Cancer Treatment Today » Chronic Myelogenous Leukemia

Atypical CML – pro

M Levin, MD — Fri, 03 Jan 2014 20:33:14 +0000

Atypical chronic myelogenous leukemia (aCML) is a leukemic disorder that exhibits both myelodysplastic and myeloproliferative features at the time of diagnosis. It is thought that these features dennote a poor prognosis. Atypical CML cases are usually BCR-ABL negative. The optimal treatment of aCML is uncertain because of the rare incidence of this chronic leukemic disorder. Treatment with hydroxyurea may lead to short-lived partial remissions of 2- to 4-months’ duration. Atypical CML, appears to respond poorly to treatment with interferon-alpha.

Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008. [PUBMED Abstract] Hernndez JM, del Caizo MC, Cuneo A, et al.: Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol 11 (4): 441-4, 2000.

Philip A. Thompson, MBBS, Hagop M. Kantarjian, MD, Jorge E. Cortes, MD, Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015. October 2015Volume 90, Issue 10, Pages 1440–1454

Abstract] Costello R, Sainty D, Lafage-Pochitaloff M, et al.: Clinical and biological aspects of Philadelphia-negative/BCR-negative chronic myeloid leukemia. Leuk Lymphoma 25 (3-4): 225-32, 1997. [PUBMED Abstract] Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 19 (11): 2915-26, 2001.

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Iclusig – pro

M Levin, MD — Thu, 28 Feb 2013 17:44:47 +0000

Ponatinib (Iclusig, AP24534) was FDA approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). It was approved based on the inital results of The PACE (Ponatinb Ph+ ALL and CML Evaluation) trial and has activity against the T315I mutation, which confers resistant to other CML drugs. It targets the Bcr-Abl tyrosine kinase, as well as VEGFR, PDGFR, FGFR, the SRC kinases, KIT, EPH receptors, RET, TIE2, and FLT3. The multi-targeting makes it an attractive candidate for personalized use for conditions that display these mutations in the Personalized Medicine approach.

Singh et al, Molecular Monitoring and Treatment of Chronic Myeloid Leukemia (CML) J Clin Exp Pathol 2012, 2:4

Huang, WS; Metcalf, CA; Sundaramoorthi, R; Wang, Y; Zou, D; Thomas, RM; Zhu, X; Cai, L et al. (2010). “Discovery of 3-2-(imidazo1,2-bpyridazin-3-yl)ethynyl-4-methyl-N-{4-(4-methylpiperazin-1-yl)methyl-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant”. Journal of Medical Chemistry 53 (12): 4701–19.

O’Hare, T; Shakespeare, WC; Zhu, X; Eide, CA; Rivera, VM; Wang, F; Adrian, LT; Zhou, T et al. (2009). “AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance”. Cancer Cell 16 (5): 401–12.

Khodadoust MS, Luo B, Medeiros BC, et al. Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. Leukemia. 2016;30(4):947‐950. doi:10.1038/leu.2015.136

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Personalized Medicine

Sprycel second line after Gleevec- pro

M Levin, MD — Thu, 17 Jan 2013 16:58:29 +0000

On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. The approval was based on four single-arm multicenter studies that combined 445 patietns and supported the efficacy and safety of dasatinib.

The FDA approval was for newly diagnosed patients; however, there is evidence that Sprycel is effective in patients who fail imatinib as well. Study CALGB 180-034 was designed to assess the efficacy and safety of dasatinib following intolerance or resistance to imatinib. With six years fo followup, thirty-one percent of patients randomised to receive dasatinib 100 mg once daily remained on treatment.
In patients with chronic phase CML, the six-year data shows progression-free survival of 49.3% and an overall survival of 71% for patients randomised to dasatinib 100 mg once daily (n=167), with 6% of patients (n=10) progressing to accelerated or blast phase on study at six years of follow-up. The primary efficacy end point in chronic phase CML was major cytogenetic response. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention.

Sprycel is FDA indicted for first line, and for second line, it is supported by the CALGB-180-34 results.

nccn, CML 2014

Brave M, Goodman V, Kaminskas E, Farrell A, Timmer W, Pope S, Harapanhalli R, Saber H, Morse D, Bullock J, Men A, Noory C, Ramchandani R, Kenna L, Booth B, Gobburu J, Jiang X, Sridhara R, Justice R, Pazdur R.Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res. 2008 Jan 15;14(2):352-9.

Shah, N., et al. Six-year follow-up of patients with imatinib-resistant
or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. Oral Presentation at: 2012 American Society of Clinical Oncology Annual Meeting. 3.Macmillan Cancer Support. Leukaemia Overview. Available at: http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Leukaemia/Leukaemiaoverview.aspx

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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

stem cell neoplasm ponatinibStem cell transplantation for CML – pro

M Levin, MD — Sun, 02 Sep 2012 13:55:19 +0000

Despite improvement of treatment with Gleevec, Sprycel and Tasigna, allogeneic stem cell transplantation remains the only curative treatment for patients with CML. This form of treatment is only available for a small minority of patients due to the advanced age of most patients at the time of diagnosis and the lack of a suitable related or unrelated allogeneic stem cell donor. Despite significant progress, allogeneic transplants are associated with significant early mortality and morbidity. Until the advent of Gleevec, “young” patients with an HLA-matched related or unrelated donor were advised to undergo a transplant without a trial of IFNa. Older patients and patients with high-risk factors for failure of transplantation were advised to have an allogeneic transplant only after failure of IFNa. The definition of who is “young” and who is at “high” risk of transplant failure varies from center to center and is evolving over time. Advising selected patients to have an immediate transplant was based on the observation that the results of transplant were worse for patients transplanted after one or two years than for patients transplanted within one year of diagnosis. Until recently, a major criterion for delay of transplant was a good initial response to IFNa treatment. Now all patients with newly diagnosed CML are receiving initial treatment with Gleevec or other newer drugs before combination with other agents or a transplant is considered. However, clinicians should identify a donor early for younger patients without significant co-morbidities since, sooner or later, the disease will progress despite Gleevec and other therapies.NCCN recommends allogeneic tansplant in blast crisis, after obtaining a remission.

Transplantation should be done sooner when there are poor-risk features, such as presentation in blast crisis.Age has consistently been an important factor for outcome of allogeneic stem cell transplantation, but the exact upper age limit for performing an allogeneic transplant in early chronic phase is controversial, with ranges from 40-65 years, depending on the institution performing the procedure. In general, treatment-related deaths increase with age in most centers. In one clinical study, no patients under age 20 died. Patients 30-40, 40-50 and 50-60 years were 1.24, 2.30 and 2.54 times more likely to die of the procedure, respectively. Patients over age 40 had a significant increase in the risk of dying of the transplant compared to younger individuals. Thus, patients under the age of 40 had a 5-year survival of 85%, compared to 65-70% for patients over 40 years of age.

Delay of transplant can also affect outcomes of patients transplanted in chronic phase. In one study, patients transplanted from HLA-matched unrelated donors while in chronic phase within one year of diagnosis had a 5-year survival of 85% while those transplanted between 1 and 2 years from diagnosis had a survival of 78%. Patients transplanted in chronic phase more than 2 years from diagnosis had a survival 50%, with the excess deaths all being related to complications of the transplant. However, these data were generated in the era of INF alfa treatment and the impact of Gleevec on survival from a subsequent transplant is unknown. This will be very important since patients will be coming to transplant after years of Gleevec treatment.Allogeneic stem cell transplantation can cure up to 80-85% of patients with newly diagnosed CML but can be associated with significant morbidity and mortality. There have been attempts to define risk factors associated with failure to assist in decision making concerning the appropriate timing of allogeneic stem cell transplantation for an individual patient with CML. However, these risk factor analyses may be dated and may not be relevant to patients being treated in the Gleevec era and an era of improving results of allogeneic stem cell transplantation.

Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century. Blood. 2015;125(21):3230‐3235. doi:10.1182/blood-2014-10-567784
Saglio, G, Kim, DW, Issaragrisil, S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9.

Maziarz, RT. Who with chronic myelogenous leukemia to transplant in the era of tyrosine kinase inhibitors? Curr Opin Hematol. 2008 Mar;15(2):127-33. Fernandez, HF, Kharfan-Dabaja, MA. Tyrosine kinase inhibitors and allogeneic hematopoietic cell transplantation for chronic myeloid leukemia: targeting both therapeutic modalities. Cancer Control. 2009 Apr;16(2):153-7. National Comprehensive Cancer Network (NCCN) Guidelines. Chronic Myelogenous Leukemia. v2.2012.

JAK2 for diagnosis – pro

admin — Sat, 01 Sep 2012 20:24:59 +0000

Lay Summary: JAK2 testing can now be performed for a diagnosis of a myeloproliferative disorder. This is now an acceptable approach to diagnosing myeloproliferative disorders.

In early 2005, several groups of investigators reported a somatic acquired point mutation in the JAK2 (Janus kinase 2) protein in the blood and bone marrow of patients with BCR/ABL-negative chronic myeloproliferative disorders. JAK2 is a tyrosine kinase which plays an important role in normal hematopoietic growth factor signaling, and the mutation results in activation of the kinase and deregulated intracellular signaling with cell proliferation that is independent of normal growth factor control.

Using sensitive assays, the JAK2 mutation can be detected in approximately 90-95% of cases of polycythemia vera, 50-70% of patients with essential thrombocythemia, and 40-50% of cases of idiopathic myelofibrosis. The mutation has also been described in rare cases of myelodysplastic syndromes, acute myeloid leukemia, systemic mastocytosis and hypereosinophilic syndrome. It is specific for diagnosis of a clonal myeloid lineage proliferative disorder. The mutation has not been described in BCR/ABL-positive chronic myeloid leukemia, any acute or chronic lymphoid disorders, any healthy persons, or any patient with secondary polycythemia or a reactive blood count elevation. The JAK2 test promises to be very useful in distinguishing between clonal myeloproliferative disorders and reactive cellular proliferations.

Mary F. McMullin, John T. Reilly, Peter Campbell, David Bareford, Anthony R. Green, Claire N. Harrison, Eibhlin Conneally, on behalf of the National Cancer Research Institute, Myeloproliferative Disorder Subgroup, Kate Ryan, on behalf of the British Committee for Standards in Haematology (2007) Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis
British Journal of Haematology 138 (6), 821–822.

James, C., Ugo, V., Le Couedic, J.P., Staerk, J., Delhommeau, F., Lacout, C., Garcon, L., Raslova, H., Berger, R., Bennaceur-Griscelli, A., Villeval, J.L., Constantinescu, S.N., Casadevall, N. & Vainchenker, W. (2005) A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature, 434, 1144–1148.

McMullin, M.F., Bareford, D., Campbell, P., Green, A.R., Harrison, C., Hunt, B., Oscier, D., Polkey, M.I., Reilly, J.T., Rosenthal, E., Ryan, K., Pearson, T.C. & Wilkins, B., General Haematology Task Force of the British Committee for Standards in Haematology. (2005) Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. British Journal of Haematology, 130, 174–195.

Prithviraj Bose and Srdan Verstovsek, AK2 inhibitors for myeloproliferative neoplasms: what is next?
Blood 2017 130:115-125;

Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667-679.

Gleevec for bcr/abl negative chronic myelogenous leukemia – pro

M Levin, MD — Tue, 28 Aug 2012 20:19:55 +0000

The diagnosis of chronic myelogenous leukemia (CML) consists of a complete blood count with differential, peripheral blood smear, and bone marrow analysis. Although typical hepatomegaly and splenomegaly may be imaged by using a liver/spleen scan, these abnormalities are often so obvious clinically that radiologic imaging is not necessary. The biologic basis of the disease is the bcr/abl compund gene and diagnosis of CML is based on the histopathologic findings in the peripheral blood and the Philadelphia (Ph1) chromosome in bone marrow cells or bcr/abl positivity. Treatment with imatinib or other tyrosine kinase inhibitors is predicated on the presence of bcr/abl.

Ph-negative CML patients should be tested for bcr/abl. Many such patients in fact have complex chromosomal abnormalities that mask the (9;22) translocation, or have evidence of the translocation by FISH or RT-PCR in spite of normal routine karyotyping. The small subset of patients without detectable molecular evidence of bcr-abl fusion may be better classified as having an undifferentiated myelodysplastic/myeloproliferative disorder, as their clinical course tends to be different from patients with CML.

Gleevec is not appropriate for bcr/abl negative patients. FDA indicates is specifically for newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase and the same population in blast phase. The drug is not indicated without a presence of the PH chromosome and is appropriate off label if PH chromosome is negative but bcr/abl is identified.

Dale Bixby and Moshe Talpaz, Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance ASHEducation Book January 1, 2009 vol. 2009 no. 1 461-476

Philipp le Coutre, Michaela Schwarz and Theo D. KimNewly Diagnosed Chronic Myeloid Leukemia Clin Cancer Res 2010;16:1771-1780.

Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman JW (2007). “Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert pane”. Blood 110 (4): 1092–7.

Interferon for Myeloproliferative disorders – pro

M Levin, MD — Mon, 27 Aug 2012 20:20:17 +0000

The myeloproliferative disorders consist of polycythemia vera, chronic myelogenous leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. All these disorders are thought to result from a hematopoietic stem cell lesion.

Interferon alfa is effective in suppressing bone marrow function in chronic myeloproliferative disorders, but this treatment requires multiple weekly injections. Pegylated interferon, on the other hand, can be given weekly. Several groups reported on the results of phase 2 trials of pegylated interferon alfa 2b in essential thrombocytosis and polycythemia vera with generally concordant results.Satisfactory platelet count reduction was achieved with 3 to 6 months of therapy in approximately 70% of patients, but the drug had to be discontinued in 15% to 52% of them because of side effects. In the one study in which marrow histology was examined, progression of myelofibrosis was not inhibited by pegylated interferon. The number of studies and quality of evidence meets Caremark criteria for approval. The therapy is not investigational and it is medically necessary.

Gugliotta L, Bulgarelli S, Tienghi A, et al. Bone marrow biopsy and aspirate evaluation in 90 patients with essential thrombocythemia treated with peg interferon alpha-2b. Preliminary results. Blood. 2004;104:11. Abstract 1523.

Samuelsson J, Hasselbalch H, Bruserud O, et al. A phase II trial of pegylated interferon alpha-2b in polycythemia vera and essential thrombocythemia: clinical responses, effects on PRV-1 expression and impact on quality of life. Blood. 2004;104:11. Abstract 1518.

Langer C, Lengfelder E, Thiele J, et al. Treatment with pegylated interferon alpha (Pegintron) for high-risk essential thrombocythemia: results of a phase II study. Blood. 2004;104:11. Abstract 1522.

Verstovsek S, Lawhorn K, Giles F, et al. PEG-intron for myeloproliferative diseases: an update on ongoing phase II study. Blood. 2004;104:11. Abstract 1517.

Umbilical cord stem cells – pro

M Levin, MD — Fri, 24 Aug 2012 01:39:37 +0000

Lay summary: Cord stem cells have been shown to be equivalent to other allogeneic cells for transplantation in leukemia but not yet for other diagnoses.

Cord blood transplantation is a fairly recent but rapidly becoming established technique for transplnatation in leukemia. The first unrelated cord blood transplantations were performed in children. The first 25 unrelated cord blood transplantations were reported in 1996. Since then a number of reports appeared. This work has been followed by several studies, showing similar results in children. The New York Blood Center reported on 562 cases, 82% children, who underwent transplantation in a variety of centers with differing conditioning regimens and graft-versus-host disease prophylaxis. However, there have been retrospective matched pair analyses. Two studies in the New England Journal of Medicine reinforce the role of cord-blood transplantation in the treatment of leukemia in adults. Although this treatment is not recommended over HLA-matched donors from unrelated donor sources, it is a viable alternative that can be effective. (N Engl J Med. 2004;351:2255-2265, 2276, 2328). Although guidelines have not yet listed this alternative, more recent review articles and an editorial state that it is an equivalently effective approach, even in adults. Both reports reinforce the role of cord-blood transplantation in the treatment of adults with leukemia. It is realistic to anticipate that the current results for cord-blood transplantation in adults with hematologic cancers will contribute to more extended use in the coming years.

There is an ongoing trial: Single or Double Umbilical Cord Blood Unit Transplantation Followed by GVHD Prophylaxis With FK506 and MMF, NCT00244036.

J. Aschan Allogeneic haematopoietic stem cell transplantation: current status and future outlook Br. Med. Bull., October 5, 2006; (2006)

Karen K. Ballen New trends in umbilical cord blood transplantation
Blood, 15 May 2005, Vol. 105, No. 10, pp. 3786-3792

Vikram Mathews, MD and John F. DiPersio, MD, PhD Stem Cell Transplantation in Acute Myelogenous Leukemia in First Remission: What Are the Options? Current Hematology Reports 2004,

Vikas Gupta1, Martin S. Tallman2, and Daniel J. Weisdorf, Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood: 117 (8); February 24, 2011