Cancer Treatment Today » Gleevec

Gleevec for Polycythemia Vera – pro

M Levin, MD — Fri, 14 Dec 2012 17:07:18 +0000

Gleevec is a drug initially approved for Chronic Myelogenous Leukemia. It wasrecently studied for P. Vera by Richard Silver at Weil-Cornell and the study was published in 2011. It described 37 patientswith an overall response of 49%. Thirty percent had a complete response, and 19%, a partial response. However, a previous study by Nussenzveig et al, did not show much activity in 27 patients. Overall, 4 (17%) patients responded: one had a complete and three partial hematological response. The median time to response was 17.5 months (range 6-28), and the median duration of response was 17 months (range 9-68). No significant changes in JAK2(V617F) mutation burden were noted during imatinib therapy when compared with pretreatment values (P = 0.46). The investigators concluded that therapy with imatinib was generally well tolerated but imatinib has minimal clinical activity in PV. Clearly more study is required before this drug can become standard for P. Vera.

Nussenzveig RH, Cortes J, Sever M, Quintás-Cardama A, Ault P, Manshouri T, Bueso-Ramos C, Prchal JT, Kantarjian H, Verstovsek S. Imatinib mesylate therapy for polycythemia vera: final result of a phase II study initiated in 2001.
Int J Hematol. 2009 Jul;90(1):58-63

Richard T. Silver et al, Treatment of polycythemia vera with imatinib mesylat Leukemia Research
Volume 36, Issue 2, February 2012, Pages 156–162

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Neupogen for Gleevec induced neutropenia – pro

M Levin, MD — Fri, 07 Dec 2012 14:52:25 +0000

Many chemotherapeutic drugs cause neutropenia and guidelines now uniformly recommend G-CSF(granulocyte growth stimulating factors) prophylactically and therapeutically for chemotherapy. However, non-chemo drugs can also cause neutropenia. Among them are bcr-abl directed drugs used for CML, such as Gleevec. Depending on the stage, up to 70% of the patients treated with imatinib for CML experience an NCI grade 3 or 4 neutropenia or thrombocytopenia during Imatinib therapy. A number of reports indicate that Neupogen can overcome neutropenia, allowing maintenence of dose and schedule of imatinib. NCCN in version 2.2013 recommends GSCF in combination with imatinib in patients with refractory neutropenia. In Asia beramine si being investigatede for this purpose.

Zaucha JM, Wyrowinska E, Prejzner W, Calbecka M, Hellmann A. Imatinib-associated neutropenia may not be overcome by filgrastim treatment in patients with blastic phase of chronic myeloid leukaemia.Clin Lab Haematol. 2006 Jun;28(3):208-10.

D Heim et al, G-CSF for Imatinib-induced neutropenia. Leukemia (2003) 17, 805–807.

nccn. org, CML 2012

Zhao Y, Tan Y, Wu G, Liu L, Wang Y, Luo Y, Shi J, Huang H. Berbamine overcomes imatinib-induced neutropenia and permits cytogenetic responses in Chinese patients with chronic-phase chronic myeloid leukemia.Int J Hematol. 2011 Aug;94(2):156-62.

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For Neupogen for interferon induced neutropenia see here

BCR/ABL Monitoring of chronic myelogenous leukemia on Gleevec – pro

M Levin, MD — Mon, 03 Sep 2012 00:56:05 +0000

There have been no studies that demonstrate that followup with BCR/ABL assists with actual clinical management of CML but it has become standard based on a guideline recommendation.It is not clear what the best monitoring stategy of imatinib might be; however, bcr/abl analysis would be a part of any finally accepted strategy. Unfortunately no trials of such strategies have been eprfomred but there is guidance from expert consensus. Some physicians get regular bcr/abl transcripts, others use FISH, others only use it for monitoring when Ph chromosome is undetectable. As noted, NCCN expresses the expert consensus and recommends BCR/ABL transcript analysis every three months until complete cytogenic response is reached and every 3-6 months thereafter.
Baccarani M, Pane F, Saglio G. Monitoring treatment of chronic myeloid leukemia. Haematologica. 2008;93:161–169.
Laboratory practice guidelines for detecting and reporting BCR-ABL drug resistance mutations in chronic myelogenous leukemia and acute lymphoblastic leukemia: a report of the Association for Molecular Pathology.

Jones D, Kamel-Reid S, Bahler D, Dong H, Elenitoba-Johnson K, Press R, Quigley N, Rothberg P, Sabath D, Viswanatha D, Weck K, Zehnder J.
J Mol Diagn. 2009 Jan;11(1):4-11. doi: 10.2353/jmoldx.2009.080095. Epub 2008 Dec 18.

Gluckman, J. Reiffers, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood, January 1, 2007; 109(1): 58 – 60.

J. V. Melo, T. P. Hughes, and J. F. Apperley. Chronic Myeloid Leukemia. Hematology, January 1, 2003; 2003(1): 132 – 152.

Hematology Disease Site Group. Walker I, Makarski J, Stevens A, Meyer RM. Treatment of chronic myeloid leukemia with imatinib. Toronto (ON): Cancer Care Ontario (CCO); 2004 Jul 16. 27 p. (Practice guideline report; no. 6-15). [39 references]

http://www.cdhb.govt.nz/chlabs/miscdocuments/CML_Monitoring_Guidelines_Jul%202007.pdf

Gleevec for acute lymphocytic leukemia – pro

M Levin, MD — Sat, 01 Sep 2012 22:12:17 +0000

Lay Summary: There is now evidence that GLeevec is very effective in Philadelphia chromosome positive ALL.

Philadelphia-positive ALL is a very difficult disease to treat successfully. In the recent past, the standard approach was to use daunorubicin/vincristine/prednisone-based induction therapy to achieve remission and then, if the patient was a reasonable candidate and a donor could be found, to perform an allogeneic transplant. Now, the use of tyrosine kinase inhibitor therapy may be altering this strategy. Single-agent treatment with imatinib and probably with dasatinib is fairly likely to achieve hematologic responses, but the likelihood of cytogenetic response is lower.

A study reported by Dr. Kirk Schultz on behalf of the Children’s Oncology Group (COG) showed that imatinib mesylate could be given safely in combination with chemotherapy in children with Philadelphia-positive ALL. Patients aged 1-21 with Philadelphia-positive ALL who achieved remission with standard COG induction therapy received an intensive multidrug combination chemotherapy regimen, with introduction of imatinib at 340 mg/m2 for 21 days into an increasing number of treatment blocks in successive cohorts of patients. Patients receiving imatinib had a higher incidence of transaminase elevation in first consolidation and maintenance. However, there were few significant additional increased toxicities compared with historical and contemporaneous controls not receiving imatinib. This appeared to be a feasible combination of a targeted therapy with chemotherapy and will be explored further in subsequent trials.

Dr. Deborah Thomas, a pioneer in the use of imatinib mesylate and chemotherapy in adults with Philadelphia-positive ALL, presented her most recent data at ASH 2007. This is the Phase II Pilot Study of Intensified Chemotherapy With or Without Allogeneic Hematopoietic Stem Cell Transplantation in Children With Very High-Risk Acute Lymphoblastic Leukemia. The chemotherapy backbone was the MD Anderson standard of hyper-CVAD, which is fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and high-dose ara-C. Although a high rate of remission was achieved historically with the use of this regimen in patients with Philadelphia-positive ALL, disease-free survival was brief. Dr. Thomas and colleagues added imatinib at 400 mg per day on days 1 through 14 to each of 8 courses followed by 12 months of imatinib. In later iterations of her work, imatinib was increased to 600 mg per day on days 1 through 14 for courses 1 through 8, with imatinib being given indefinitely after maintenance was completed. Overall, 52 patients with imatinib-naive or minimally treated Philadelphia-positive ALL received therapy from April 2001 to July 2006. With a 3-year treatment follow-up, there were only 7 relapses (14%); however, 12 patients died. The 3-year remission and disease-free survival rates for the combination compared favorably with hyper-CVAD alone (83% vs 24%, and 55% vs 14%, respectively).

Schultz KR, Aledo A, Bowman WP, et al. Minimal toxicity of imatinib mesylate in combination with intensive chemotherapy for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) in children: a report of the Children’s Oncology Group (COG) AALL0031 protocol for very high risk ALL. Blood. 2006;108:87a. Abstract 283.
Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103:4396-4407
Oliver G. Ottmann andBarbara WassmannTreatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia ASH Hematology 2005© 2005 The American Society of Hematology

Adjuvant Gleevec for GIST – pro

M Levin, MD — Fri, 31 Aug 2012 18:18:16 +0000

Results from several randomized, placebo-controlled clinical trials for patients with primary gastrointestinal stromal tumor (GIST), a type of tumor usually found in the stomach or small intestine, showed that patients who received imatinib mesylate (Gleevec ®) after complete removal of their tumor were significantly less likely to have a recurrence of their cancer compared to those who did not receive imatinib. For example, ACOSOG Z9001 trial was stopped early when planned interim analysis disclosed that significantly fewer patients in the treated group recurred. At a median follow-up of 20 months, 30 patients in the imatinib group recurred or died, versus 70 in the placebo group (8 versus 20 percent). The one-year RFS rate was 98 versus 83 percent favoring imatinib, with a hazard ratio for RFS of 0.35, 95% CI 0.22 to 0.53. On farther followup, no overall survival differences have emerged in favor of imatinib in the ACOSOG Z9001 trial. It is not clear why this is so. Among the possible reasons are the short duration of follow-up, the limited number of relapses, and the high degree of efficacy of imatinib in relapsed disease. Furthermore, after the study was unblinded, all patients randomized to placebo were allowed to crossover to active treatment, thus obscuring any potential differences in overall survival between the groups. The role of KIT and PDGFR overexpression must be clarified because some patients who lack detectable KIT or PDGFRA mutations or who have specific mutations that are known to be insensitive to imatinib (eg, PDGFRA exon 18 D842V) may not benefit.

Imatinib was given accelerated approval in the US in 2008 for adjuvant treatment of completely resected GISTs ≥3 cm in size, without definitive guidance as to the optimal duration of treatment or which patients are most likely to benefit.

The Scandinavian Sarcoma Group (SSG) XVIII trial compared 36 versus 12 months of adjuvant therapy. Data from the SSGXVIII trial provide compelling evidence that at least three years of adjuvant imatinib therapy is both safe and effective in reducing GIST recurrence and that it improves overall survival as well. Whether longer duration of therapy than three years will provide additional benefit and the optimal selection of patients for adjuvant therapy remains unclear.

In 2008, the FDA granted accelerated approved for imatinib in the adjuvant setting for completely resected primary GIST ≥3 cm without indicating the optimal length of therapy; labeling was updated in January 2012 to include the significantly prolonged survival seen with three years of therapy as compared to one year of adjuvant imatinib. However, whether all patients in this broad category have a high enough risk of recurrence to warrant adjuvant therapy is not established. The EMA (European Medicines Agency) has extended the licensed indications of imatinib to include adjuvant treatment of adult patients who are at “significant risk of relapse” after resection of a KIT-positive GIST, but does not define these subsets further.

Clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) suggest adjuvant imatinib for at least 36 months for patients with high risk GIST (tumor >5 cm in size with high mitotic rate [>5 mitoses/50 HPF] or a risk of recurrence that is >50 percent). The European Society of Medical Oncology (ESMO) does not give a strong recommendation for the use of adjuvant imatinib, stating that its use can be “proposed as an option for those patients with a substantial risk of relapse for shared decision-making”; however, these recommendations were written prior to the publication of results from the SSGXVIII trial, which established a survival benefit from the use of three as compared to one year of adjuvant imatinib.

Uptodate, 2012
Adjuvant and neoadjuvant imtinib for GIST

Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K, American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study TeamSO, Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.AUDematteo RP, Ballman KV, Antonescu CR, Lancet. 2009;373(9669):1097.

AUJoensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial.PSOJAMA. 2012 Mar;307(12):1265-72.

AUCasali PG, Blay JY, Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up., ESMO/CONTICANET/EUROBONET Consensus Panel of ExpertsSOAnn Oncol. 2010 May;21 Suppl 5:v98-102.

For Lay version see here

nccn, GIST(Sarcoma) 2012

Metastatic chordoma – pro

M Levin, MD — Tue, 28 Aug 2012 20:37:04 +0000

Chordomas are tumors originating from embryonic remnants of the primitive notochord. Metastatic spread is observed in 7-14% of patients and imatinib mesylate exhibits antitumor activity in some reports of patients with chordoma. Obviously, for a rare cancer like chordoma, there is not muche experi3nce with chemotherapy. Some patents have been reported to have received and responded to gemcitabine or navelbine. There are no drugs currently approved to treat chordoma, however a clinical trial conducted in Italy using imatinib demonstrated a modest response in some chordoma patients. The same group in Italy found that the combination of imatinib and sirolimus caused a response in several patients whose tumors progressed on imatinib alone. A phase II study has been was published in 2007. In it: In 44 pts evaluable for antitumor response, 37 (84%) had stable disease as their best RECIST response, which was maintained for more than 6 months in 32, for a clinical benefit rate (CR+PR+SD=6mos) of 73%. In 7 of these SD pts (16%), a degree of objective tumor shrinkage was reported. Centralized. On ITT analysis, median PFS was 32 wks, with 38% of pts free from progression at one year, and 16% on treatment at 18 months.

S. Stacchiotti, S. Ferrari, V. Ferraresi, G. Grignani, F. Crippa, A. Messina, C. Spreafico, E. Tamborini, A. Gronchi, P. G. Casali Imatinib mesylate in advanced chordoma: A multicenter phase II study. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 10003

McPherson CM, Suki D, McCutcheon IE, et al. Metastatic disease from spinal chordoma: a 10-year experience. J Neurosurg Spine. Oct 2006;5(4):277-80.

Casali PG, Messina A, Stacchiotti S, et al. Imatinib mesylate in chordoma. Cancer. Nov 1 2004;101(9):2086-97

Gleevec for melanoma – pro

M Levin, MD — Tue, 28 Aug 2012 20:34:36 +0000

Currently, interferon is the only approved adjuvant treatment for melanoma but it is unsatisfactory in several respects and intensive search for alternatives is ongoing. Among such options is Gleevec.

Results of Phase II trials of Gleevec in metastatic disease have not been very impressive. One trial involving 26 patients did not produce any clinical responses, but the course of treatment was limited in most patients by drug toxicity. Data on expression of known drug targets in tumors was not reported. A second trial from was limited to 21 patients with biopsies demonstrating expression of relevant PTK in over 25% of tumor cells.2 A near complete response was seen in one patient with the strongest expression of c-kit, but the remaining 20 patients experienced progressive disease over 6–12 wk. I was not able to find any trials exploringg Gleevec in adjuvant setting.

A new, ongoing, Phase II trial of Gleevec therapy for metastatic melanoma patients was recently presented by Dr. Carvajal at Sloan Kettering at ASCO 2009 as an interim update of results. This trial required all patients to have genetic sequencing of their tumors and limited enrollment to patients with specific mutations in KIT (at exons 9, 11, 13, 17 or 18) and/or amplification of KIT.

At the time of presentation, 15 patients had been treated on protocol with Gleevec 400 mg twice a day. Of the twelve evaluable subjects, two had complete responses, two had partial responses, six had stable disease and two had progressive disease as their best response, for a 33% (4/12) overall response rate.

Both of the two complete responders had Exon 11 mutation (designated L576P) and also KIT amplification). The two partial responders had Exon 11 (same mutation) and Exon 13 mutations, respectively, without KIT amplification. All four of those patients remain on treatment; the two complete responses appear to be durable. Most of the stable disease patients had Exon 13 mutations with or without KIT amplification. The two stable disease patients had other mutations (Exon 9 or different locus in Exon 13) and no KIT amplification.

This study is a preliminary indication that Gleevec may work best for patients with specific melanoma mutations. However, it is only a preliminary indication and requires confirmation in prospective clinical trials.

Douglas Grossman Imatinib Mesylate for Melanoma: Will a New Target be Revealed?Journal of Investigative Dermatology (2004) 123, xi–xiii

Eton O, Billings L, Kim K, et al: Phase II trial of imatinib mesylate (STI-571) in metastatic melanoma. Proc Am Soc Clin Oncol 23:713, 2004.

Wyman K, Atkins M, Hubbard F, et al: A phase II trial of imatinib mesylate at 800 mg daily in metastatic melanoma: Lack of clinical efficacy with significant toxicity. Proc Am Soc Clin Oncol 22:713, 2003.

Kevin Kalinsky, Frank G Haluska Novel inhibitors in the treatment of metastatic melanoma
Expert Review of Anticancer Therapy 7 (5), 2007, p.715

Gleevec for follicular dendritic cell tumor – pro

M Levin, MD — Tue, 28 Aug 2012 20:31:58 +0000

Follicular dendritic cell sarcoma is a rare, malignant, non-lymphoid cell-derived tumor that originates from B-lymphoid follicles of nodal and extranodal sites. These rare tumors form a spectrum within a rare and difficult to diagnose category of diseases known as histiocytic and dendritic cell neoplasms. It has been reported in around 100 cases in the literature, mostly for the head and neck region.As such, there are no standard treatmetn recommendations and no prospective studies. Gleevec is recommended based on a case report referenced below. In that case, imatinib was given in combination with gemcitabine and cisplatin for treating a male patient with metastatic follicular dendritic sarcoma to the liver and lung and the patient achieved complete pathological remission confirmed by positron emission tomography (PET) scan after 8 cycles.

Perez-Ordoñez B, Rosai J
Follicular dendritic cell tumor: review of the entity.Semin Diagn Pathol. 1998 May;15(2):144-54
H.A. Azim et al, Imatinib in the Treatment of Follicular Dendritic Sarcoma: A Case Report and Review of LiteratureOnkologie Vol. 30, No. 7, 2007

Gleevec for systemic mastocytosis – pro

M Levin, MD — Tue, 28 Aug 2012 20:28:12 +0000

Gleevec is in a clinical study: Therapy of HES, PV, Atypical CML or CMML, and Mastocytosis With Imatinib Mesylate, NCT00038675. The goal of this clinical research study is to see if Gleevec, known as imatinib mesylate (STI571), can improve the disease condition in patients with hypereosinophilic syndrome (HES), polycythemia vera, atypical chronic myeloid leukemia (CML) or CMML with PDGF-R fusion genes, or mastocytosis.

There is significant supporting evidence. Gleevec may be useful in those types of systemic mastocytosis (systemic mast cell disease) that do not have mutations of the codon 816 on the c-kit gene and carry the wild-type kit. Imatinib mesylate may also be useful in a subtype of systemic mastocytosis that carries the FIP1L1-PDGFRA rearrangement.

Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. Nov 1 2003;102(9):3093-6

Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL. Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006 Jul 15;107(2):345-51

Imatinib and dasatinib for histiocytosis – pro

M Levin, MD — Tue, 28 Aug 2012 20:26:59 +0000

Histiocytosis is an excessive number of histiocytes and it is used to refer to a group of rare diseases which share this as a characteristic. The histiocytes may infiltrate skin, bone, muscles, and vital organs, such as the liver, lung, spleen, and hematopoietic system. The disease is somewhat similar to cancer, and treatment often involves radiation and chemotherapy.

It often possesses a c-kit mutation and there are several case reports of using a related drug, imatinib for Langerhans histiocytosis. There are also reports of the use of dasatinib, a closely related drug. One phase II study found it to be effective for patients with histiocytosis ahe D816V negative patients did ntor espond to imatinib. There is also preclinical evidence that D816V mutation negative patients will respond to dasatinib but not imatinib.

Considering the rarity of D816V negative patients with systemic histiocytosis, the avaialble literature evidence should be consdered to support its use.

Christina Wagner; Henrik Mohme; Tanja Kromer-Olbrisch; Rudolf Stadler; Sergij Goerdt; Hjalmar Kurzen
Langerhans Cell Histiocytosis: Treatment Failure With Imatinib
Arch Dermatol. 2009;145(8):949-950.

CORRESPONDENCE
Montella, Liliana, Insabato, Luigi, Palmieri, Giovannella
Imatinib Mesylate for Cerebral Langerhans’-Cell Histiocytosis
N Engl J Med 2004 351: 1034-1035

Verstovsek S, et al, Pahse II study of dastinib in PH chromosome negative acute and chronci myeloid diseaes, inclusing systemic histiocytosis, Clin Cancer Res 2008 15;14:12:3906-15.

Shah NP et al, Dasatinib inhibits KITD86V, an imatinib resistant activating mutation that tiggers neoplastic growth in most patients with systemic mastocytosis, Blood 2006 1:108;(1):286-91

Christina Wagner; Henrik Mohme; Tanja Kromer-Olbrisch; Rudolf Stadler; Sergij Goerdt; Hjalmar Kurzen
Langerhans Cell Histiocytosis: Treatment Failure With Imatinib
Arch Dermatol. 2009;145(8):949-950.

CORRESPONDENCE
Montella, Liliana, Insabato, Luigi, Palmieri, Giovannella
Imatinib Mesylate for Cerebral Langerhans’-Cell Histiocytosis
N Engl J Med 2004 351: 1034-1035