Cancer Treatment Today » M Levin, MD

Lapatinib and tastuzumab for HER+ colorectal cancer – pro

M Levin, MD — Fri, 27 Dec 2019 19:06:24 +0000

There is evidence to support HER based therapy from the phase II HERACLES-A study that used meticulous biomarker selection of patients with HER2-amplified colorectal cancer, who typically do not respond well to conventional treatment options A two-pronged strategy, with lapatinib and trastuzumab yielded positive results in this subset of patients.
Lapatinib plus trastuzumab is a potential new treatment option for treatment-refractory HER2-positive colorectal cancer. seven trials: two diagnostic, three therapeutic (HERACLES-A, HERACLES-B, and HERACLES RESCUE), and two translational studies. HERACLES-B is evaluating pertuzumab (Perjeta) and ado-trastuzumab emtansine (also known as T-DM1 [Kadcyla]), and HERACLES RESCUE is looking at ado-trastuzumab emtansine monotherapy in metastatic colorectal cancer that has progressed on lapatinib and trastuzumab in HERACLES-A. IT is specifically the combined treatment that showed efficacy.
These studies need to be completed and published before one can conclude that this combined treatment is medically necessary.

.Siena S, Sartore-Bianchi A, Trusolino L, et al: Final results of the HERACLES trial in HER2-amplified colorectal cancer. 2017 AACR Annual Meeting. Abstract CT005. Presented April 2, 2017.

http://www.abstractsonline.com/pp8/#!/4292/presentation/12323

S. Siena et al, Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol 2018 May; 29(5): 11081119

Cytogenetics for myelofibrosis -Pro

M Levin, MD — Sun, 09 Mar 2014 12:28:23 +0000

Cytogenetics are now routinely recommended for myelofibrosis. Guidelines (Reilly et al) indicate that beyond a routine bone marrow aspiration and biopsy, JAK2 V617F mutation screening should be carried out routinely in patients with primary myelofibrosis (PMF). Quantitative results are not required for clinical management.BCR-ABL1 rearrangement should be excluded in cases with atypical trephine biopsy features, or if the patient lacks a mutation in JAK2 or MPL. PDGFRA and PDGFB rearrangements should be excluded in the presence of significant eosinophilia. (Screening for other mutations remains a research tool and routine screening cannot be justified, apart from in cases of diagnostic difficulty where detection of a clonal abnormality would be informative) (Evidence level 2, Grade B). This recommendation does not include cytogenetics.

Recently there is evidence that cytogenetics can refine prognostic information which can help make decision, especially about stem cell transplantation. The factors not included in the IPSS that affect survival are represented by red cell transfusion need,12 thrombocytopenia,13 and “unfavorable” karyotype. Regarding the latter, patients with unfavorable karyotype, which includes a complex karyotype or sole or 2 abnormalities such as +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p−, or 11q23, had a median survival of 2 years compared with 5.2 years for those with a “favorable” karyotype, defined as no abnormality or any other apart from those included in the above category, the 5-year survival rates were 8% and 51%, respectively. The newly devised DIPSS Plus score11 incorporates these additional 3 variables for improved prognostic categorization. In a series of 793 patients, median survival times were 185, 78, 35, and 16 months for the low, intermediate-1, intermediate-2, and high-risk categories, respectively.

Based on its inclusion into a recommended prognostic tool DIPSS Plus, cytogenetics should not longer be considered investigational
.

Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe A, Green AR, George Michaeel N, Gilleece MH, Hall GW, Knapper S, Mead A, Mesa RA, Sekhar M, Wilkins B, Harrison CN, Writing group: British Committee for Standards in Haematology. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012 Aug;158(4):453-71. [123 references]
Jennifer Dunlap, MD, Katalin Kelemen, MD, PhD, Nicky Leeborg, MD, Rita Braziel, MD, Susan Olson, PhD, Richard Press, MD, PhD, James Huang, MD, Ken Gatter, JD, MD, Marc Loriaux, MD, PhD, Guang Fan, Association of JAK2 Mutation Status and Cytogenetic Abnormalities in Myeloproliferative Neoplasms and Myelodysplastic/Myeloproliferative Neoplasms Am J Clin Pathol. 2011;135(5):709-719.

DLI for T cell leukemia and lymphoma – pro

M Levin, MD — Fri, 10 Jan 2014 16:27:04 +0000

Donor lymphocyte infusions are designed to awaken some degree of graft versus host reaction, which contains within it also the graft versus disease effect. It is a modality that can be used after allogeneic transplantation to treat relapse by “awakening” an immune response. . Almost all work on DLI was in B cell leukemias and lymphomas. How it affects T cell malignancies is not well studied and most of what is known was in Adult T-Cell leukami/Lymphoma. Many questions remain. For example, achieving hematologic remission with DLI is not an easy task, especially in patients with a high tumor burden and rapidly proliferating leukemic cells.. Cytoreductive therapy before DLI is thought to improve effectiveness of DLI. Unfortunately, which regimens to use for this cytoreduction has not been defined. How to induce and manage graft versus host reaction has not been defined. Even the very effectiveness of allogeneic transplantation in T-Cell Leukemias continues to be studied. To conclude, DLI remains experimental for T Cell malignancies due to lack of reliable information on how to do it and how effective it is.

Hidehiro Itonag et al, Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience Blood January 3, 2013 vol. 121 no. 1 219-225

Gabriel IH. Graft versus lymphoma effect after early relapse following reduced-intensity sibling allogeneic stem cell transplantation for relapsed cytotoxic variant of mycosis fungoides. Bone Marrow Transplant 2007;40(4):401-403.

Herbert KE, . Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant 2004;34(6):521-525.

For Lay version see here

Symphony suite of tests for Breast Cancer – pro

M Levin, MD — Fri, 03 Jan 2014 20:54:49 +0000

Symphony suite of tests includes Mammaprint, BluePrint and TargetPrint. According to the online article titled “Comparison of MammaPrint, BluePrint, and TargetPrint with Clinical Parameters in Patients with Breast Cancer: Findings from a Prospective United States Cohort”, it states that the multigene signature MammaPrint, as well as BluePrint and TargetPrint, provides additional information for treatment guidance. By combining MammaPrint with the BluePrint molecular subtyping profile, specific groups of patients can be recognized that are at high risk for recurrence and that would possibly benefit from specific treatment. It further stated that the study showed that TargetPrint provides a high quality second opinion for local IHC/FISH assessment. Another similar article titled “Comparison of molecular subtyping with BluePrint, MammaPrint, and TargetPrint to local clinical subtyping in breast cancer patients” states that the implementation of multigene assays such as TargetPrint, BluePrint, and MammaPrint may improve the clinical management of breast cancer patients. The TargetPrint is considered a macro array based gene expression test which offers a quantitative assessment of the patient’s overall level of estrogen receptor (ER), progesterone receptor (PR), and HER2/NEU overexpression within the breast cancer. By utilizing the TargetPrint studies, physicians are provided with additional insight into the biology of the patient’s individual tumor which can assist in the treatment decisions. Lastly, the BluePrint gene expression signature was developed for the classification of breast cancer into either a basal type, luminal type, or ERBB2-type. By identifying tumors that can be responsible for the hormonal interventions (which would be the luminal type), or sensitive to trastuzumab therapy or to cytotoxic therapy (which is basal type), the different subtypes can respond differently to different types of therapies and combination of therapies. Overall, the BluePrint provides a more personalized result to the physician which allows them to get the patient the most likely effective treatment for the patient—hormonal therapy, combined hormonal and chemo therapy, and combined chemo therapies alone. The three tests are put together in a panel in the Symphony panel.

At the same time, guidelines have not recommended this panel for this situation. Mammaprint is a test that purports to determine aggressiveness of breast cancer. It is widely accepted in Europe and less so in the USA. More recently. TargetPrint is another iteration that purports to provides reliable, quantitative assessment of mRNA expression levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) and BluePrint similarly attempts to provide prognostic information. BluePrint, an 80-gene expression signature for the classification of breast cancer into Basal-type, Luminal-type and ERBB2-type.

Besides that these two latter tests still need to be fully validated, there is no literature support for the three together being more accurate or productive of more benefit than either one. Therefore, it would be important to perform definitive comparison of combinations of these assays.

References:

Nguyen, B., Sinha, R., Kerlin, D., Barone, J., Garcia, A., Yao, K., … & Deck, K. (2011). P3-04-06: Comparison of MammaPrint, BluePrint, and TargetPrint with Clinical Parameters in Patients with Breast Cancer: Findings from a Prospective United States Cohort. Cancer Research, 71(24 Supplement 3).

Nguyen, B., Cusumano, P. G., Deck, K., Kerlin, D., Garcia, A. A., Barone, J. L., … & Generali, D. (2012). Comparison of molecular subtyping with BluePrint, MammaPrint, and TargetPrint to local clinical subtyping in breast cancer patients. Annals of surgical oncology, 19(10), 3257-3263.

Daniel D. Von Hoff et al, Pilot Study Using Molecular Profiling of Patients’ Tumors to Find Potential Targets and Select Treatments for Their Refractory Cancers JCO October 4, 2010

Companion Diagnostics in Personalized Medicine and Cancer Therapy, Trimark Publications (190 pages), published Apr 2008

Raman G, Avendano EE, Chen M.Update on Emerging Genetic TestsCurrently Available for Clinical Use in Common CancersEvidence Report/TechnologyAssessment.

(Prepared by the Tufts Evidence based Practice Center under Contract No.290-2007-10055-I.)Rockville, MD: Agency for Healthcare Research and Quality.July2013

www.effectivehealthcare.gov/reports/final.cfm

Alice P. Chung, Marissa K. Srour, Farnaz Dadmanesh, Sungjin Kim, Armando E. Giuliano, Jennifer Wei, Yen Huynh, Josien Haan, Shiyu Wang, Andrea Menicucci, Patricia Dauer, and M. William Audeh
Journal of Clinical Oncology 2022 40:16_suppl, 585-585

Atypical CML

M Levin, MD — Fri, 03 Jan 2014 20:38:28 +0000

Atypical chronic myelogenous leukemia (aCML) is a leukemic disorder that exhibits both myelodysplastic and myeloproliferative features at the time of diagnosis. What this means is that it is not truly a CML but a condition that can be confused with CML, but is essentially different. It is not very common. It is thought that these features denote a poor prognosis, but these cases ahve a variety of genetic abnormalities that are different from CML and not much is known about how theya ffect 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 or other CML treatments.

For Professional version see here

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.

For Lay version see here

BREVAgen

M Levin, MD — Fri, 03 Jan 2014 14:39:58 +0000

Personalized medicine is an up and coming approach, by which individual’s risks and factors are taken into account to prescribe therapy. Genetic tests are a part of the approach. BREVAGen evaluates 7 breast cancer-associated factors. Risk is calculated by multiplying the product of the individual risks by the Gail model risk The Gail model is the first of several proposed ways to calcucalte an individual’s riask for breast cancer. BREVAGen has been evaluated for use in Caucasian women of European descent age 35 years and older. According to the BREVAGen website, “suitable candidates” for testing include women with a Gail lifetime risk of 15% or greater; with high lifetime estrogen exposure (e.g., early menarche and late menopause); or with relatives diagnosed with breast cancer. BREVAGen is not suitable for women with previous diagnoses of lobular carcinoma in situ, ductal carcinoma in situ, or breast cancer, since the Gail model cannot calculate breast cancer risk accurately for such women, or for women with an extensive family history of breast and ovarian cancer.

BREVAgen was validated only in comparison to Gail score. Being that the Gail score is the least sensitive scoring tool available and that it is widely considered inadequate, it is hard to have confidence in the validation process. In addition, the risk calculation that depends on multiplying SNP risks by Gail raises its own questions of accuracy. Finally, there is no prospective evidence that BREVAgen produces clinical evidence.

Olysio and Sovaldi: Two new drugs for Hepatitis C

M Levin, MD — Fri, 03 Jan 2014 14:24:52 +0000

Hepatitis C is a major public health problem, especially in Southeast Asia. Interferon and ribavirin have been the standard of care in various combinations. The literature supports intereferon with the two recently FDA approved oral medications that can be used in combination with the current antiviral regimen or to replace the injectable component of the regimen, peginterferon alfa.

The two new drugs are Olysio (simeprevir) capsules and Sovaldi (sofosbuvir) tablets. Both work by stopping the replication of the Hepatitis C virus.

Olysio 150 mg capsules are a once-daily treatment that must be used in combination with pegylated interferon (peginterferon alfas like Pegasys or Pegintron) and ribavirin. It cannot currently be used as monotherapy, which means it can’t be used alone. Sovaldi 400 mg tablets are a once-daily treatment that can be used without the injectable peginterferon alfa. This is novel and helpful in hepatitis therapy because the peginterferon alfa injectable often contributes to patients not finishing their course of Hep C therapy due to the unfavorable side effects.

Based on a side-by-side review if disparate studies, Sovald appears to be more versatile than Olysio as it is approved for treatment of genotypes 1, 2, 3 and 4. Also, for genotype 2 and 3, Sovaldi can be taken with ribavirin alone, excluding the need for interferon altogether. (Interferon, perhaps the most dreaded component of HCV therapy, is administered by injection and many side effects. On the other hand, Olysio must always be used in combination with interferon and ribavirin for the duration of either 24 weeks (for treatment-naive patients) or 48 weeks (for patients previously exposed to HCV therapy). However ,it cannot be used with many retroviral drugs.

Using the two together is beginning to be explored, with early results showing efficacy in even hard-to-treat cases. In early January, the New England Journal published a study of the combination of these two drugs. he New England Journal of Medicine, investigators designed a Phase II open-label study of Gilead Sciences’ recently approved nucleotide analogue NS5B polymerase inhibitor Sovaldi and Bristol-Myers Squibb’s NS5A replication complex inhibitor daclatasvir.

Sulkowski MS, et al “Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection” N Engl J Med 2014; 370: 211-221.

Sovaldi, Prescribing Information 2014

Does measuring antibodies to infliximab help?

M Levin, MD — Fri, 03 Jan 2014 01:07:36 +0000

Antibodies to infliximab (ATIs) have been associated with loss of clinical response and lower serum infliximab (IFX) levels in some studies of patients with inflammatory bowel disease (IBD). Presumable lower levels mean less effectiveness, but it needs to be proven. It may be clinically useful to be able to assess and predict diminishing response. A recent meta-analysis of all available studies concluded that the presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD. However, most studies were flawed in that published studies on this topic lack uniform reporting of outcomes and high risk of bias was present in all the included studies. This means that the method of metanalysis may not be accurate in pooling all studies and obtaining a meaningful result.

Similar conclusions are reached by reviews that look at this question. For example, a recent paper outlines why antibodies to infliximab (ATI) cannot be used as a surrogate marker for immunogenicity, or to predict clinical outcome or safety. This is because up to half of patients still need dose adjustment for recurrent symptoms and 20% of patients lose response, even when treatment is optimised to avoid ATI through scheduled maintenance therapy or concomitant immunomodulators

Measurement of serum antibodies to infliximab has not received clearance by the FDA and there is not sufficient peer-reviewed scientific literature that demonstrates that the procedure is effective.

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Rituxan for Hairy Cell Leukemia

M Levin, MD — Wed, 01 Jan 2014 18:49:22 +0000

Recent literature suggests that a subgroup of Hairy Cell Leukemia(HCL), sometimes called Variant Hairy Cell(HCL-V) may in fact be a different type of Lymphoma and not Hairy Cell, and that it may respond to rituximab to a much higher extent than common Hairy Cell does. It is what was called Leukemic Reticuloendotheliosis in the past. It accounts for approximately 0.4% of chronic lymphoid malignancies and 10% of all HCl cases. In contrast to HCl-C, HCl-V is a more aggressive disease and according to the new WHO classification it is no longer considered to be biologically related to HCl-C. Patients with HCl-V have an elevated white blood count, easy-to-aspirate bone marrow (unlike HCL) and weak reactivity to tartrate – resistant acid phosphatase (TRAP). HCl-V cells are positive for CD103 and CD11c and negative for CD25. The HCl-V cells express also the B-cell antigens, CD19, CD20 and CD22. The HCl-V patients frequently have an unmutated Ig gene configuration. Currently, the principles of therapy for this rare disease derive from uncontrolled single institutional studies, or even single case reports. In contrast to HCl-C, the HCl-V respond to purine nucleoside analogs (PNA) but response is limited to partial responses in approximately 50% of patients. However, complete responses were observed in some patients treated with rituximab and anti-CD22 immunotoxins.

For Professional version see here