Cancer Treatment

Haploidentical donors

There are different kinds of donor for stem cell transplantation. The best matched donors as siblings. The ultimate such donor is an identical twin, which is called syngeneic transplantation. On the other end of the spectrum is unrelated donor. Not everyone has siblings.

Related haploidentical BMT is an alternative method for expanding the potential pool of stem cell donors; any patient shares one HLA haplotype with each biologic parent or child and siblings or half-siblings have a 50% chance of being haploidentical and 50% chance of not being haploidentical. The more differences between the patient and the donor , they higher is the incidence of graft rejection and severe graft vs. host disease. The disadvantage of the haploidentical approach has been the high incidence of graft rejection and severe GVHD.

Continued research is needed to better define preferred conditioning regimens, methods and degree of T-cell depletion, and optimal CD34+ cell dose in the allograft. Although haploidentical transplantation is a potentially curative option for AML patients lacking a suitable sibling or unrelated donor, experts believe that at this time it should be performed only in experienced centers, within the context of clinical trials, especially in patients with poor-risk AML in CR1.

Alternatives include umbilical cell and and related donor transplantation.

One emerging matter of dealing with this problem is forced transplant treatment with Cytoxan.

S Tuve al, Haploidentical bone marrow transplantation with post-grafting cyclophosphamide: multicenter experience with an alternative salvage strategy, Leukemia 25, 880-883 (May 2011)

R A Brodsky, L Luznik, J Bolaños-Meade, M S Leffell3, R J Jones and E J Fuchs  Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases Bone Marrow Transplantation (2008) 42, 523–527

 

Salem Alshemmari

Haploidentical Hematopoietic Stem-Cell Transplantation in Adults Bone Marrow Research
Volume 2011

Incomplete response to induction in acute myelogenous leukemia and salvage approaches

Standard Therapy of of acute myelogenous leukemia (excluding acute promyelocytic leukemia) begins with induction. Various acceptable induction regimens are available. The most common approach is called ”3 and 7,” which consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m2 of arabinosylcytosine (araC) as a 24-hour infusion daily for 7 days. Idarubicin is given at a dose of 12 mg/m2/d for 3 days, daunorubicin at 45-60 mg/m2/d for 3 days, or mitoxantrone at 12 mg/m2/d for 3 days. Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy. Prognosis does not change based on whether one or two inductions were required to achieve a remission. A retrospective analysis of six Eastern Cooperative Oncology Group (ECOG) studies that included both younger and older adults demonstrated that 26% of patients achieving complete remission (CR) following anthracycline and cytarabine-based induction therapy required a second cycle of identical induction therapy to do so [Rowe et al. 2010].

Occasionally, a patient largely responds to two induction chemotherapies but is found to have persistent leukemia cells in the marrow. It is clear that without farther intervention, such a patient is destined to relapse within a few months. Studies in 1980s and 1990s demonstrate that effective salvage regimens for relapsed or refractory AML include Ara-C and anthracycline-like compounds as the backbone of the regimens. Combinations that included flu-darabine and/or combinations of both Ara-C and anthracycline-like compounds also demonstrated efficacy and three drug salvage regimens are being studied. Also being explored are targeted agents, and allogeneic SCT, alone of in combinaitons. Prognostic significance of cytogenetic and other markers that can guide this choice is also being explored.

 

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):2349-2361

Bob Löwenberg, M.D., Thomas Pabst, M.D., Edo Vellenga, M.D., Wim van Putten, M.Sc., Harry C. Schouten, M.D., Carlos Graux, M.D., Augustin Ferrant, M.D., Pieter Sonneveld, M.D., Bart J. Biemond, M.D., Alois Gratwohl, M.D., Georgine E. de Greef, M.D., Leo F. Verdonck, M.D., Martijn R. Schaafsma, M.D., Michael Gregor, M.D., Matthias Theobald, M.D., Urs Schanz, M.D., Johan Maertens, M.D., and Gert J. Ossenkoppele, M.D. for the Dutch–Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group
Cytarabine Dose for Acute Myeloid Leukemia, N Engl J Med 2011;

Ades 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).

Rowe JM, Kim HT, Cassileth PA, et al. Adult patients with acute myeloid leukemia who achieve complete remission after one or two cycles of induction have a similar prognosis. Cancer. 2010; 116(21):5012-5021.

Rowe JM, Tallman MS. How I treat acute myeloid leukemia. Blood. 2010 Oct 28;116(17):3147-56.

 

Sorafenib for FLT3+ AML

Sorafenib (Nexavar,) has been approved for the treatment of metastatic renal cancer and advanced hepatocellular carcinoma. It inhibits the serine threonine kinase RAF-1, but also the FLT3-RTK and FLT3-ITD, suggesting that it may have a role in treating AML with FLT3 mutations.Sorafenib in a phase 1 clinical trial on 16 patients with AML was found to be active in 6 of the 7 Flt3-ITD–positive patients.11 However, treatment duration was short (21-70 days), and no durable responses were reported. Notably, a complete molecular remission has recently been reported in a patient relapsing after stem cell transplantation (SCT).

There is a high degree of interest in the use of sorefenib with other drugs or alone for FLT+ AML but corroborating literaure is still very preliminary and at the level of case reports. For this reason, it is still experimental at this time.

Delmonte J, Jr, Kantarjian HM, Andreeff M, Faderl S, Wright JJ, Zhang W, et al. Update of a Phase I Study of Sorafenib in Patients with Refractory/Relapsed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome. ASH Annual Meeting Abstracts. 2007 November 16;110(11):893. 2007.

Zhang W, Konopleva M, Shi YX, et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst 2008;100:184-198

Mori S, Cortes J, Kantarjian H, Zhang W, Andreef M, Ravandi F. Potential role of sorafenib in thetreatment of acute myeloid leukemia. Leuk Lymphoma 2008;49:2246-2255.

Safaian NN, Czibere A, Bruns I, et al. Sorafenib (Nexavar[registered]) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD(+) acute myeloid leukemia. Leuk Res 2009;33:348-350.

Stephan Metzelder et al, Compassionate use of sorafenib in FLT3-ITD–positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation Blood June 25, 2009 vol. 113 no. 26 6567-6571

Hu S, Niu H, Inaba H, Orwick S, Rose C, Panetta JC, Yang S, Pounds S, Fan Y, Calabrese C, Rehg JE, Campana D, Rubnitz JE, Baker SD. Activity of the multikinase inhibitor sorafenib in combination with cytarabine in acute myeloid leukemia.J Natl Cancer Inst. 2011 Jun 8;103(11):893-905.

Inaba H, Rubnitz JE, Coustan-Smith E, Li L, Furmanski BD, Mascara GP, Heym KM, Christensen R, Onciu M, Shurtleff SA, et al.
Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol. 2011 Aug 20; 29(24):3293-300

Neulasta after treatment for AML

Patients with acute myeloid leukemia (AML) are often neutropenic becasue of leukemia and they also experience profound neutropenia following induction and/or consolidation chemotherapy, which may result in serious, potentially life-threatening, infection. Prophylactic use of myeloid growth factors reduces the severity and duration of neutropenia. Pegylated filgrastim (pegfilgrastim), or Neulasta, has the same mechanism of action as the first generation agent filgrastim, but has markedly reduced renal clearance, with neutrophil-mediated clearance being the major route of elimination. It, therefore, requires only a single dose.

Despite consistently demonstrating a shorter duration of neutropenia, multiple, prospective, randomized trials have documented only modest benefits in terms of reduction in the incidence and severity of infections, without substantial gains or impact in complete remission, overall survival, and disease-free survival rates. Randomized trials to evaluate this priming strategy have consistently demonstrated an improvement in terms of disease-free or event free survival in the intermediate risk group of patients with acute myeloid leukemia, but no overall survival benefit. This was confirmed by a meta-analysis(Wang et al).

G-CSF is usually well tolerated and medullary bone pain is the most frequently reported side-effect. Sierra et al and Bosi et al demonstrated that Neulasta and Neupgen have the same efficacy. Other less common adverse effects include headaches, generalized musculoskeletal pain, and exacerbation of underlying inflammatory skin disease. A 2005 guideline says: "Similarly there is insufficient evidence to support routine use of G-colony stimulating factor (CSF) or granulocyte macrophage (GM)-CSF with induction chemotherapy in patients over 60 years of age, although this may be appropriate if it is desirable to reduce hospitalisation or antibiotic usage". 

 

Jorge Sierra et al, A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial BMC Cancer. 2008; 8: 195.

Milligan DW, Grimwade D, Cullis JO, Bond L, Swirsky D, Craddock C, Kell J, Homewood J, Campbell K, McGinley S, Wheatley K, Jackson G. Guidelines on the management of acute myeloid leukaemia in adults. London (UK): British Society of Haematology (BSH); 2005 May 23. 77 p. [202 references]

Bosi A, Szer J, Kassis J, et al. A Multicentre, Double-Blind, Randomized, Phase 2 Trial Comparing Pegfilgrastim with Filgrastim as an Adjunct to Chemotherapy for Acute Myeloid Leukaemia (AML). Proceedings from the 46th annual meeting of the American Society of Hematology (ASH). December 2004. Abstract # 866.

Wang J, An L, Chen S, et al. Prophylactic use of granulocyte colony-stimulating factor after chemotherapy does not affect survival rate in acute myeloid leukemia: A meta-analysis. Acta Haematol. 2009;121(4):223-226.

 

Prolonged Neupogen administration after a stem cell transplant

 

There is some concern that administration of Neupogen will delay engraftment of non-myeloid cells after a stem cell transplant but a recent review found this not to be the case. It also found that G-CSF is beneficial  in allogeneic as well as autologous transplantation. It did recommend that it be delayed for 5 days after transplantation because there was no difference in outcome between delaying it for up to 5 days or starting immediately after transplant. The administration of Neupogen in most studies was for variable periods, including for more than 14 days.

REFERENCES:

M Trivedi et al, Optimal use of G-CSF administration after hematopoietic SCT Bone Marrow Transplantation (2009) 43, 895–908

Smith TJ, Khatcheressian J, Lyman GH: 2006 update of recommendations for the use of white blood cell growth factors: An evidence-based, clinical practice guideline. J Clin Oncol 24:3187-3205, 2006

Lyman GH: Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: A review of the evidence. J Natl Compr Canc Netw 3:557-571, 2005

Dacogen maintenance in AML

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

Thus, it is still experimental.

 

  

  

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.

 

Vidaza Maintenance in AML

The issue is the status of maintenance with any single agent drug. The maintenance concept has not been proven.  As for Dacogen, Vidaza is not sufficiently studied to be routinely adopted. 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).

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, B ritish 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/

Revlimid for AML with 13q abnormality.

Revlimid is a derivative of thalidomide with less toxic side effects. A multicenter U.S. trial has reported hematologic activity of Revlimid in patients with myelodysplastic syndromes (MDS). The U.S. Food and Drug Administration has approved Revlimid for the treatment of low- to intermediate-risk MDS in patients who are transfusion-dependent associated with a 5q cytogenetic abnormality, with or without other cytogenetic abnormalities. There is a study in such patients:

Revlimid in Patients With Acute Myelogenous Leukemia and Myelodysplastic Syndrome

This study is currently recruiting participants.

Verified by M.D. Anderson Cancer Center, July 2009

First Received: August 4, 2006   Last Updated: July 30, 2009   History of Changes

Sponsor:	M.D. Anderson Cancer Center
Collaborator:	Celgene Corporation
Information provided by:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT00360672

 

 Several patients with 13q abnormality with acute myeloid leukemia (AML) associated with trisomy 13 achieved a complete remission following treatment with Revlimid® (lenalidomide).  These remain anecdotal reports and not a basis for approval.

Fehniger TA, Byrd JC, Marcucci G, et al. single agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13. Blood [early online publication]. September 29, 2008.

Farag SS, Archer KJ, Mrozek K, et al. Isolated trisomy of chromosomes 8, 11, 13 and 21 is an adverse prognostic factor in adults with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. International Journal of Oncology.2008;21:1041-1051.

FLAM for AML

The serine/threonine kinase inhibitor flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation. Preliminary reports suggest that flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. The proposed protocol is Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia, NCT00407966. This phase II trial is studying the side effects and how well giving flavopiridol together with cytarabine and mitoxantrone works in treating patients with newly diagnosed acute myeloid leukemia.

Karp, Judith E., Ross, Douglas D., Yang, Weidong, Tidwell, Michael L., Wei, Yuetong, Greer, Jacqueline, Mann, Dean L., Nakanishi, Takeo, Wright, John J., Colevas, A. Dmitri
Timed Sequential Therapy of Acute Leukemia with Flavopiridol: In Vitro Model for a Phase I Clinical Trial
Clin Cancer Res 2003 9: 307-315

J. E. Karp, B. D. Smith, M. J. Levis, S. D. Gore, J. Greer, C. Hattenburg, J. Briel, R. J. Jones, J. J. Wright, and A. D. Colevas
Sequential Flavopiridol, Cytosine Arabinoside, and Mitoxantrone: A Phase II Trial in Adults with Poor-Risk Acute Myelogenous Leukemia
Clin. Cancer Res., August 1, 2007; 13(15): 4467 - 4473.

Neulasta and neupogen for acute myeloid leukemia: An Update.

Previous review, here.

Myeloid growth factors granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been extensively studied in acute leukemias. Whether administered before, during, or after chemotherapy for acute myeloid and acute lymphoblastic leukemias, these agents reduce the duration of neutropenia and appear to be safe and well tolerated. Despite consistently demonstrating a shorter duration of neutropenia, multiple, prospective, randomized trials have documented only modest benefits in terms of reduction in the incidence and severity of infections, without substantial gains or impact in complete remission, overall survival, and disease-free survival rates. Growth factors have also been used to recruit quiescent leukemia cells into the S phase of the cell cycle to increase their susceptibility to chemotherapy with the goal to reduce relapse and resistance. Randomized trials to evaluate this priming strategy have consistently demonstrated an improvement in terms of disease-free or event free survival in the intermediate risk group of patients with acute myeloid leukemia, but no overall survival benefit.G-CSF is usually well tolerated and medullary bone pain is the most frequently reported side-effect. Other less common adverse effects include headaches, generalized musculoskeletal pain, and exacerbation of underlying inflammatory skin diseaseNeulasta is not used routinely in acute myeloid leukemia but is not harmful if used appropriately. A recent guideline says: "Similarly there is insufficient evidence to support routine use of G-colony stimulating factor (CSF) or granulocyte macrophage (GM)-CSF with induction chemotherapy in patients over 60 years of age, although this may be appropriate if it is desirable to reduce hospitalisation or antibiotic usage".

Milligan DW, Grimwade D, Cullis JO, Bond L, Swirsky D, Craddock C, Kell J, Homewood J, Campbell K, McGinley S, Wheatley K, Jackson G. Guidelines on the management of acute myeloid leukaemia in adults. London (UK): British Society of Haematology (BSH); 2005 May 23. 77 p. [202 references]