for idarubicin, and prednisone for dexamethasone, and the study reopened accruing a total of 127 eligible patients (120 B-precursor-ALL, 7 T-ALL) from August 2003 through December 2005. Seventy-two patients had early marrow relapse (< 36 months from initial diagnosis) (ER) and 55 patients had late marrow relapse (LR). Four B-lineage patients were Ph+. Subsequent analyses include only patients enrolled following the modification in block 1 therapy. Complete remission (CR2) rates at the end of block 1 were 67% ± 5.9% for ER (n=63) and 96% ± 2.8% for LR (n=48). Patients with ≥ 5% residual blasts (M2 or M3 marrows) at the end of block 1 continued on protocol therapy. However, only 2 of 13 B-lineage patients with M2/3 marrows at the end of block 1 responded to subsequent chemotherapy. Event-free survival (EFS) at 4 months was 64% ± 6.7% for ER (n=72) and 93% ± 4.3% for LR (n=55). Outcome for T-ALL patients (n=7, 6 ER) was poor with complete remission achieved in only 2 of 7 patients. Toxicity was acceptable during all 3 blocks. The most common toxicities were hematopoietic and infectious, with the highest incidence during blocks 1 and 3. Five toxic deaths occurred (4%), all from infections: 3 during block 1, and 2 during block 3. MRD was measured by flow cytometry at the end of each block. MRD was detected in 79% ± 6.2% of ER (n=43), vs. 50%± 8.3% of LR (n=36) at the end of block 1 in an analysis restricted to B-lineage, CNS-negative, Ph-negative patients, regardless of their morphological response. Four month EFS was 95% ± 3.5% vs. 78% ± 5.3% in patients who were MRD-negative vs. positive at the end of block 1 (p<0.01). The AALL01P2 regimen is a tolerable and active re-induction platform, acceptable for testing in combination with novel agents. The COG ADVL04P2 study, which uses this regimen in combination with epratuzumab (anti-CD22), is currently underway. MRD measurements are also feasible at serial time points during re-induction, and early response is prognostic. Alternative strategies are urgently needed for patients with relapsed T-ALL and for early marrow relapse.

High Levels of Tumor Load Reduction after Intensive Chemotherapy Favorably Affect the Prognosis of BCR/ABL+ ALL Adult Patients Receiving Imatinib Mesylate Alone as a Post-Consolidation Treatment According to the Italian GIMEMA LAL 0201/A Protocol.

Thirty-six adult patients aged between 20 and 60 years (median age: 44) with BCR-ABL+ ALL were prospectively monitored by Q-RT-PCR between December 2001 to November 2005. All patients were treated according to the GIMEMA LAL 0201/A protocol, in which Imatinib alone, was administered as post-consolidation therapy, in responding patients after high-dose induction and consolidation treatment, at the dosage of 400 mg x 2 daily for at least six months and continued on the basis of the opinion of physicians. Twenty-three (64%) were p190+ and 13 (36%) p210+. At presentation, the median BCR-ABL/ABL ratio was 1.33 (range 0.23 to 7.8). Before Imatinib, all patients were in 1st CR (34 after the first induction and consolidation course; 2 after a salvage treatment). At this time point, the median reduction from baseline in BCR-ABL transcripts, calculated for each individual patients, was 2.1 log (range: 0 to 6.1). In particular, 18 of the 36 cases showing a log reduction of the BCR-ABL/ABL ratio > 2.1 (p190=14 cases; p210 = 4 cases) were considered as good responders to the antecedent chemotherapies, whereas 18 cases (p190=9; p210=9 cases) showing a log reduction ≤2.1 were considered as bad responders. The median reduction from baseline in BCR-ABL levels was 2.49 log (range: 0.00–6.1) and 1.45 log ( range: 0.19–5.34) in p190 and p210 positive cases, respectively (p=.16). During Imatinib treatment, 10 (56%) of the 18 poor responders patients presented a relapse of disease versus 5 (28%) ( 3 =BM; 2=CNS) of the 18 good responders.At last follow-up 16 patients were in first CR; of these patients, only 4 were allo-transplanted (2 good, 2 bad responders), therefore 12 (9 good, 3 bad responders) persisted in first CR maintained by Imatinib alone after a median follow-up of 24 months (range: 7–48). At 24 months, the cumulative incidence of relapse was 29% vs 44% for good and bad responders (p=.034), respectively, whereas, the DFS and OS rates were 65% vs 33% ( p=.0032) and 76% vs 32% (p=.0056) for good and poor responder patients, respectively. Monitoring of MRD was prospectively evaluated at the starting of Imatinib therapy and afterwards at the 3rd, 5th and 6th month. At these time points, the median BCR-BCR/ABL ratio were 0.015, −0.006, −0.008 and −0.009, respectively. In addition to the classification as good/ bad responders, the current variation of BCR-ABL ratio (used as time-dependent covariate in a Cox model), was associated with an increase of the hazard of failure (hazard ratio of an increase by 2 log of the BCR-ABL levels compared to a constant ratio equal to 2.1). In conclusion, Imatinib mesylate is a highly effective post-consolidation treatment for adult Ph+ ALL patients. However, the clinical outcome after Imatinib was significantly affected by the level of molecular response evaluated before the starting of Imatinib, resulting excellent for the good responders but remaining dismal for patients who responded poorly to the initial chemotherapy.

Comparison of Combination Therapy of Imatinib with Trisenox Versus Imatinib Monotherapy for Chronic Myeloid Leukemia Patients in Chronic Phase.

Targeted therapy with the Bcr-Abl tyrosine kinase inhibitor Imatinib Mesylate can induce high response rates in chronic myelogenous leukemia (CML) patients. However, evidences that discontinuation of imatinib mesylate inevitably exerts rapid loss of response and some patients with imatinib mesylate monotherapy virtually occur potential relapse suggest that the modification of treatment strategy is critical. We have previously demonstrated that the combination of trisenox (arsenic trioxide) with the tyrosine kinase inhibitor imatinib mesylate or genistein appears to induce markedly more cell apoptosis than imatinib mesylate alone through downregulating Bcl-XL and Bcr-Abl in Bcr-Abl gene transfected HL-60 cells. We here report the preliminary results of a pilot study comparing imatinib mesylate plus trisenox with imatinib mesylate alone for frontline treatment of CML patients.Up to date 56 patients were enrolled in this clinical trail. All patients (required to be 18 years or older with Bcr-Abl positive CML in chronic phase within three month of diagnosis) were divided into two groups, i.e., monotherapy group and combined therapy group. 42 patients entering monotherapy received imatinib mesylate 400mg daily and 14 patients entering combined therapy imatinib mesylate 400mg daily plus trisenox 10mg daily for one week and then twice a week. We compared treatment results of both groups including complete hematologic response(CHR), major/complete cytogenetic response(MCR/CCR),–defined as 1–35% Ph+ and 0% Ph+ metaphases respectively and major/complete molecular response(MMR/CMR),–defined as ≥ 3 log reduction and negative expression in Bcr-Abl transcript numbers assayed by RQ-PCR respectively. The median follow-up for patients in both groups lasted 36 months. In the combined therapy group, the median age of patients is 42 years old (range, 22–61), the CHR, MCR, CCR, MMR and CMR is 92.8%, 64.3%, 42.9%, 35.7% and 21.4%, respectively. While in the imatinib mesylate monotherapy group, the median age of patients is 46 years old (range, 23–65), the CHR, MCR, CCR, MMR and CMR is 85.7%, 59.5%, 40.5%, 33.3% and 19%, respectively.Although combination therapy of imatinib with trisenox is not significantly superior to imatinib mesylate monotherapy in efficacy, no resistance case happens in the combination therapy group, in the imatinib mesylate monotherapy group, imatinib resistance occurs in 4 patients. In addition, the safety and tolerability of a combination of imatinib mesylate and trisenox is good. This result indicates that the combination of imatinib and trisenox to treat chronic myeloid leukemia may be promising in avoiding the occur of imatinib resistance.