Cancer Treatment Today » Professional

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.

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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 – 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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Xifaxin

M Levin, MD — Fri, 27 Dec 2013 17:53:24 +0000

Xifaxin ( rifaximin) is approved by the U.S. Food and Drug Administration to treat traveler’s diarrhea caused by E. coli. It is especially effective for prophylaxis. It is not effective against Campylobacter jejuni, and there is no evidence of efficacy against Shigella or Salmonella species. It is, therefore, narrower in scope than other drugs used for these conditions.

There is evidence that it may be efficacious in relieving chronic functional symptoms of bloating and flatulence that are common in irritable bowel syndrome (IBS). Rifaximin is licensed by the U.S. Food and Drug Administration to treat traveler’s diarrhea caused by E. coli. Clinical trials have shown that rifaximin is highly effective at preventing and treating traveler’s diarrhea among travelers to Mexico, with few side effects and low risk of developing antibiotic resistance. It is not effective against Campylobacter jejuni, and there is no evidence of efficacy against Shigella or Salmonella species.

It may be efficacious in relieving chronic functional symptoms of bloating and flatulence that are common in irritable bowel syndrome (IBS). There was recently a pilot-study done on the efficacy of rifaximin as a means of treatment for rosacea, according to the study, induced by the co-presence of small intestinal bacterial overgrowth.

In the United States, rifaximin has orphan drug status for the treatment of hepatic encephalopathy.

There was recently a pilot-study done on the efficacy of rifaximin as a means of treatment for rosacea, according to the study, induced by the co-presence of small intestinal bacterial overgrowth.

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Xifaxin – pro

M Levin, MD — Fri, 27 Dec 2013 15:28:15 +0000

The drug Xifaxin is approved for traveler’s diarrhea but not for bacterial overgrowth. Xifaxin ( rifaximin) is approved by the U.S. Food and Drug Administration to treat traveler’s diarrhea caused by E. coli. It is especially effective for prophylaxis. It is not effective against Campylobacter jejuni, and there is no evidence of efficacy against Shigella or Salmonella species.

In the United States, rifaximin has orphan drug status for the treatment of hepatic encephalopathy.

There was recently a pilot-study done on the efficacy of rifaximin as a means of treatment for rosacea, according to the study, induced by the co-presence of small intestinal bacterial overgrowth.

Martinez-Sandoval F, Ericsson CD, Jiang ZD, Okhuysen PC, Romero JH, Hernandez N, Forbes WP, Shaw A, Bortey E, DuPont HL. (2010 Mar-Apr). “Prevention of travelers’ diarrhea with rifaximin in US travelers to Mexico.”. J Travel Med. 17 (2): 111-7.

Lawrence KR, Klee JA (2008). “Rifaximin for the treatment of hepatic encephalopathy”. Pharmacotherapy 28 (8): 101932.

Peralta S, Cottone C, Doveri T, Almasio PL, Craxi A. Small intestine bacterial overgrowth and irritable bowel syndrome-related symptoms: experience with Rifaximin. World J Gastroenterol. Jun 7 2009;15(21):2628-31.

Pimentel M. Review of rifaximin as treatment for SIBO and IBS. Expert Opin Investig Drugs. Mar 2009;18(3):349-58.

Scarpellini E, Gabrielli M, Lauritano CE, Lupascu A, Merra G, Cammarota G. High dosage rifaximin for the treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther. Apr 1 2007;25(7):781-6.

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BREVAgen – pro

M Levin, MD — Fri, 20 Dec 2013 17:02:34 +0000

BREVAGen evaluates 7 breast cancer-associated SNPs identified in genome-wide association studies (GWAS). Risk is calculated by multiplying the product of the individual SNP risks by the Gail model risk. 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.

Darabi H, Czene K, Zhao W et al. Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement. Breast Cancer Res 2012; 14(1):R25.
Armstrong K, Handorf EA, Chen J et al. Breast cancer risk prediction and mammography biopsy decisions: a model-based study. Am J Prev Med 2013; 44(1):15-22.
Mealiffe ME, Stokowski RP, Rhees BK et al. Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information. J Natl Cancer Inst 2010; 102(21):1618-27.
Zheng W, Wen W, Gao YT et al. Genetic and clinical predictors for breast cancer risk assessment and stratification among Chinese women. J Natl Cancer Inst 2010; 102(13):972-81.
Campa D, Kaaks R, Le Marchand L et al. Interactions between genetic variants and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium. J Natl Cancer Inst 2011.
Wacholder S, Hartge P, Prentice R et al. Performance of common genetic variants in breast-cancer risk models. N Engl J Med 2010; 362(11):986-93.

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Medicaid on CT surveillance of bladder cancer after radical cystectomy – pro

M Levin, MD — Sun, 15 Dec 2013 17:11:56 +0000

CMS requires that the CT scan be reasonable and necessary based on the literature and opinion. Reasonableness and opinion is expressed by guidelines,

After radical cystectomy, NCCN recommends:

Urine cytology, liver function tests, creatinine, and electrolytes every 3 to 6 mo for 2 y and then as clinically indicated
Imaging of the chest, upper tracts, abdomen, and pelvis every 3 to 6 mo for 2 y based on risk of recurrence and then as clinically indicated
Urethral wash cytology every 6 to 12 mo, particularly if Tis was found within the bladder or prostatic urethra
If a continent diversion was created, monitor for vitamin B12 deficiency annually.

ACR has similar recommendations: CT is recommended at 6, 12, and 24 months for follow-up of patients with minimal muscle invasion (T2) who elect either cystectomy or other types of therapy without cystectomy, since most recurrences become evident within the first 2 years after surgery.

NCCN, BLadder Cancer, BL-E, 2013

CMS Guidelines National Coverage Determination (NCD) Computed Tomography (220.1)
2013

Leyendecker JR, Francis IR, Casalino DD, Arellano RS, Baumgarten DA, Curry NS, Dighe M, Fulgham P, Israel GM, Papanicolaou N, Prasad S, Ramchandani P, Remer EM, Sheth S, Expert Panel on Urologic Imaging. ACR Appropriateness Criteria follow-up imaging of bladder carcinoma. [online publication]. Reston (VA): American College of Radiology (ACR); 2009. 10 p. [80 references]

Afinitor with octreotide for eenuroendocrine cancer – pro

M Levin, MD — Sun, 15 Dec 2013 14:17:59 +0000

Both Afinitor (everolimus) and octreotide are FDA approved for neuroendocrine cancer. The phase III RADIANT-2 trial conducted in 429 patients with advanced neuroendocrine tumors (NETs) previously established that the addition of everolimus to long-acting octreotide led to a clinically meaningful 5.1-month delay in disease progression compared with octreotide alone. However, this value just missed the prespecified boundary for statistical significance (prespecified p value ≤ 0.0246; actual p value = 0.026).

Closer inspection of the data revealed that more patients with a poor prognosis were randomly assigned to the experimental arm versus the control arm, potentially attenuating the observed benefit of everolimus. Future studies will attempt to confirm the benefit of combining these two drugs.

Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group.Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study.Lancet. 2011 Dec 10;378(9808):2005-12. doi: 10.1016/S0140-6736(11)61742-X. Epub 2011 Nov 25.

http://gicasym.org/radiant-2-reanalysis-everolimus-might-be-more-beneficial-against-advanced-nets-previously-recognized

Everolimus is beneficial

Octreotide is beneficial

Rituxan or Rituxan with cladribine for Variant Hairy Cell Leukemia – pro

M Levin, MD — Fri, 18 Oct 2013 14:01:45 +0000

Recent literature suggests that a subgroup of Hairy Cell Leukemia(NCL), sometimes called Variant Hairy Cell Leukemia(HCL-V)l my in fact be a different disease not related to HCL at all and which my respond to rituximab to a much higher extent than common Hairy Cell does. It is thought that this variant is what used to be called Leukemic Reticuloendotheliosis in the past. It is an uncommon disorder accounting 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 which is difficult to aspirate, and weak reactivity to tartrate – resistant acid phosphatase (TRAP). Immunophenotypically, 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 have frequently 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 response to purine nucleoside analogs (PNA) is limited to partial responses in approximately 50% of patients. However, complete responses were observed in patients treated with rituximab and anti-CD22 immunotoxins.

For non-variant type, the use fo the first two together is based on a study reported very recently in ASCO on 3/2020 byKreitmen et al as reported in ASCO 2020. This regimen is for patients who have minimal residual disease after 6 months. In the trial, 68 patients with purine analog-naive classic hairy cell leukemia were randomly assigned to receive 0.15 mg/kg of cladribine intravenously on days 1 to 5 with eight weekly doses of rituximab at 375 mg/m2 started on day 1 (concurrent group, n = 34) or 6 months later after detection of minimal residual disease in their blood (delayed group, n = 34). Minimal residual disease tests included blood and bone marrow flow cytometry and bone marrow immunohistochemistry.

Patients in either group could receive a second course of rituximab 6 months after the first. The primary endpoint was 6-month minimal residual diseasefree complete remission rates with concurrent treatment vs cladribine monotherapy in the delayed group. THe delayed group did better nad ahd less toxicity. In the trial, 68 patients with purine analognaive classic hairy cell leukemia were randomly assigned to receive 0.15 mg/kg of cladribine intravenously on days 1 to 5 with eight weekly doses of rituximab at 375 mg/m2 started on day 1 (concurrent group, n = 34) or 6 months later after detection of minimal residual disease in their blood (delayed group, n = 34). Minimal residual disease tests included blood and bone marrow flow cytometry and bone marrow immunohistochemistry.

Patients in either group could receive a second course of rituximab 6 months after the first. The primary endpoint was 6-month minimal residual disease-free complete remission rates with concurrent treatment vs cladribine monotherapy in the delayed group, which favored the concurrent group, but with more thrmbocytopenia..
The investigators concluded: “Achieving minimal residual disease-free complete remission of hairy cell leukemia after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if minimal residual disease-free survival leads to less need for additional therapy or cure of hairy cell leukemia.”

NCCN lists single-agent cladribine or pentostatin in first line and a purine analog with rituximab for recurrent or refractory disease only. and Elitek, not in combination.

Jones G, Parry-Jones N, Wilkins B, Else M, Catovsky D, British Committee for Standards in Haematology. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant. Br J Haematol. 2012 Jan;156(2):186-95. [60 references]

Jones G, Parry-Jones N, Wilkins B, et al. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant. Br J Haematol 2012; 156:186.

Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol 2001; 115:609.

Robak T. Current treatment options in hairy cell leukemia and hairy cell leukemia variant. Cancer Treat Rev 2006; 32:365.

Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood 2009; 114:4687.

Robak T. Hairy-cell leukemia variant: recent view on diagnosis, biology and treatment. Cancer Treat Rev 2011; 37:3.

Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood 2017; 129:553.

https://www.ascopost.com/news/march-2020/first-line-cladribine-with-concurrent-or-delayed-rituximab-for-hairy-cell-leukemia/

nccn, hcl-1, A- 2020

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Velcade for Graft Versus Host DIsease – pro

M Levin, MD — Wed, 16 Oct 2013 21:01:41 +0000

Koreth found that Velcade was beneficial in GVHD; but his was a phase II trial and other phase II trials are ongoing. He found that i the 45 patients who were treated in the study; 89% of patients were treated with a one-locus and 11% of patients were treated with a two-loci mismatch. With a median follow-up of 3 years, the 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22%, and the 1-year cumulative incidence of chronic GVHD was 29%. The non-relapse mortality rate was only 11%, and the relapse rate was 38%. Results were comparable with patients who received HLA-matched transplants with the unexpected observation that bortezomib therapy enhanced immune reconstitution on the basis of measurements of CD8+ T cells and natural killer cells.
The editorial by Giralt that accompanied Koreth report, pointed out that there are four potential current approaches that all are at the same stage of development and that it may be necessary to perform a randomized phase III trial with a short primary end point to be able to rapidly pick a winner from among these competing approaches, one that could be compared with the current standard in a definitive trial.

Koreth J, Stevenson KE, Kim HT, McDonough SM, Bindra B, Armand P, Ho VT, Cutler C, Blazar BR, Antin JH, Soiffer RJ, Ritz J, Alyea EP 3rd. Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation.J Clin Oncol. 2012 Sep 10;30(26):3202-8.

Teresa Caballero-VelázquezPhase II clinical trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post-allogeneic transplantation for high-risk myeloma patients. Phase II clinical trial for the evaluation of bortezomib within the reduced intensity conditioning regimen (RIC) and post-allogeneic transplantation for high-risk myeloma patients, British Journal of Haematology, Volume 162, Issue 4, pages 474–482, August 2013

Koreth J, Stevenson KE, Kim HT, McDonough SM … Antin JH, Soiffer RJ, Ritz J, Alyea EPBortezomib-Based Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Unrelated Donor Transplantation. J Clin Oncol. 2012 Aug 6

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