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

For Lay version see here

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

 For Lay version see here

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)

For Lay version see here

John Koreth, et al, Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission Consolidation Therapy With Autologous Bone Marrow Transplantation in Adults With Acute Myeloid Leukemia: A Meta-analysis 2009;301(22):2349-2361Ades L, Sanz MA, Chevret S et al.: Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood 111,1078-1084 (2008).

Schlenk RF, Dohner K, Krauter J et al.: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N. Engl. J. Med. 358,1909-1918 (2008).

Richard M. Stone, Consolidation Chemotherapy for Adults With AML in First Remission: Is There a Best Choice?Journal of Clinical Oncology 31, no. 17 (June 2013) 2067-2069.

Hervé Dombretcorresponding author and Claude Gardin,An update of current treatments for adult acute myeloid leukemia.Blood. 2016 Jan 7; 127(1): 53–61.

A mini-review on second allogeneic transplant found that a second allogeneic hematopoietic cell transplant does have an important potential role in treating relapse after failing allogeneic transplant in selected patients. Those patients who have an early relapse, high tumor burden, or chemo-resistant disease are not patients who should undergo second transplant, as the literature does not support the clinical benefit for these selected patients. Thus the decision to undergo a second transplant should be weighed against the associated co-morbidities that can contribute to transplant-related mortality, for which a reduced-intensity approach can certainly be considered, with earlier tapering of immunosuppression. With regard to the donor, under most circumstances the same donor is used, but if there is a different HLA-matched sibling or unrelated donor, this also could be considered, especially if there was no antecedent GVHD. As randomized-controlled trials are non-existent to answer the question of the role of second allogeneic transplant to treat relapse, multi-institutional observational studies were used in this mini-review to make these recommendations.

Literature supports individualizing recommendations. A short interval to relapse is a factor that speaks against repeating an allogeneic transplant. A recent review wrote: ” The prognosis for relapsed hematological malignancies after SCT depends on four factors: the time elapsed from SCT to relapse (with relapses occurring within 6 months having the worst prognosis), the disease type (with chronic leukemias and some lymphomas having a second possibility of cure with further treatment), the disease burden and site of relapse (with better treatment success if disease is treated early), and the conditions of the first transplant (with superior outcome for patients where there is an opportunity to increase either the alloimmune effect, the specificity of the antileukemia effect with targeted agents or the intensity of the conditioning in a second transplant). These features direct treatments toward either modified second transplants, chemotherapy, targeted antileukemia therapy, immunotherapy or palliative care.”

Transplantation for consolidation of high-risk is standard of care. AML Literature supports individualizing recommendations. A short interval to relapse is a factor that speaks against repeating an allogeneic transplant. A recent review wrote: ” The prognosis for relapsed hematological malignancies after SCT depends on four factors: the time elapsed from SCT to relapse (with relapses occurring within 6 months having the worst prognosis), the disease type (with chronic leukemias and some lymphomas having a second possibility of cure with further treatment), the disease burden and site of relapse (with better treatment success if disease is treated early), and the conditions of the first transplant (with superior outcome for patients where there is an opportunity to increase either the alloimmune effect, the specificity of the antileukemia effect with targeted agents or the intensity of the conditioning in a second transplant). These features direct treatments toward either modified second transplants, chemotherapy, targeted antileukemia therapy, immunotherapy or palliative care.”

Recently mismatched unrelated transplants have come to fore. The conclusions of a 2012 ASH review were that patient factors such as phase of the disease remain critical predictors of survival: when the disease is advanced, identifying a fully matched donor may not improve survival significantly and must be balanced against the risk that the disease will progress while a prolonged search is ongoing.
The recent review by SWaraceni et al concluded that : ” that in AML patients in CR1 lacking an HLA-matched sibling donor, 10/10 UD-HSCT significantly improves LFS, but this advantage does not translate in better OS compared to auto-HSCT. In intermediate-risk patients lacking a fully HLA-matched donor, auto-HSCT should be considered as a valid option, as better survival appears to be provided by auto-HSCT compared to mismatched UD-HSCT. Finally, auto-HSCT provided an encouraging outcome in patients with favorable risk AML.:
Saraceni F, Labopin M, Gorin NC, et al. Matched and mismatched unrelated donor compared to autologous stem cell transplantation for acute myeloid leukemia in first complete remission: a retrospective, propensity score-weighted analysis from the ALWP of the EBMT. J Hematol Oncol. 2016;9(1):79.

Hosing C, Saliba RM, Shahjahan M, Estey EH, Couriel D, Giralt S, et al. Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia. Bone Marrow Transplant. 2005;36:157-62.

M. S. Thakar and S. J. Forman ASH evidence-based guidelines: is there a role for second allogeneic transplant after relapse? Hematology, January 1, 2009; 2009(1): 414 – 418.

nccn.org, AML 2018, AML-14

Barrett, A John; Battiwalla, Minoo Relapse after allogeneic stem cell transplantation Expert Review of Hematology, Volume 3, Number 4, August 2010 , pp. 429-441(13)

When purine analogs were first introduced in the treatment ofpatients with CLL, the issue of whether or not these agentsshowed cross-resistance was a matter of extensive debate. Thecurrent notion is that cross-resistance does exist. However,pentostatin combined with cyclophosphamide has been reportedto produce responses (77% including one CR) in a small seriesof 13 patients who did not respond to fludarabine-based therapy. A second phase II study was recentlypublished. In fludarabine-refractory patients,75% responded. Toxicity was acceptable, with grade 3/4 infections(including fever of unknown origin) in 28%. The regimen waswell tolerated, with 72% of patients receiving the planned treatmentat full dose.

Mark A. Weiss, Peter G. Maslak, Joseph G. Jurcic, David A. Scheinberg, Timothy B. Aliff, Nicole Lamanna, Stanley R. Frankel, Steven E. Kossman, Denise Horgan , Pentostatin and Cyclophosphamide: An Effective New Regimen in Previously Treated Patients With Chronic Lymphocytic Leukemia Journal of Clinical Oncology, Vol 21, Issue 7 (April), 2003: 1278-1284
N. Lamanna, M. Kalaycio, P. Maslak, J. G. Jurcic, M. Heaney, R. Brentjens, A. D. Zelenetz, D. Horgan, A. Gencarelli, K. S. Panageas, D. A. Scheinberg, and M. A. Weiss
Pentostatin, Cyclophosphamide, and Rituximab Is an Active, Well-Tolerated Regimen for Patients With Previously Treated Chronic Lymphocytic Leukemia
J. Clin. Oncol., April 1, 2006; 24(10): 1575 – 1581.

E. Montserrat, C. Moreno, J. Esteve, A. Urbano-Ispizua, E. Gine, and F. Bosch
How I treat refractory CLL
Blood, February 15, 2006; 107(4): 1276 – 1283.

The purine nucleoside analogues (PNA), fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and 2′-deoxycoformycin (DCF), represent a novel group of cytotoxic agents with high activity in low-grade lymphoid malignancies. However, several investigations have revealed that these agents are active also in acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). Synergistic interaction between FA or 2-CdA with cytarabine (Ara-C) have been demonstrated in both preclinical and clinical studies. The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. Clinical studies have confirmed the efficacy of PNA alone or in combination protocols in the treatment of AML. These regimens seem to produce superior results with acceptable toxicities in previously treated and relapsed, poor risk AML. However, early relapses remain a significant problem in a majority of refractory or relapsed patients in CR after treatment with PNA based regimens. To prolong remission duration or even cure AML, auto–or allo stem cell transplantation should be considered. However, FAMP or 2-CdA containing regimens may impair mobilization and collection of stem cells from peripheral blood for autotransplantation. On the other hand, cladribine is sometimes used in non-myeloablative allogeneic transplants.

In the final analysis, I consider the CLAG regimen to be within the standard of care for relapsed AML, or in preparation for a stem cell transplant in poor risk patients.In the final analysis, I consider this drag and the CLAG regimen to be within the standard of care for relapsed AML, unless there is specific plan language that excludes it on specific grounds.

http://nccn.org/professionals/physician_gls/PDF/aml.pdf, 2012

Becker PS, Kantarjian HM, Appelbaum FR, et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol 2011; 155:182.

Chantry AD, Snowden JA, Craddock C, et al. Long-term outcomes of myeloablation and autologous transplantation of relapsed acute myeloid leukemia in second remission: a British Society of Blood and Marrow Transplantation registry study. Biol Blood Marrow Transplant 2006; 12:1310.

Allogeneic bone marrow transplantation results in the lowest incidence of leukemic relapse, even when compared with bone marrow transplantation from an identical twin (syngeneic bone marrow transplantation). This has led to the concept of an immunologic graft-versus-leukemia effect, similar to (and related to) graft-versus-host disease. The improvement in freedom from relapse using allogeneic bone marrow transplantation as the primary postremission therapy is offset, at least in part, by the increased morbidity and mortality caused by graft-versus-host disease, veno-occlusive disease of the liver, and interstitial pneumonitis. Disease-free survival rates using allogeneic transplantation in first complete remission have ranged from 45% to 60%. The use of allogeneic bone marrow transplantation as primary postremission therapy is limited by the need for a human leukocyte antigen (HLA)-matched sibling donor and the increased mortality from allogeneic bone marrow transplantation of patients who are older than 50 years. The mortality from allogeneic bone marrow transplantation that uses an HLA-matched sibling donor ranges from 20% to 40%, depending on the series. The use of matched, unrelated donors for allogeneic bone marrow transplantation is being evaluated at many centers but has a very substantial rate of treatment-related mortality, with disease-free survival rates less than 35%.
Because bone marrow transplantation can cure about 30% of patients who experience relapse following chemotherapy, some investigators suggested that allogeneic bone marrow transplantation can be reserved for early first relapse or second complete remission without compromising the number of patients who are ultimately cured; however, clinical and cytogenetic information can define certain subsets of patients with predictable better or worse prognoses using consolidation chemotherapy. Good-risk factors include t(8;21), inv(16) associated with M4 AML with eosinophilia, and t(15;17) associated with M3 AML. Poor-risk factors include deletion of 5q and 7q, trisomy 8, t(6;9), t(9;22), and a history of myelodysplasia or antecedent hematologic disorder. FLT status is now generally agreed to denote poor prognosis and warrant a consolidative transplant. Patients in the good-risk group have a reasonable chance of cure with intensive consolidation, and it may be reasonable to defer transplantation in that group until early first relapse. The poor-risk group is unlikely to be cured with consolidation chemotherapy, and allogeneic bone marrow transplantation in first complete remission is a reasonable option for patients with an HLA-identical sibling donor. However, even with allogeneic stem cell transplantation, the outcome for patients with high-risk AML is poor (5-year disease-free survival of 8% to 30% for patients with treatment-related leukemia or myelodysplasia). The efficacy of autologous stem cell transplantation in the poor-risk group has not been reported to date but is the subject of active clinical trials. Patients with normal cytogenetics are in an intermediate-risk group, and postremission management should be individualized or, ideally, managed according to a clinical trial.

In regard to MUD allogeneic transplant, a recent guideline says: “In the absence of an HLA-identical family donor, it seems reasonable to offer allogeneic SCT from a matched unrelated donor (MUD) to patients with poor-risk disease, either for biological features or for late achievement of CR. With the use of MUD transplantation, a long-term OS comparable to that obtained with a sibling donor, and far exceeding that observed with autotransplant, has been observed by some authors in this high-risk cohort However, the evidence supporting an advantage with MUD-SCT in high-risk patients without a sibling donor is weak.”

2016 NCCN generally recommends consolidation with Cytarabine or reduced intensity transplant but says in a footnote that says that patients who are good candidates and have an appropriate donor should be transplanted in first remission (AML-13).

Majhail, Navneet S. et al.Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation , Volume 21 , Issue 11 , 1863 – 1869

Hübel K, Weingart O, Naumann F, Bohlius J, Fresen MM, Engert A, Wheatley K.
Allogeneic stem cell transplant in adult patients with acute myelogenous leukemia: a systematic analysis of international guidelines and recommendations.Leuk Lymphoma. 2011 Mar;52(3):444-57.

Yanfeng Liu et al,Prognostic significance of NPM1 mutations in acute myeloid leukemia: A meta-analysis. Oncology.
March 2014, Volume 2 Issue 2

NCCN, AML 2022

M.A. Sekeres et al, American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv (2020) 4 (15): 3528–3549.

Rautenberg C, Germing U, Haas R, Kobbe G, Schroeder T. Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment. Int J Mol Sci. 2019;20(1):228. Published 2019 Jan 8. doi:10.3390/ijms20010228

It used to be thought that allogeneic transplantation in the refractory setting can salvage about a third of patients but most recur quickly after obtaining a transient remission. More recent studies are showing that modern treatment methods are resulting in much higher response and cure rates.

An allogeneic HSCT using a matched related donor (MRD) or matched unrelated donor (MUD) represents the only potentially curative option for these individuals. In several retrospective studies OS rates have ranged from 13% at 5 years to 30% at 3 years, although this procedure is accompanied by NRM rates of 25%–62% in this setting. NCCN does nto discuss the refractory subtype of AML but a recent Canadiain guideline says: “Allogeneic stem cell transplantation offers the best chance of survival for relapsed or refractory AML patients.”

Mato AR, Morgans A, Luger SM.

Novel strategies for relapsed and refractory acute myeloid leukemia. Curr Opin Hematol. 2008 Mar;15(2):108-14.

Estey EH. Treatment of acute myeloid leukemia. Haematologica. 2009 Jan;94(1):10-6.

Hamadani M, Awan FT, Copelan EA. Hematopoietic stem cell transplantation in adults with acute myeloid leukemia. Biol Blood Marrow Transplant. 2008 May;14(5):556-67.

nccn.org, AML

http://www.cancercare.ns.ca/site-cc/media/cancercare/Acute%20Myelogenous%20Leukemia.pdf

Updated 6/29/2011

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.

NCCN recommends low intensity maintenance with drugs that include azacytidine as an option on p. AML-11.

Gemtuzumab ozogamicin (GO) (Mylotarg, CMA-676) is a novel chemotherapeutic agent consisting of an anti-CD33 monoclonal antibody linked to calicheamicin, and is associated with a 30% response rate in patients with CD33-positive acute myeloid leukemia (AML) in first relapse.

nccn, AML 2012

Edlin R, Connock M, Tubeuf S, Round J, Fry-Smith A, Hyde C, Greenheld W. zacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia. Health Technol Assess. 2010 May;14 Suppl 1:69-74.