Cancer Treatment Today » Drug Treatment

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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Topical cidofovir in immunocompromised patients – pro

M Levin, MD — Fri, 09 Nov 2012 13:10:59 +0000

VISTIDE (cidofovir) is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). The FDA says: “THE SAFETY AND EFFICACY OF VISTIDE (cidofovir) HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (SUCH AS PNEUMONITIS OR GASTROENTERITIS), CONGENITAL OR NEONATAL CMV DISEASE, OR CMV DISEASE IN NON-HIV-INFECTED INDIVIDUALS.”

It is a nephrotoxoc drug and cannot be administered to people with kidney dysfunction, which, however, is common after stem cell transplantation or aggressive chemotherapy. Therefore, some attempt to reconstitute the IV formulation and use it topically. It is a water-soluble polar molecule and is predicted to be absorbable across the gastrointestinal tract following oral administration although. No oral formulations are currently available and bioavailability studies have been performed to a limited extent only in animals. It has been compounded in bases for topical use although topical formulations are prohibitively expensive (approximately $65 US per gram of extemporaneously compounded 3% cidofovir cream or it can be compounded as a 1% solution. There are case reprots of using these preparations for condyloma acumina, veruca vulgaris, laryngeal papillomatosis, Kaposi’s sarcoma, poxvirus infections and herpetic infections.

De Clercq and Holy demonstrated that topical cidofovir was effective against human herpesvirus types 1 and 2 and thymidine kinase deficient herpesvirus type 1 in mice. They demonstrated that its efficacy was superior to acyclovir. Snoeck et al reported successful the use of topical cidofovir in 2 patients, one with AIDS and the othe, a bone amrrow transplant patient, with resistant herpesvirus infections. Lateef et al used a topical preparation for a 4-year-old child with AIDS and a large facial ulcer secondary to herpesvirus type 1. Other case reprots were published by C.R.SIms in 2007, B. Muluneh in 2012

Lalezari et al reported a randomized, double blind, placebo controlled phase I/II clinical study of cidofovir gel in 30 patients with AIDS, all of whom had acyclovir-resistant herpes simplex infections. Eleven patients received 0.3% gel, nine patients received 1.0% gel and 10 were treated with placebo once a day for 5 days. Fifty percent of cidofovir patients had at least 50% improvement in infection in contrast with no improvement in the placebo patients. Thirty percent of the cidofovir treated patients had complete healing, compared with none of the placebo treated patients. The median time for negative viral cultures to be obtained from lesions in the cidofovir treated group was 2 days. Eighty seven per cent of CDV treated patients and no placebo treated patients developed negative viral cultures. Application site reactions occurred in 25 % of cidofovir-treated patients and in 20% of placebo-treated patients. Of the 6 patients treated with CDV who had complete healing, the response was sustained in 3.

Sacks et al described the successful use of cidofovir topical gel in otherwise healthy patients with recurrent genital herpes infection. Ninety-six patients were randomized in a double blind, placebo controlled trial. All patients were confirmed by viral culture or serology as having recurrent genital herpes simplex. Treatment consisted of a single application of cidofovir gel 1%, 3%, 5% or placebo within 12 hours of an outbreak. All patients treated with cidofovir showed a decrease both in median time for cultures to become negative and in the number of days to complete healing. Sacks et al concluded that topical cidofovir gel was well tolerated and possessed significant antiviral activity.

In conclusion, there a a number of case reports and series that support this drug, as well as two Phase II studies, one randomized. 1%, 3% and 5% solutions have shown activity.
Edward J. Zabawski, Review of Topical and Intralesional Cidofovir
Jr.Dermatology Online Journal 6(1): 3, 2000

De Clercq E. Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections. Verh K Acad Geneeskd Belg 1996;58(1):19-47; discussion 47-9.

Snoeck R, Andrei G, Gerard M, Silverman A, Hedderman A, Balzarini J, Sadzot-Delvaux C, Tricot G, Clumeck N, De Clercq E. Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Clin Infect Dis 1994;18(4):570-8.

Lateef F, Don PC, Kaufmann M, White SM, Weinberg JM. Treatment of acyclovir-resistant, foscarnet-unresponsive HSV infection with topical cidofovir in a child with AIDS [letter; comment] Arch Dermatol 1998;134(9):1169-70.

Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T, Kramer F, Kessler H, Corey L, Drew WL, Boggs J, McGuire B, Jaffe HS, Safrin S. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis 1997;176(4):892-8.

Sacks SL, Shafran SD, Diaz-Mitoma F, Trottier S, Sibbald RG, Hughes A, Safrin S, Rudy J, McGuire B, Jaffe HS. A multicenter phase I/II dose escalation study of single-dose cidofovir gel for treatment of recurrent genital herpes. Antimicrob Agents Chemother 1998;42(11):2996-9.

Sims CR, Thompson K, Chemaly RF, Shpall EJ, Champlin RE, Safdar A. Oral topical cidofovir: novel route of drug delivery in a severely immunosuppressed patient with refractory multidrug-resistant herpes simplex virus infection.Transpl Infect Dis. 2007 Sep;9(3):256-9.

B. Muluneh et al, Successful clerance of acyclovir resistant, foscarnet refractory herpes virus lesions with topical cidifivit in allogneic hematoppoietic stem cell transplant patient, J Oncol Pharm Pract, published online 24 May 2012

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Promacta for AML or MDS – pro

M Levin, MD — Fri, 05 Oct 2012 02:32:34 +0000

Thrombocytopenia is a frequent symptom in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Eltrombopag is a small molecule thrombopoietin receptor agonist that might be a new option to treat thrombocytopenia in these diseases, provided that it can be shown does not stimulate malignant hematopoiesis. Unfortunately, there is no significant literature to support Promacta in the setting of ongoing treatment for AML or in MDS. Currenlty PROMACTA is not indicated for the treatment of thrombocytopenia due to causes of thrombocytopenia (eg, myelodysplasia or chemotherapy) other than chronic ITP. Several studies showed that Eltrombopag was capable of increasing megakaryocytic differentiation and formation of normal megakaryocytic colonies in patients with AML and MDS but the clinical significance of this observation remains unclear. Promacta is currenlty in a study: Eltrombopag in Myelodysplastic Syndrome (MDS) Patients With Thrombocytopenia, NCT01286038.

Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U.
Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009 Oct 29;114(18):3899-908

S. Wroblewski, W. Shi, P. Mudd Jr., M. Aivado;Eltrombopag in thrombocytopenic patients with advanced myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia after MDS: A phase I/II study.J Clin Oncol 28:15s, 2010 (suppl; abstr TPS184)

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Vidaza Maintenance in AML – pro

M Levin, MD — Sat, 30 Jun 2012 12:59:43 +0000

The issue is the status of maintenance with any single agent drug. The most recent phase II study concluded: “5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients”.

The Scottish Medicines Consortium does not recommend azacitidine (Vidaza®) for use within NHS Scotland for the treatment of adults who are not eligible for haematopoietic stem cell transplantation (SCT) with intermediate-2 and high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML) or acute myeloid leukaemia (AML).

On May 19, 2004 the U.S. Food and Drug Administration approved azacitidine as injectable suspension (Vidaza) for treatment of patients with the following MDS subtypes: RA or RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), RAEB, RAEB-T, and CMML. Azacitidine is the first agent approved for treatment of myelodysplastic syndrome. However, though approved for MDS, there is good evidence for its effectiveness in AML as well. Subset analysis of the international phase III trial (AZA-001) demonstrating that the overall survival benefit observed in higher-risk MDS patients extended to patients with acute myeloid leukemia (AML). It is listed by NCCN as a low-intensity option for AML.

Almost one third of the patients (113 of 358) enrolled in the AZA-001 study met the WHO criteria for AML (median 23% bone marrow blasts), which has a poor prognosis and does not respond well to conventional chemotherapy. This subset analysis of the AZA-001 study showed the median overall survival was 24.5 months with VIDAZA compared to 16.0 months with CCR (p=0.005). Additionally, 50 percent of the AML patients who were treated with VIDAZA survived at least two years, compared to only 16 percent of AML patients treated with CCR.

Michael Grövdal et al, Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy, British Journal of Haematology
Volume 150 Issue 3, Pages 293 – 302, 2010

Reference: No. (589/09)
Source: Scottish Medicines Consortium (SMC)
Date published: 12/04/2010 16:30

http://www.nelm.nhs.uk/en/NeLM-Area/Evidence/Drug-Specific-Reviews/SMC-does-not-recommend-azacitidine-Vidaza-for-MDS-CMML-or-AML/

NCCN, AML-11, 2017

Marcos De Lima et al., Blood, 200Decitabine As Salvage Therapy for Relapse of AML and MDS after Allogeneic Stem Cell Transplantation – a Retrospective Multicenter Analysis on Behalf of the German Cooperative Transplant Study Group

Thomas Schroeder et al., Blood, 2016Prospective Phase II Study of Prophylactic Azacitidine and Donor Lymphocyte Infusions Following Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome Blood, 2016

Dacogen Maintenance in AML – pro

M Levin, MD — Sat, 30 Jun 2012 12:55:15 +0000

Dacogen (decitabine) is a new drug, a DNA methyltransferase inhibitors (DMTI), that approved by the FDA for use in all French- American British (FAB) categories for MDS. This drug is now FDA approved for MDS. For acute myelogenous leukemia (AML), less is known. A 2007 review, looked at 33 patients with the World Health Organization (WHO) criteria of AML that were treated with decitabine alone (23 patients) or in combination with valproic acid (10 patients) as first-line therapy. There were 20 men (61%) and their median age was 72, range 39 to 85. Median bone marrow blasts at study entry was 26%, and 14 (42%) had >30% blasts. There were three different schedules of decitabine IV, which gave a total of 100–150 mg/m2/course over 3–10 days. Of the 33 patients treated, there were 8 CRs (24%) and 9 marrow CR/PR/Hematologic improvement (27%) for a total response rate of 17 (52%). Overall mortality at 4 weeks and 8 weeks was 3% and 15%, respectively. At a median follow-up of 20 months, median survival of the entire group was 12.6 months (95% CI: 6.5–23.0), and 2-year survival was 25% (95% CI: 13–48), which compares favorably to reported AML survival in this age group in the United States. The study concluded that decitabine is an effective and less toxic treatment in this AML age group and may prolong survival compared with supportive care. MGI Pharma is currently conducting a phase III pivotal trial to evaluate Dacogen in patients with AML. Additional phase II studies are also underway to evaluate alternative dosing regimens for Dacogen in patients with MDS, AML and chronic myelogenous leukemia. For maintenance there is: Decitabine as Maintenance Therapy After Standard Therapy in Treating Patients With Previously Untreated Acute Myeloid Leukemia, NCT00416598.

NCCN lists both Dacogen and Vidaza for low intensity therapy on p. AML-11

REFERENCES: Silverman L, Demakos E, Peterson B, et L. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J. Clin. Oncol 2002; 10: 2241-2252. Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64. Kantarjian H, O’Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522. Hagop M. Kantarjian et al, Survival Advantage With Decitabine Versus Intensive Chemotherapy in Patients With Higher Risk Myelodysplastic Syndrome Comparison With Historical Experience Cancer. 2007 March 15; 109(6): 1133–1137

Decitabine for acute myelogenous leukemia – pro

M Levin, MD — Sat, 23 Jun 2012 01:29:16 +0000

Dacogen (decitabine) is a new drug, a DNA methyltransferase inhibitors (DMTI) that approved by the FDA for use in all French- American British (FAB) categories for MDS. The response rates for Dacogen were 30% (9% CR, 8% PR, 13% HI). Median TTP was prolonged from 7.8 months to 12.1 months compared to supportive care (p=0.1). Higher response rates have been reported in a single institution trial using lower doses of Dacogen. This drug is now FDA approved for MDS.

For acute meulogenous leukemia, less is known. A 2007 review, looked at 33 patients. with the WHO criteria of AML that were treated with decitabine alone (23 patients) or in combination with valproic acid (10 patients) as first-line therapy. There were 20 men (61%) and their median age was 72, range 39 to 85. Median bone marrow blasts at study entry was 26%, and 14 (42%) had >30% blasts. There were three different schedules of decitabine IV, which gave a total of 100–150 mg/m2/course over 3–10 days. Of the 33 patients treated, there were 8 CRs (24%) and 9 marrow CR/PR/Hematologic improvement (27%) for a total response rate of 17 (52%). Overall mortality at 4 weeks and 8 weeks was 3% and 15%, respectively. At a median follow-up of 20 months, median survival of the entire group was 12.6 months (95% CI: 6.5–23.0), and 2-year survival was 25% (95% CI: 13–48), which compares favorably to reported AML survival in this age group in the United States. The study concluded that decitabine is an effective and less toxic treatment in this AML age group and may prolong survival compared with supportive care.

NCCN(p. AML-11) lists it along with other drugs for induction therapy for patients older than 60.

In 2011, ASCO, a phase III study was presented. Xavier G. Thomas, MD, from the Hospital Edouard Herriot, Lyon, France, and colleagues performed a randomized, controlled, open-label trial that enrolled 485 patients with poor- or intermediate-risk cytogenetics, and ECOG PS 0–2. They were randomized to either supportive care (n=28) or 20mg/m² AraC SQ once daily for 10 consecutive days, every 4 weeks (n=215) or DAC 20mg/m² as a 1-hour IV infusion once daily for 5 consecutive days, every 4 weeks (n=242). An updated unplanned OS analysis with 446 (92%) deaths showed the same median survival with strengthened, albeit nominal evidence of the DAC effect (P=0.037) (0.82, 95%CI [0.68–0.99]). The secondary endpoint of complete remission (CR) + complete remission in the absence of total platelet recovery (CRp) rate was 17.8% (DAC) versus 7.8% (SC) with overall response (CR + CRp + partial response) of 2.5 (P=0.001). Safety rates were consistent with the known DAC safety profile and without major differences between the treatment arms.

Silverman L, Demakos E, Peterson B, et L. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J. Clin. Oncol 2002; 10: 2241-2252.

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Data from DACO-016 study at 2011 American Society of Clinical Oncology Annual Meeting

Kantarjian H, O’Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.