Symposium on Cancer - September 2010
Tex Med . 2020;106(9):59-63.
By Nicholas C. D'Cunha, MD, and Everardo Cobos, MD
Hematological malignancies are a group of disorders that affect blood, bone marrow, lymph nodes, and spleen. They account for 9.5% of all new cancer diagnoses in the United States. Of the hematological malignancies, lymphoma accounts for 55%; leukemia, 30%; and multiple myeloma, 15%. Non-Hodgkin lymphoma accounts for 85% of lymphomas, and chronic lymphocytic leukemia accounts for 34% of leukemia. We'll provide a brief, current up-date of the more common hematological malignancies.
Myelodysplastic syndrome (MDS) is characterized by dysplastic cells in the marrow and a hypercellular marrow with peripheral cytopenias. Increase in DNA methyltransferases and/or histone deacetylase activity is seen in these dysplastic cells. Hypermethylation of DNA by methyltransferases results in silencing of genes involved in normal hematopoiesis. Hypomethylating agents like 5-azacytadine and decitabine inhibit methyltransferases, causing hypomethylatation of DNA and gene reactivation.
Histone in deacetyl form acts as a spool to coil DNA. Histone acetylation by histone acetylase is essential to uncoil DNA for replication and gene expression. Increased histone deacetylase activity prevents histone acetylation and hence uncoiling of DNA essential for replication and gene expression for normal hematopoiesis. Histone deacetylase inhibitor brings about histone acetylation, DNA uncoiling, replication, gene expression, and normal hematopoiesis.
Immunomodulator lenalidomide causes T-cell activation and secretion of cytokine like IL-2, INF-gamma, which activates NK-cells, ultimately killing abnormal clone-like MDS and myeloma cells. They also inhibit angiogenesis by inhibiting secretion of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).
The aim for treating low-grade MDS is to improve cytopenias with erythropoietin ± G-CSF, lenalidomide (del5q), ATG/cyclosporine (hypoplastic MDS, Int-1, HLA-DR15 + age < 60 years), or hypomethylating agent (unresponsive patients).
High-grade MDS can be cured by allogeneic stem cell transplantation.
Acute Myelogenous Leukemia
Acute myelogenous leukemia (AML) is a heterogeneous group of disorders characterized by uncontrolled proliferation of early myeloid progenitor cells, giving rise to abnormal hematopoiesis. It accounts for 90% of acute leukemia in adults. Risk factors of AML include exposure to benzene, herbicides, and ionizing radiation, genetic disorders such as Down syndrome, myelodysplastic syndrome, and treatmetn with alkylating agent and topoisomerase II inhibitor. Alkylating agent-related AML has preceding MDS, has a latent period of 4 to 10 years, and is mainly associated with abnormalities of chromosome 5 or 7.
Topoisomerase II inhibitor-related AML has a latent period of 2 to 3 years, exhibits monocytic morphology, lacks preceding MDS, and involves deletion of chromosome 11q. Tissue infiltration (chloromas) carries a worse prognosis. Cytogenetic analysis and gene mutation testing are the most reliable prognostic tools. Approximately 50% to 60% of patients have chromosomal abnormality. The good-risk group includes inversion 16, t(8;21), t(16;16) and t(15;17). Poor risks include -5, -7, 5q-, 7q-, t(3;3), t(6;9) 11q 23, inversion 3, and complex1 Patients with normal cytogenetic analysis frequently have genetic mutation that may affect outcome.
FMS-like tyrosine kinase 3 (FLT3) genes, encoding tyrosine kinase 3, a growth factor receptor involved in hematopoiesis, is mutated in 30% of the patients, giving rise to constitutively activated proteins and poor prognosis, only when the allelic burden is greater than 40%. Only FLT3-ITD mutation is associated with a poor prognosis, increased risk for relapse, and decreased survival. NPM1 gene encoding the nuclear cytoplasmic shuttling protein is mutated in 50% of patients with normal cytogenetic analysis. EVI1 gene (ecotropic viral integration 1)located on chromosome 3 is involved with certain and predicted low complete remission (CR) rate and a very poor relapse-free and event-free survival.
Treatment for acute AML consists of induction therapy with cytarabine (Ara-C) and an anthracycline, followed by consolidation with 3 to 4 cycles of high-dose Ara-C.2 In patients who relapse, the chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission.3
Patients with initial remission longer than 2 years had a 73% CR rate with the same initial therapy compared with 47% CR rate in patients with remission duration of 1 to 2 years. Patients with remission duration of more than 1 year may be treated with fludarabine, Ara-C, granulocyte colony-stimulating factor, idarubicin (FLAG-Ida) and mitoxantrone, etoposide, and Ara-C (MEA).
Myelotarg, an immunotoxin in which monoclonal antibody targeting CD33+ blast is conjugated with calicheamicin, a cytotoxic agent, has been approved as monotherapy for patients who are older than 60 years in first relapse and are not candidates for cytotoxic chemotherapy. In patients with first relapse and with no antecedent hematologic disorder, myelotarg produced 16% CR and 13% CRp (CR but did not have the required platelet recovery). Toxicity included infusion reactions, myelosuppression, hepatic toxicity, and veno-occlusive disease (VOD).4
Clofarabine, a second-generation purine analogue, is a potent inhibitor of ribonucleotide reductase. Clofarabine monotherapy may be used in untreated older patients with unfavorable prognostic factors with response rate of 46%, a median duration of response of 56 weeks, median overall survival (OS) of 41 weeks, and 30 days mortality of 10%.5 In combination with Ara-C, it increases antileukemic activity of Ara-C. Clofarabine given as 40 mg/m2 intravenous infusion daily on days 2-6, with intermediate dose of Ara-C 1 gm/m 2 daily on days 1-5 (given 4 hours after clofarabine infusion) produced a CR rate of 52% and CRp rate of 8% and 7% induction deaths in newly diagnosed patients aged 50 years or older with AML.6 The hypomethylating agents, 5-azacytidine and decitabine, approved for use in patients with MDS have activity in AML (CR, 15% to 20%), are well tolerated and are therefore being used in elderly patients.7
AC220 is a new-generation FLT3 inhibitor that has a broader range of targets, including cKIT. In a phase 1 study, 13% of patients had CR, and the treatment was well tolerated. 8 AC220 might be more promising when added to chemotherapy or to other targeted agents. Sapacitabine, an As a single agent, it produces 25% CR rate in older adults who may not be candidates for intensive chemotherapy.9 It is given as an interrupted-dose 400 mg twice daily on days 1-3 and 8-10 and is well tolerated. Another drug that may be used to treat AML is lenalidomide.10
Acute Promyelocytic Leukemia
Acute promyelocytic leukemia (APL) cells have t(15; 17), which inhibits myeloid differentiation. The standard induction approach is the combination of all-trans-retinoicacid (ATRA) and anthracycline-based chemotherapy. Patients in remission receive consolidation therapy. The addition of arsenic trioxide to Ara-C and daunorubicin in the consolidation setting increases event-free and overall survival at 3 years (77% vs. 59% and 86% vs.77%, respectively).
Maintenance therapy with ATRA, 6-mercaptopurine, and methotrexate for 1 to 2 years is effective in preventing relapse. Relapse patients are usually treated with arsenic trioxide, which induces CR in 85% of patients. Myelotarg in 3 doses produces 100% response rate in patients with molecular relapse.11
Acute Lymphoblastic Leukemia»
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease and can be grouped by cytogenetic abnormalities. Patients with t(4; 11) and t(9; 22) translocation have poor prognosis. Treatment with the Linker regimen, Larson regimen, or hyperCVAD has about 40% 5-year disease-free survival (DFS). Pediatric regimen is well tolerated and produces a better result in young adults. Recent studies have shown that intensification of postremission and continuous asparagines depletion with L-asparaginase (also depletes asparagines in CNS) prolong survival. Of adult patients, 25% to 30% are Philadelphia positive (increases with age) and are treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), which produces a better CR, OS, and DFS than chemotherapy alone, with more patients able to undergo stem cell transplantation. The standard of care today is allogeneic transplantation after successful treatment with a TKI plus chemotherapy to get the patients into remission without waiting for molecular CR.12
Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML) is due to evolution and uncontrolled growth of abnormal Philadelphia+ (9;22 translocations) clone cells of myeloid series, causing increased tyrosine kinase BCR-ABL activity, promoting cell proliferation. For treatment purpose, a major cytogenetic response is defined as decrease in Ph+ cell to 35% or less. Major molecular response is defined as ≥ 3-log reduction in the number of BCR-ABL transcripts. Cytogenetic response is assessed at 6, 12, and 18 months on therapy. Mutational testing may be considered in patients who fail to achieve hematologic response at 3 months, cytogenetic response at 6 months, and major cytogenetic response at 12 months, or loss of response.
Organic cation transporter-1 (OCT-1) serves as the major active influx protein for imatinib, a first line TKI into target BCR-ABL- positive cells. Patients with high OCT-1 activity are more likely to achieve a major molecular response and event-free survival at 5 years compared with patients with low OCT-1 activity (89% vs. 55%).13 Patients with low OCT-1 activity may benefit from high-dose Imatinib.
BCR-ABL mutations are the cause of imatinib resistance in 40% of resistance cases.14 Second-line TKIs such as nilotinib, dasatinib, and bosutinib result in hematologic and cytogenetic responses in patients with resistance caused by most BCR-ABL or intolerance to imatinib. Bosutinib is least myelosuppressive. Dasatinib causes more pleural effusion.
Imatinib-resistant patients treated with dasatinib or nilotinib who have minor cytogenetic response by 6 months have more than a 50% chance of having major cytogenetic response at 12 months, compared with 3% to 7% of patients 15,16 These patients should be considered for allogeneic stem cell transplantation.
Patients with T315I mutation are resistant to all currently approved drugs and should be considered for transplantation. Omacetaxine (Homoharringtonine), a protein synthesis inhibitor produces 82% hematologic response and 23% major cytogenetic response.17
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL), the most common leukemia in U.S. adults, has a median age at diagnosis of 65 years. Complications of CLL include infection, autoimmune cytopenias, and transformation into Richter syndrome (a large cell transformation, 15%). Richter syndrome usually presents with sudden onset of B symptoms, progressive lymphadenopathy, a high lactate dehydrogenase (LDH) level, and poor prognosis even with treatment. Rarely, CLL may transform into prolymphocytic leukemia (prolymphocyte > 55% on peripheral smear), with progressive splenomegaly and worsening cytopenias.
Cytogenetic abnormalities occur in 50% to 80% of patients. Patients with single abnormality of 13q deletion, a normal karyotype, or trisomy 12 have a better prognosis then those with 11q or 17p deletion. CD 38 expressions are associated with diffuse bone marrow involvement; higher stage disease; high LDH, microglobulin, and lymphocyte count; and an aggressive clinical presentation and worse prognosis, and require early treatment. Patients with unmutated IgVH gene experience a more aggressive clinical course and shorter survival than do patients with mutated IgVH genes.
Indication for treatment of CLL includes disease-related symptoms, bulky lymphadenopathy, massive splenomegaly, cytopenias due to marrow involvement, and rapidly increasing lymphocytosis. The treatment for high-risk patients with 11q deletion and unmutated status is fludarabine, cyclophosphamide, and rituximab (FCR), which has higher CR rate and a longer progression-free survival (PFS). However, patients with 17p- have a low CR (20%) and poor OS. For patients with 17p-, alemtuzumab alone or in combination with fludarabine is a good alternative.
For fludarabine-refractory CLL, alemtuzumab with or without steroids may be used. Fit, high-risk patients (fludarabine-refractory or p53 defective) may be treated with nonmyeloablative stem cell transplantation. Allogeneic stem cell transplantation is a reasonable treatment option for treatment indicated in high-risk young patients (e.g., p53 mutations, nonresponsive, or early relapse after purine analogue or after auto stem cell transplant).18 Ofatumumab (HuMax-CD20) inhibits early-stage B lymphocyte activation. It is approved for people with refractory CLL. Cladribine and fludarabine are equally effective and safe in combination with cyclophosphamide as first-line treatment for CLL.19
Novel therapies for CLL include ABT-263 and CAL-101. ABT-263 is a small molecule BH3 (Bcl-2 Homology region 3) mimetic that binds to and inhibits the activity of Bcl-2.20 CAL-101 is a specific inhibitor of phosphatidylinositol-3-kinase (antiapoptosis pathway). In a phase 1 study of patients with CLL and lymphoma, CAL-101 had a 60% response rate in indolent lymphoma and an 86% response rate in patients with mantle cell lymphoma.21
Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoid tumors with distinct clinical, morphologic, immunohistochemical, and molecular subtypes as defined in the 2008 World Health Organization classification.22 The major risk factor for NHL is immune dysfunction as in AIDS and autoimmune diseases. Infectious agents implicated are gamma herpes virus, Epstein-Barr virus, herpes virus 8, HTLV1, and hepatitis C virus. International prognostic features include age, stage, LDH, and number of extranodal sites. BCL6 expression is an independent predictor of improved DFS in aggressive lymphoma. PET scans are used in both Hodgkin and non-Hodgkin lymphomas to evaluate residual masses and extra nodal sites and to predict DFS and OS.
For treatment purpose, NHLs are classified as indolent or aggressive. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is most widely used for diffuse large B-cell lymphoma (DLBCL). In mantle cell lymphoma, R-CHOP followed by autologous stem cell transplantation in first CR was superior to R-CHOP alone, but appears to be equivalent to that of patients treated with R-hyperCVAD.23 Lenalidomide as a maintenance strategy could have a significant role in the future.
Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma with an overall response rate (ORR) of 75% (14% complete response [CR] and 58% partial response [PR]). Rummel et al compared bendamustine + rituximab vs. R-CHOP as upfront treatment in patients with indolent lymphoma. CR rate as well as PFS favored bendamustine-rituximab arm. It was associated with a far superior safety profile.24
Agents such as bendamustine, lenalidomide, pralatrexate, histone deacetylase inhibitor romidepsin, new-generation proteasome inhibitor carfilzomib, and new monoclonal antibodies ofatumumab (HuMax-CD20) have either been recently approved or are presently in pivotal studies in the treatment of NHL.
Primary Central Nervous System Lymphoma
Ninety percent of primary central nervous system lymphomas (PCNSLs) are diffuse large B-cell lymphoma. Patients should have slit-lamp examination for vitreous lymphoma. Combination chemotherapy with radiation therapy produces high incidence of dementia. High-dose methotrexate (8 g/m2 IV biweekly) is the single most effective chemotherapeutic agent for PCNSL.
For relapse or nonresponding patients, radiation therapy is probably the best second-line anti-PCNSL treatment. One could consider high-dose cytarabine. Patients receiving immunosuppressive therapy after organ transplantation should receive the smallest effective doses to prevent rejection.
Multiple myeloma (MM) is characterized by clonal proliferation of abnormal plasma cells. Lenalidomide with dexamethasone is used by most hematologists as initial treatment. Pomalidomide, the most potent immunomodulatory drug, is not associated with significant neuropathy and has manageable myelosuppression.
Patients with relapsed/refractory myeloma treated with pomalidomide (4 mg/day PO)+ low-dose dexamethasone have durable responses.25 Responses were seen even in bortezomib and lenalidomide-refractory patients. Neutropenia was a dose-limiting toxicity.
Novel agents in younger patients include 3-drug combinations, which produce better response than do 2-drug combinations. T2 . The CR plus near-CR rate was 57%, compared with those achieved with transplantation. At a median follow-up of 21 months, the estimated 18-month PFS rate was 75% among all patients, with no significant difference in PFS rates seen whether or not patients received autologous stem cell transplantation. Adverse cytogenetic-del(13q), del(17p), and t(4;14) did not affect PFS rates. Management of patients who will not undergo transplantation includes melphalan/prednisone/thalidomide (MPT), bortezomib/melphalan/prednisone (VMP), and lenalidomide/low-dose dexamethasone.
VMP has a rapid response, higher CR, and better efficacy in patients with abnormal cytogenetics. Carfilzomib, a new generation of irreversible proteasome inhibitors like bortezomib, has a response rate as good as bortezomib with less peripheral neuropathy, and hence allows for longer use of a single agent. Carfilzomib combined with lenalidomide may have improved tolerability over bortezomib/lenalidomid in the treatment of bortezomib-intolerant or resistant patients. Also, the addition of carfilzomib to lenalidomide/dexamethasone may increase efficacy.26
Nicholas C. D'Cunha, MD, is associate professor of medicine and medical director of the BMT Unit at the Texas Tech University Health Sciences Center School of Medicine in Lubbock. Cobos Everardo, MD, is professor of medicine and associate dean of the Texas Tech University Health Sciences Center School of Medicine in Lubbock.
- Byrd JC, Mrózek K, Dodge RK, et al; Cancer and Leukemia Group B (CALGB 8461). Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood . 2002;100(13):4325-4336.
- Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia.Cancer and Leukemia Group B. N Engl J Med . 1994;331(14):896-903.
- Estey E, Kornblau S, Pierce S, Kantarjian H, Beran M, Keating M. A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. Blood . 1996;88(2):756.
- Sievers EL, Larson RA, Stadtmauer EA, et al, for the Mylotarg Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol . 2001;19(13):3244-3254.
- Hagop M. Kantarjian, Harry P. Erba, David Claxton et al: Phase II study of Clofarabine monotherapy in previously untreated older patients with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol. 2010;28:549-555.
- Faderl S, Verstovsek S, Cortes J, et al. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older. Blood . 2006;108(1):45-51.
- Blum W, Klisovic RB, Hackanson B, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol . 2007;25(25):3884-3891.
- Cortes J, Foran J, Ghirdaladze D, et al. AC220, a potent, selective, second generation FLT3 receptor tyrosine kinase (RTK) inhibitor, in a first-in-human (FIH) phase 1 AML study. Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#636.
- Kantarjian HM, Garcia-Manero G, Luger S, et al. A randomized phase 2 study of sapacitabine, an oral nucleoside analogue, in elderly patients with AML previously untreated or in first relapse. Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#1061.
- Vij R, Nelson A, Uy GL, et al. A phase II study of high dose lenalidomide as initial therapy for acute myeloid leukemia in patients > 60 years old. Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#842.
- Douer D. Acute promyelocytic leukemia: a target for preemptive strike? Blood . 2004;104(7):1913-1914.
- Bassan R, Rossi G, Pogliani EM, et al. Short chemotherapy-phased imatinib (IM) pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#2029.
- White DL, Saunders VA, Frede A, et al. The functional activity of the OCT-1 protein is predictive of molecular response and survival in CP-CML patients treated with imatinib: a 5 year update of the TIDEL trial. Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#507.
- Hochhaus A, Kierl S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002; 16(11):2190-2196.
- Cortes J, O'Brien S, Jones D, et al. Efficacy of nilotinib in patients (pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myeloid leukemia in early chronic phase (CML-CP). Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#341.
- Cortes J, Borthakur G, O'Brien S, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#338.
- Cortes-Franco J, Raghunadharao D, Parikh P, et al. Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients who are resistant or intolerant to two or more tyrosine kinase inhibitors: results of a multicenter phase 2/3 study. Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#861.
- Dreger P, Kimby E et al. Chronic Leukemia Working Party of the EBMT. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia . 2007;21(1):12-17.
- Robak T, Jamroziak K, Gora-Tybor J, et al. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol . 2010;28(11):1863-1869.
- Roberts AW, Seymour JF, Brown JR, et al. An ongoing phase 1/2a study of ABT-263; pharmacokinetics (PK), safety and anti-tumor activity in patients (pts) with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood . (ASH Annual Meeting Abstracts). 2009;114:364. Abstract #883.
- Flinn IW, Byrd JC, Furman RR, et al. Evidence of clinical activity in a phase 1 study of CAL-101, an oral P110? Isoform-selective inhibitor of phosphatidylinositol 3-kinase, in patients with relapsed or refractory B-cell malignancies. Blood . (ASH Annual Meeting Abstracts). 2009;114:380. Abstract #922.
- Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Lyon, France: IARC; 2008.
- Hoster E, Metzner B, Forstpointner R, et al. Autologous stem cell transplantation and addition of rituximab independently prolong response duration in advanced stage mantle cell lymphoma. Blood . (ASH Annual Meeting Abstracts). 2009;114:362. Abstract #880.
- Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the STIL (Study Group Indolent Lymphomas, Germany). Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#405.
- Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol . 2009;27(30):5008-5014.
- Niesvizky R, Wang L, Orlowski RZ, et al. Phase Ib multicenter dose escalation study of carfilzomib plus lenalidomide and low dose dexamethasone (CRd) in relapsed and refractory multiple myeloma (MM). Blood . (ASH Annual Meeting Abstracts). 2009;114(11):#304.
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