Was Mom Right About Eating Veggies?
Charles Abrams, MD
Dr. Abrams indicated no relevant conflicts of interest.
Ray JG, Kearon C, Yi Q, et al. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Annals Int Med. 2007;146:761-767.
The Heart Outcomes Prevention Evaluation 2 (HOPE-2) trial was designed to evaluate the effect of lowering homocysteine on the development of arterial vascular disease. In this five-year study, a daily combination of folate, vitamin B6, and vitamin B12 was administered to 2,758 participants, while another 2,764 participants took matching placebos. In conjunction with this trial, separate analysis was done to determine whether decreasing plasma homocysteine levels reduced the occurrence of symptomatic venous thromboembolic disease.
Of the 5,522 participants, 72 percent were from the United States and Canada where food is fortified with folate. Consequently, the mean plasma homocysteine level at entry into the trial was only 11.5 mmol/l. At the end of the trial, the mean homocysteine level decreased by 2.2 mmol/l in the treatment group and increased by 0.8 mmol/l in the control group. It is notable that in the treatment group, the mean homocysteine level decreased by 1.9 mmol/l in participants from regions with folate food fortification and decreased by 4.8 mmol/l in participants from regions that do not fortify food with folate. This suggests that patients in regions without folate-rich diets derive the most benefit from vitamin supplementation. Despite changes in plasma homocysteine levels, the treatment and the control groups had an identical number (44) of symptomatic venous thromboembolisms. Restricting the analysis to the 821 participants who had plasma homocysteine levels in the highest quartile (>13.8 mmol/l) still did not show a benefit for folate therapy.
Homocystinuria is a rare inborn error of metabolism associated with extremely high plasma homocysteine levels, premature cardiovascular disease, and developmental abnormalities of the ocular, skeletal, and nervous systems. Less significant elevation of plasma homocysteine is common and is not associated with developmental abnormalities. Analysis of patients and matched control subjects participating in the Leiden Thrombophilia Study suggested that plasma homocysteine levels above the 95th percentile in the control group (>18.5 mmol/l) is a risk factor for venous thrombosis1. It is notable that there was a very high risk for thromboembolic events in participants with homocysteine levels greater than 22 mmol/l. Since modest elevations of plasma homocysteine to less than 18.0 mmol/l were not associated with any increased risk of thrombosis, data from the Leiden study suggested that there might be a threshold level when homocysteine may induce venous thrombosis.
The results of the HOPE-2 trial failed to demonstrate a benefit for homocysteine lowering therapy in the analyzed cohorts. Does this mean that homocysteine is never a risk factor for thromboembolic disease, and patients with hyperhomocysteine will not benefit from folate supplementation? The patients enrolled in the HOPE-2 study, as well as the patients enrolled in the recently published VITRO study2, were selected for their overall cardiovascular risk, not their baseline plasma homocysteine levels. Consequently, there were very few analyzed participants with plasma homocysteine levels above the critical threshold as proposed by the Leiden Thrombophilia Study group. Therefore, it is still unclear whether the risk of thromboembolic events in patients with very high plasma homocysteine levels would be reduced by a combination of folate, vitamin B6, and vitamin B12.
What does all this mean for mothers (and physicians) who recommend eating lots of veggies? First, it emphasizes that food in the United States and Canada that is fortified with folate has made significant hyperhomocysteinemia a rare occurrence in these countries. Second, patients with mild hyperhomocysteinemia do not benefit from therapy designed to reduce plasma homocysteine. Third, it is still unknown whether the exceptional patient with a plasma homocysteine level greater than 22 mmol/l would still benefit from folate therapy, and this demands further study. However, given the available data and the minimal toxicity of therapy, it appears that treatment for these select few is for now still a worthwhile endeavor.
References:
- NEJM. 1996;334:759-6.
- Blood. 2007;109:139.
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Fetal and Maternal Thrombophilia Genes Cooperate to Influence Pregnancy Outcomes
Roy Silverstein, MD
Dr. Silverstein indicated no relevant conflicts of interest.
Sood R, Zogg M, Westrick RJ, et al. Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers. J Exp Med. 2007 May;204:1049-56.
To study the impact of maternal thrombophilia on pregnancy outcomes, the authors carried out a series of elegant and complicated breeding experiments utilizing multiple mouse strains engineered with genetic defects in the protein C pathway. They found that mothers homozygous for factor V Leiden or for a thrombomodulin point mutation with severe inability to activate protein C showed consistent, severe fetal loss only when the offspring were homozygous for the thrombomodulin mutation, or heterozygous for both the thrombomodulin mutation and the Leiden mutation, or homozygous for a mutation in the endothelial protein C receptor (EPCR) gene. EPCR serves as a binding site for protein C and facilitates its activation by the thrombin/thrombomodulin complex. The mice did not have spontaneous systemic thrombi, but the placentas were markedly abnormal, showing a defect at the maternal-fetal interface with abnormal development of the labyrinth layer and severely diminished fetal and maternal vessel in-growth. No placental thrombi or infarcts were seen. Interestingly, deficiency of tissue factor pathway inhibitor in these models was associated with severe systemic thrombosis, but not fetal loss. Surprisingly, if the pregnant mice were depleted of platelets before the tenth day of gestation (normal gestation for mice is ~22 days), or if the mice were genetically null for the platelet thrombin receptor PAR4, the phenotype of fetal loss was rescued.
Multiple case-controlled, epidemiologic studies have shown an association between genetic thrombophilias ― particularly factor V Leiden ― and recurrent pregnancy loss. Many obstetricians routinely screen high-risk women with recurrent, spontaneous abortions for thrombophilia based on these studies and on data suggesting improved outcomes with anti-coagulation therapy. This study provides important new insights into the problem by 1) confirming that (at least in mice) the factor V Leiden mutation does indeed cause fetal loss and 2) showing that the risk and timing of the loss is clearly dependent on the genotype of both the mother and the fetus. Homozygosity for the mutation in the mothers was associated with earlier fetal loss than heterozygosity, and penetrance of the phenotype of fetal loss was dramatically enhanced if the fetus had a genetic defect in the protein C pathway. Rescue of the phenotype by depleting the mothers of platelets or by preventing thrombin-dependent platelet activation, along with the pathologic data showing abnormal development of the maternal-fetal interface but no systemic or placental thrombosis, leads to the following model: The placental trophoblast (which is of fetal origin) constitutively expresses tissue factor and generates small amounts of thrombin that is "balanced" by robust expression of the protein C activating system (thrombomodulin and EPCR). Maternal resistance to activated protein C (for example, factor V Leiden) coupled with fetal inability to generate sufficient protein C could lead to inappropriate thrombin generation at the maternal-fetal interface resulting in inappropriate platelet activation and faulty placental development. These studies suggest that investigators should include examination of paternal or fetal genetics in future studies assessing the role of thrombophilia in recurrent fetal loss. In addition, they suggest that efficacy of heparin in preventing early fetal loss may be due to prevention of thrombin-induced platelet activation rather than protection from placental thrombosis, and that early therapeutic intervention is likely to be critical to allow normal placental development.
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New Insights into the Role of DNA Damage and Repair in Age-Related Changes of Hematopoietic Stem Cells
Michael Linenberger, MD
Dr. Linenberger indicated no relevant conflicts of interest.
Nijnik A, Woodbine L, Marchetti C, et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007;447:686-90.
Rossi DJ, Bryder D, Seita J, et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447:725-9.
Normal hematopoiesis and peripheral blood counts are maintained throughout life. However, observations in mice indicate that lymphopoiesis declines with age and hematopoietic stem cells (HSCs) undergo numerical and qualitative changes, including telomere shortening, accumulation of DNA double-strand breaks, increased frequencies of long-term reconstituting HSCs (LT-HSCs), and reduced ability to self-renew under the proliferative stress of multiple serial transplantations. To better understand the mechanisms responsible for these alterations, Nijnik et al. and Rossi et al. characterized HSC subpopulations from young and old mice with defects in DNA repair pathways. The mouse strain used by Nijnik et al. contains a hypomorphic mutation in DNA ligase IV (Lig4Y288C ), which specifically impairs non-homologous end-joining (NHEJ) repair of DNA double-strand breaks and recapitulates many features of the human DNA ligase IV syndrome. The Rossi group studied three genetically engineered strains of mice deficient in NHEJ repair (Ku80-/-), nucleotide excision repair (XPDTTD), or telomere maintenance (late-generation [G3] mTR-/-). With aging, the absolute numbers of LT-HSCs, short-term HSCs, and multipotent progenitors in Lig4Y288C mice decreased significantly, in contrast to the stable cell numbers maintained in older wild-type (WT) control animals. Marrow cell counts and erythroid cell percentages were also reduced in older compared with younger mutant mice. HSCs from Lig4Y288C mice competed poorly in co-transplantation models, and progenitor growth in cobblestone-area-forming cell cultures was greatly compromised. These changes were not due to defective Lig4Y288C marrow stromal cells or macrophages. Double-stranded DNA breaks were more frequent in progenitors from 18- week-old Lig4Y288C mice than in age-matched WT controls. Rossi et al. found that the numbers of LT-HSCs in older Ku80-/-, XPDTTD, and G3 mTR-/- mice were equivalent to WT controls. However, diminished frequencies of multipotent and oligopotent progenitor populations were observed in an age-independent pattern. Serial transplantation and competitive repopulation experiments revealed severe, age-dependent deficits in the self-renewal and proliferative capacities of LT-HSCs from each of these mouse strains; this was associated with increased apoptotic activity in cultured progenitors. Age-related increases in DNA damage were observed in normal mouse HSCs and early multipotent progenitors, with the greatest increases in the LT-HSC population, thus suggesting that the more primitive, quiescent stem cells are less efficient at repairing genomic damage and/or better able to tolerate unrepairable lesions.
These studies indicate that DNA repair mechanisms and telomere maintenance are important for preserving the functional integrity of LT-HSCs during the accumulation of genomic damage with normal aging and under the stress of proliferation and reconstitution. They complement previous observations that DNA damage response mediators, including p16INK4, p53, and ATM, also modulate autonomous HSC functions with aging and that age-dependent telomere shortening can reduce the supportive function of marrow micro-environmental stromal cells1. Since genes involved in myeloid and lymphoid leukemic transformation are upregulated in LT-HSCs from older mice2 and the greatest accumulation of age-related DNA damage occurs in LT-HSCs and primitive progenitors, it is possible that abnormalities in DNA repair pathways could predispose older stem cells to oncogenic mutations. Studies to define the roles of age-related DNA damage and repair in human HSCs are needed to determine whether these or similar mechanisms might be responsible, at least in part, for the significantly increased incidence of hematologic malignancies in elderly men and women.
References:
- Ju Z, Jiang H, Jaworski M, et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med. 2007;13:742-7.
- Rossi DJ, Bryder D, Zahn JM, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA. 2005;102:9194-9.
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How Sweet Is It?
Nelson Chao, MD
Dr. Chao indicated no relevant conflicts of interest.
Voltarelli JC, Couri CE, Stracieri AB, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007;297:1568-76.
Diabetes is the fifth leading cause of death by disease in the United States. Diabetes also contributes to higher rates of morbidity — people with diabetes are at higher risk for heart disease, blindness, kidney failure, extremity amputations, and other chronic conditions. Direct medical and indirect expenditures attributable to diabetes in 2002 were estimated at $132 billion. Attributable indirect expenditures resulting from lost workdays, restricted activity days, mortality, and permanent disability due to diabetes totaled $39.8 billion. When adjusting for differences in age, sex, and race/ethnicity between the population with and without diabetes, people with diabetes had medical expenditures that were ~2.4 times higher than expenditures that would be incurred by the same group in the absence of diabetes. Clearly, diabetes is a major health problem. There are two broad types of diabetes, type 1 and 2.
Type 1 diabetes mellitus (DM) is an autoimmune disease resulting from an immune mediated cellular attack on the pancreatic beta cells, which produce insulin. The beta cells are destroyed and thus insulin is no longer produced. At the time of clinical diagnosis, approximately 60 percent to 80 percent of the beta-cell mass has been destroyed. Therefore, preservation of the beta cells is an important target in the management of type 1 DM and in the prevention of its related complications.
The authors report in this manuscript the conduct of a study to examine the effect of high-dose immunosuppression followed by autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) to preserve beta-cell function in 15 patients with newly diagnosed type 1 DM. During a seven- to 36-month follow-up, 14 patients became insulin-free (one for 35 months, four for at least 21 months, seven for at least six months, and two with late response were insulin-free for one and five months, respectively). Among those, one patient resumed insulin use one year after AHST. The only severe adverse effects were pneumonia in one patient and endocrine dysfunction in two others. Ninety-three percent of patients achieved different periods of insulin independence, and treatment-related toxicity was low, with no mortality.
What happened here? There are extensive data demonstrating the success of utilizing allogeneic hematopoietic cell transplantation in animal models and data in humans that type 1 diabetes could be transferred to allogeneic recipients, as well as reversed in allogeneic recipients. This study, however, uses the patients’ own cells, and it is important to note that these cells were not selected, that is, no T-cell depletion of the graft (to remove the autoreactive T cells) as is being done for the national studies on scleroderma and lupus. Moreover, the patients were all young, without an excessive body mass index (BMI), and selected to be very early in the onset of their disease. They were all were intensively immune suppressed with anti-thymocyte globulin and a large dose of cyclophosphamide.
Will the hematopoietic cell transplant community be performing autologous rescue for diabetes? There are several caveats to the data presented. First and foremost is the known "honeymoon" period that many patients have in which patients have a relative remission after the onset of the disease. This period can be quite variable, and since there was not a control group in this study, this potential spontaneous remission significantly confounds the results. The follow-up of the whole group is short and thus it is not known if there will be a lasting response. The intensive immune suppression might be beneficial for the patients, but one would predict that returning autologous immune cells back to the patient with the stem cell graft would return the autoimmune cells as well, unless the preparatory regimen changed the presentation of autoimmune antigens. Finally, there is the possibility that there are "other cells" found in the marrow that could possibly repair the damaged pancreas. As the authors conclude, we will need a prospective randomized study to determine the utility of this approach.
This study is the first of what will be many different approaches of cellular therapy for diabetes and other autoimmune diseases. In addition to the use of hematopoietic cells, there is strong interest in regulatory T cells, umbilical cord cells, dendritic cells, mesenchymal cells, and embryonic cells, to name a few. Look for more on the field of cellular therapy and regenerative medicine.
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GVHD: Gene Profiling Comes of Age
Gérard Socié, MD, PhD
Dr. Socié indicated no relevant conflicts of interest.
Baron C, Somogyi R, Greller LD, et al. Prediction of graft-versus-host disease in humans by donor gene-expression profiling. PLoS Medicine. 2007;4:69-82.
Graft-versus-host disease (GVHD) continues to be the leading cause of non-relapse mortality following allogeneic stem cell transplantation (AHCT). Unfortunately, what determines who will develop GVHD after major histocompatibility complex (MHC)-matched AHCT, even from an HLA-identical sibling, is unpredictable. Although GVHD only develops if there are some mismatches in histocompatibility antigens between the donor and host, it does not inevitably develop. Until now, scientists have mainly investigated whether differences between AHCT recipients might explain this observation.
In this study, the researchers have examined the donors to see whether differences in their immune responses might make some donors stronger "responders" than others and consequently more likely to cause GVHD. They measured the gene-expression profiles of CD4 and CD8 T cells from 50 AHCT donors with micro arrays. They report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, they found that for chronic GVHD the "dangerous donor" trait (occurrence of GVHD in the recipient) is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-beta signaling and cell proliferation. These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient.
In micro array experiments, the donor-gene profile defined on day 0 showed exceedingly strong correlation with that of recipient CD4 and CD8 T cells harvested on day 365. For most genes tested by quantitative RT-PCR, differential gene expression between patients with chronic GVHD and those without was confirmed to be robust, on the basis of statistical tests and computational analysis of independent training-test datasets. From a pathway perspective, differential expression of TGF-beta-related transcripts was entirely consistent with increased TGF-beta signaling in T cells.
Can identification of strong versus weak responders be used to select AHCT donors? The predictive value of the best genes was about 80 percent. However, predictive models can be fine tuned for clinical decision-making to either optimize sensitivity or specificity. An increase in sensitivity usually comes at the expense of a decrease in specificity, and vice versa. Given that the avoidance of GVHD is usually paramount, one would expect that a bias toward the best achievable sensitivity, allowing for the most reliable selection of donors, would be clinically desirable. Other results in the article (as in others) also suggest that higher-order combinatorial searches beyond two genes could improve significantly the predictive performance of gene-expression profiling. However, higher-order predictive variable combinations do require the support of many more samples to prevent over-fitting of the model.
However, when considering the negative impact of such "dangerous donor" cells, it is critical to keep in mind that GVHD likely participates to a great extent in the generation of potent anti-tumor immune responses and that their elimination may also reduce the graft-versus-tumor effect associated with AHCT.
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Prostaglandins Play a Role in Maintenance and Expansion of Hematopoietic Stem Cells
Diane Krause, MD, PhD, and Louis M. Pelus, PhD
Drs. Krause and Pelus indicated no relevant conflicts of interest.
North TE, Goessling W, Walkley CR, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447:1007-11.
A chemical genetic screen for compounds affecting hematopoietic stem cell (HSC) survival/expansion has revealed that prostaglandin E2 promotes hematopoietic stem cell self renewal, and that inhibitors of PGE2, such as indomethacin, decrease functional HSC.
This study demonstrates the power of large-scale biologic screening to reveal new therapeutic approaches. The researchers screened more than 2,000 compounds including known U.S. Food and Drug Administration (FDA)-approved drugs. Zebrafish were used because they 1) are transparent, allowing visualization of developing blood cells; 2) mature quickly with blood cells visualized within 1.5 days of fertilization; and 3) can survive without blood, thus allowing compounds inhibiting HSC maintenance or differentiation to be assessed. The investigators previously showed that a line of flattened endothelial cells with a small cluster of hematopoietic cells can be visualized by probing for cells that co-express the zebrafish homologues of Runx1 (AML1) and cMyb. Zebrafish embryos were individually exposed to the compounds and HSC assessed by visualization of runx1+cmyb+ cells. Eighty compounds either increased or decreased HSC numbers, 10 of which were known to affect the prostaglandin pathway. On closer analysis, chemicals enhancing PGE2 synthesis increased HSC numbers, and those blocking prostaglandin synthesis decreased stem cell numbers. Data were confirmed by functional analyses of zebrafish HSC. Similar data were obtained for murine cells; PGE2 increased differentiation of murine embryonic stem cells to hematopoietic progenitors as assessed by colony-forming units and increased the frequency of functional HSC in competitive bone marrow transplant studies. Conversely, indomethacin and cox2 inhibitors decreased mouse hematopoietic stem and progenitor cells.
PGE2 and prostaglandin synthesis inhibitors have been known to affect hematopoiesis in human and mouse cells. Similar studies were reported previously; however, at that time, the data could not be completely interpreted to be affecting HSC because functional HSC assays were not yet well established. Addition of PGE to human bone marrow cells increased the number of CFU-GM and the proportion of cycling CFU-GM. It was proposed that PGE may have dual effects on hematopoiesis, limiting proliferation of CFU-GM at higher concentrations and promoting CFU-GM differentiation from earlier stem cells at low as well as high concentrations1. In other studies, PGE enhanced proliferation of BFU-E and CFU-GEMM2. In vivo administration of PGE2 in mice resulted in a decrease in CFU-GM, which, based on these new studies, could represent an effect on HSC self-renewal.
The data reported by North and colleagues are very important as they suggest that BM engraftment may be delayed by PGE2 inhibitors. Clinicians have routinely avoided prescribing NSAIDs or aspirin during engraftment or BM recovery due to the functional inhibition of already low numbers of platelets, and these new data suggest that specific cox2 inhibitors may need to be avoided as well. The data also suggest that stable forms of PGE2 or similar agents may enhance BM recovery following conventional-dose or high-dose chemotherapy. However, we need to take into consideration previous data showing that sustained administration of 16, 16 dimethyl PGE2 reduces restoration of hematopoiesis following cyclophosphamide administration3. Additional studies will be required before we know for certain how to utilize the prostaglandin pathway for therapeutic manipulation of hematopoiesis.
References:
- Pelus LM. Association between colony forming units-granulocyte macrophage expression of Ia-like (HLA-DR) antigen and control of granulocyte and macrophage production. A new role for prostaglandin E. J Clin Invest. 1982;70:568-78.
- Lu L, Pelus LM, Broxmeyer HE, et al. Enhancement of the proliferation of human marrow erythroid (BFU-E) progenitor cells by prostaglandin E requires the participation of OKT8-positive T lymphocytes and is associated with the density expression of major histocompatibility complex class II antigens on BFU-E. Blood. 1986;68:126-33.
- Gentile P, Byer D, Pelus LM. In vivo modulation of murine myelopoiesis following intravenous administration of prostaglandin E2. Blood. 1983;62:1100-7.
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Mantle Cell Lymphoma: Quantifying Prognosis
Michael Williams, MD
Dr. Williams serves on the Executive Committee of the Lymphoma Research Foundation Mantle Cell Lymphoma Consortium and on the European Mantle Cell Lymphoma Network Scientific Advisory Board.
Kienle D, Katzenberger T, Ott G, et al. Quantitative gene expression deregulation in mantle-cell lymphoma: correlation with clinical and biologic factors. J Clin Oncol. 2007;25:2770-7.
Mantle cell lymphoma (MCL) is clinically heterogeneous; some patients demonstrate an indolent course over several years, while others experience early progression and short survival. In order to better refine prognostic markers, Kienle and colleagues analyzed archival MCL samples obtained at the time of diagnosis by real-time quantitative reverse transcriptase PCR, targeting 20 genes previously associated with MCL pathogenesis and prognosis. Although lymph node (n=65) and peripheral blood (n=13) samples were similar for overall tumor cell content, differing gene expression profiles were noted between these compartments, and correlative analyses were restricted to the lymph node cohort. CCND1, the gene encoding the hallmark MCL cyclin D1 protein, was verified to produce either a short or long variant transcript based upon differences in length of the untranslated region. Those patients with the short form (n=9) had higher CCND1 expression levels, higher proliferative rates, and a median survival of only 8.4 months, versus 45.1 month median survival for patients with the long variant. Immunostaining with Ki-67, a marker of proliferation, also stratified patients into low- and high-risk groups. Those with more than 40 percent positive cells had a median survival of 17 months, versus 52.5 months for those with a lower percent positivity. Increased CCND1 expression levels and the short variant CCND1 correlated positively with Ki-67 index, whereas low expression of ataxia telangiectasia gene (ATM), retinoblastoma gene (RB1) and an antiapoptosis gene (MCL1), among others, had a negative correlation. In a multivariate analysis of clinical and molecular parameters with decreased patient survival, significant positive correlations were found for Ki-67 protein expression, the presence of B symptoms, and gene expression of MYC, MDM2, EZH, and CCND1.
MCL is among the most challenging subtypes of lymphoma, with no curative standard therapeutic approach yet identified. There is, however, reason for optimism that improved outcomes may be realized through novel agents now in clinical trials and by individualization of therapy based upon molecular and phenotypic biomarkers. The present report verifies and extends earlier correlative work that defined markers of proliferation and apoptosis and, as noted by the authors, implicates the relevance of "gene dosage" for proliferation — promoting genes, proliferation inhibitors, and regulators of apoptosis. Although complex to orchestrate within prospective clinical trials, biomarker and bioinformatic analyses hold considerable promise for individualization of treatment and improved outcomes. Close collaboration between clinical and laboratory scientists in the design and conduct of therapeutic trials, and in prioritizing clinical studies of novel targeted therapies, will be critical to this process.
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Is Transplantation for CML Dead?
Jerald Radich, MD
Dr. Radich indicated no relevant conflicts of interest.
Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood. 2007;109:4686-92.
 |
Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting
as first-line therapy in chronic myeloid leukemia. Blood.
2007;109:4686-92. Figure 3. |
Chronic myeloid leukemia (CML) is hardly a public health menace, yet it embodies the "bench to bedside" mantra that drives translational medicine. The discovery of the Philadelphia chromosome, the juxtaposition of the BCR and ABL genes to form the t(9;22), fostered understanding of aberrant signal transduction, targets for minimal residual disease monitoring by PCR, and ultimately "targeted" therapy by tyrosine kinase inhibitors (for example, imatinib). Prior to the advent of imatinib, biologic therapy with interferon was shown to lengthen the natural history of CML and was deemed to be appropriate therapy for patients without an allogeneic transplant option. Transplantation has been considered a "curative" therapy for CML, but not without the trade-off of considerable morbidity and mortality.
How to treat newly diagnosed chronic phase CML has changed dramatically with imatinib.
- Imatinib is remarkably effective for patients treated in chronic phase, as greater than 75 percent of patients obtain a complete cytogenetic remission (CCyR). In the IRIS trial, approximately 70 percent of cases remain in a CCyR at five years of follow-up1. Treatment of advanced phase (accelerated of blast disease) is associated with much poorer outcomes.
- Allogeneic transplantation is generally associated with 10-year survivals of 70 percent or better for patients in chronic phase, but survival likewise falls in accelerated or blast-phase disease2-4.
- Relapse occurs for chronic-phase patients treated with imatinib, but outcome can be effectively monitored by sensitive RT-PCR assays5-7.
Current recommendations from advisory panels, such as the European Leukemia Net and the National Cancer Care Alliance, state that all chronic phase patients start on imatinib therapy, but allow for consideration of transplantation based on the patient’s age, preference, and response to initial imatinib8,9. The tacit assumption is that, given the excellent results of both imatinib and transplantation, a contemporary randomized trial comparing the methods would be very unlikely.
Given this background, the paper by Helmann et al. bears consideration10. This trial looked at 621 patients with chronic phase CML; of these, 354 were considered eligible for transplantation and "biologically randomized" based on the availability of a related donor. Of the 123 patients who received a transplant, the 10-year estimate of survival was 53 percent. Those 219 patients without a related donor were treated with interferon until imatinib became available later in the trial. Imatinib was then offered to patients whose disease did not respond to interferon. The 10-year estimate of survival in this group was 52 percent. The survival curves of these two groups are shown in the figure above and show the not-surprising results: the transplant group suffers a higher early mortality, with a relative flattening of the survival curves, whereas group 2 has a better early outcome, with the survival curves continuing to drop. The cross-over of the curves comes at eight years. A statistical analysis showed that the survival rate of group 2 was significantly superior (though marginally, with a p=0.049). The authors conclude that transplantation can no longer be recommended as first-line therapy.
The undertaking of such a study is Herculean, but the conclusions deserve some scrutiny. First, the survival experience for group 2 was a blend of those who received interferon and (in some cases) imatinib, and those cases that went on to an unrelated transplant when a donor became available. The survival of those 122 patients in group 2 who only received interferon/imatinib was 50 percent; of the 97 patients who went on to receive an unrelated transplant, 69 percent survived. Moreover, it may be hard to translate this study to contemporary practice. Given the remarkable success of imatinib as first-line therapy, it would be expected that the survival curves for patients treated with imatinib up front would be superior to that of the interferon/imatinib group in this study. In addition, most transplant centers would be disappointed with the survival statistics in the transplant arm of this study of long-term outcomes (~50 percent).
Other studies have attempted to address the issue of up-front imatinib versus transplantation. One such study examined published survival data for patients who received a transplant and imatinib, modeling survival and life expectancy based on age, gender, and treatment strategies11. In most models, survival and life expectancy in the newly diagnosed chronic phase cases that initially received imatinib was superior compared with patients who initially received a transplant. The superiority of imatinib was greatest under the conditions of the low progression rate, older age, comparison to the CIBMTR transplant experience, and unrelated donor transplants. Transplantation appeared to be similar or somewhat superior to imatinib when one assumed better transplant outcomes, younger patient age, and higher imatinib relapse rates.
So, is transplantation for CML dead? Probably not. Given the ability to monitor imatinib response by sensitive PCR techniques and mutation analysis, and the suggestion that prior imatinib therapy does not compromise later transplant results12,13, it is reasonable to start most patients who have chronic-phase CML on imatinib, with consideration for transplant for those candidates with sub-optimal or lost response. Waiting for frank progression to advanced-stage disease to move to transplantation is a strategy that may reduce the potential for cure and should be reserved for patients at high risk for transplant-related complications, whether they are from age or other health complications.
References:
- Druker BJ, Guilhot F, O’Brien S, et al., on behalf of the IRIS (International Randomized IFN vs. STI571) Study Group. Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study. J Clin Oncol. 2006;24:6506.
- Goldman JM, Sobocinski KM, Zhang MJ, et al. Long-term outcome after allogeneic hematopoietic stem cell transplantation (HCT) for CML. Biol Blood Marrow Transplant. 2006;12:17.
- Radich JP, Gooley T, Bensinger W, et al. HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood. 2003;102:31–5.
- Gratwohl A, Brand R, Apperley J, et al. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data, and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2006;91:513–521.
- Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2:117–25.
- Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276–283.
- Hughes TP, Kaeda J, Branford S, et al. International Randomised Study of Interferon versus STI571 (IRIS) Study Group. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423–32.
- Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-20.
- O’Brien S, Berman E, Bhalla K, et al. Chronic myelogenous leukemia. J Natl Compr Canc Netw. 2007;5:474-96.
- Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood. 2007;109:4686-92.
- Simon W, Segel GB, Lichtman MA. Early allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era: A preliminary assessment. Blood Cells, Molecules and Diseases. 2006;37:116-24.
- Deininger M, Schleuning M, Greinix H, et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica. 2006;91:452–9.
- Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood. 2007;109:1782-9.
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