despite significant progress over the past several decades in understanding the biology of acute myeloid leukemia ( aml ) and despite important advances in treatment approaches , the majority of patients who develop acute myeloid leukemia will still die from their disease . a recent analysis by southwest oncology group investigators of data from 1344 patients with newly diagnosed aml enrolled into swog studies between 1986 and 2009 , excluding acute promyelocytic leukemia , illustrated this point dramatically . in that study , overall survival at 4 years was only 49% for patients with favorable cytogenetics ; overall survival was approximately 25% for those with intermediate - prognosis cytogenetics , and only 9% for those with unfavorable cytogenetics . among the most important advances made in recent decades in the treatment of aml was the recognition of the exquisite sensitivity of acute promyelocytic leukemia ( apl ) to differentiation therapy using all - trans - retinoic acid ( atra ) . this observation was , shortly thereafter , accompanied by the identification of the retinoic acid receptor alpha ( rara ) gene as a partner in the balanced translocation that drives apl . the dual recognition of a novel mechanism of disease  in the case of apl , overexpression of rara , a protein that participates in proliferation and differentiation of hematopoietic cells  along with the identification of a compound , atra , that is a derivative of a vitamin , has provided a powerful paradigm for cancer therapy . this parallels the dramatic progress that has been made in the past fifteen years in the use of rationally designed , small molecules that target specific intracellular signal transduction pathways in cancer , best exemplified by the development of imatinib , and followed by many new agents effective in a variety of solid tumors . the remarkable improvement in the rates of remission and survival for patients with apl has stimulated our laboratory , and many others to explore a similar approach for the treatment of non - apl subsets of aml , using vitamin d and analogs ( collectively referred to henceforth as vitamin d and deltanoidsvdd  ) . investigations have focused on either vdd alone , or in combination with other compounds , in an effort to induce differentiation of leukemia cells , and allow for less toxic chemotherapy , as is the case now in the treatment of patients with apl . the observation that vitamin d can induce acute myeloid leukemia blast cells in vitro to differentiate along the monocytic lineage was made approximately 30 years ago ; however , it remains to translate this observation into a clinically meaningful strategy . the barriers to translating this observation from the bench to the bedside include the induction of hypercalcemia vdd , as well as the need to identify which , if any , subset of patients with aml will be sensitive to vdd . the current understanding of the biologic basis for vdd effects in aml in vitro and ex vivo has recently been reviewed in detail . the following is a review of published clinical experience that has accumulated to date regarding the use of vdd either alone or in combination with cytotoxic agents , other differentiating agents , or both . in many of these reports , the investigators included patients with a diagnosis of myelodysplasia ( mds ) , as well as aml , in their treatment cohorts , and for this reason , the effects of vdd in mds patients are included in the discussion below . given the a priori expectation that there would be a low probability of a favorable clinical response to the use of single agent vitamin d or its derivatives to treat aml , it is readily understandable that there are few published reports of their use as single agents in such patients . however , in the late 1980 's investigators at kagawa medical school in japan reported a series of 3 patients treated using oral administration of from 4.5 up to 15  micrograms / day of 1 alpha ( oh ) vitamin d3 . two of these patients carried a diagnosis of aml , and the third patient had a diagnosis of the myelodysplastic syndrome refractory anemia with excess blasts . the authors reported a decrease in bone marrow blast percentage for each of the three patients , with transient hypercalcemia developing in one patient and resolving within three days of cessation of vitamin d3 . shortly thereafter , takahashi and colleagues   reported their experience using alfacalcidol in a cohort of 13 patients , of whom two patients had aml  one patient with apl , and one with fab - m4 histology by report . patients received single - agent alfacalcidol at doses that ranged from 0.25  microgram / day up to 10  microgram / day orally , for at least one month of therapy ; drug was administered only intermittently in order to avoid hypercalcemia . the authors reported that the patient with aml fab - m4 had a minor response , utilizing response criteria developed by koeffler ; the patient with apl did not respond . of note , among the patients with a diagnosis of mds , nakayama reported a single case of aml responding favorably to treatment using 1 alpha(oh)d3 in a brief communication . in this report , the patient was an 81-year - old man with pancytopenia on presentation , whose initial marrow exam reportedly showed 20% myeloblasts . he was treated using 1 alpha ( oh ) vitamin d3 at a dose of 6  micrograms daily by mouth as single - agent therapy . he achieved a normalization of blood counts by 4 weeks of therapy , with normalization of marrow morphology . the response was lost after the dose of 1 alpha ( oh ) vitamin d3 was tapered , and reescalation of the dose failed to achieve a second response . these appear to be the only reports published to date of single agent vdd used as therapy for aml . there are at least six reports in the literature of single agent vdd treatment of patients with a diagnosis of myelodysplastic syndrome . in 1985 , koeffler , a leading investigator in this field , and colleagues administered 2  microgram / day of 1,25(oh)2d3 to 18 patients with myelodysplastic syndrome in an attempt to improve their hematopoiesis . they reported that during therapy , peak peripheral blood granulocyte , platelet , and macrophage concentrations were slightly elevated as compared to baseline levels . eight patients had a partial or minor peripheral blood response during the administration of 1,25(oh)2d3 . however , no patient showed significant improvement of peripheral blood cell or marrow blast cell counts by the end of the study ( greater than or equal to 12 weeks ) as compared to their starting levels . nine of the 18 patients developed hypercalcemia . in this paper , ex vivo treatment of dysplastic myeloid cells did demonstrate differentiation in response to 1,25(oh)2d3 . in the 1989 report of takahashi and colleagues from japan discussed earlier , in addition to treating two patients with aml using alfacalcidol at doses ranging from 0.25  microgram / day up to 10  microgram / day orally for at least one month , there were 11 patients with various subtypes of myelodysplastic syndromes in the fab classification schema . of these , three patients showed partial responses , 2 patients showed minor responses and remainder of the patients did not respond . the hematological improvement of 6 responders was transient , reported by the authors to range from 1 to 2 months ; however , one patient with low - risk mds demonstrated an improvement in blood counts that persisted for more than 1 year ( , op cit ) . in 1991 , motomura and colleagues published a clinical trial in a series of 30 patients with myelodysplasia . in 15 patients , 46  micrograms / day of 1-hydroxyvitamin d3 was administered , for a median duration of 17 months ; a control group had no therapy . leukemia - free survival of the d3-treated group was reported to be statistically superior to the control group ; 7 patients in the control group developed acute leukemia , in contrast to only one in the d3 treated group . in 1998 , mellibovsky and colleagues   described their experience in treating a series of 19 patients with low - to - intermediate grade mds , as determined by the bournemouth criteria , using single agent vdd . the first five patients in this study received 266  microgram calcifediol three times per week ; the remaining twelve patients received calcitriol , in doses ranging from 0.25  microgram / day increasing up to a maximum of 0.75  microgram / day by mouth , provided that plasma calcium concentrations remained in the normal range . of the total of nineteen patients , patients were categorized by the fab classification scheme ; seven had refractory anaemia with ringed sideroblasts , five had refractory anaemia , one had refractory anaemia with excess of blasts , and six had chronic myelomonocytic leukemia . responders were defined as having experienced either a granulocyte or platelet count increase by 50% , hemoglobin increase of 1.5  g / dl , or transfusion needs decreased by 50% . treated group , one case responded , three were nonresponders , and one showed progression of disease . one responder was maintained on calcifediol for two years , stopped at his own request , and experienced a fall in hemoglobin , which then improved after resuming calcifediol . in the calcitriol group , 10 were responders ( two with major response ) , and four were nonresponders . no correlation was observed between baseline levels of vitamin d metabolites and the presence of response . these authors concluded that treatment with vdd could induce long - standing responses in blood counts in some low - intermediate risk mds patients without inducing hypercalcemia . in 1993 , yoshida and colleagues published a multicenter randomized clinical trial of alfacalcidol ( 1 alpha hydroxyvitamin d3 ) meant to evaluate the therapeutic effect of alfacalcidol in patients with mds . twenty - three evaluable patients were randomized to receive either a single daily oral dose of 6  micrograms of alfacalcidol , or supportive care as a control . response was assessed by weekly blood counts , clinical course , and repeated marrow examinations . three of the 13 patients in the alfacalcidol group and two of the 10 patients in the control group experienced progression of disease . one patient with refractory anemia showed a favorable response to alfacalcidol in all three hematopoietic cell lineages ; the response , however , was not maintained , and discontinuation of the drug resulted in a worsening of pancytopenia which was refractory to a second course of alfacalcidol therapy . these authors concluded that single - agent alfacalcidol therapy does not yield a significant clinical beneficial in patients with mds . most recently , juckett and colleagues at the university of wisconsin published a phase ii clinical trial of single agent doxercalciferol , a vitamin d2 analogue , in 15 patients with mds . nine of 15 patients completed the prescribed course , and of these six had stable disease . no patient had a favorable clinical response based upon international working group criteria , and eight patients experienced progressive disease while on therapy . of interest , however , two patients with chronic myelomonocytic leukemia ( cmml ) had a marked rise in monocytes documented while on study , and one patient experienced hypercalcemia . these authors concluded that a twelve - week course of therapy using single - agent doxercalciferol has very limited activity in patients with mds . several groups have reported the clinical use of vdd in combination with other agents intended to force differentiation of pathologic myeloid progenitor cells , in a few series without the inclusion of classical cytotoxic antineoplastic agents . most commonly , a vdd has been combined with a retinoid , with or without , a third agent or even a fourth agent . in 1991 , blazsek and colleagues in france reported their experience in treating two patients ; one patient had apl in relapse and responded to single - agent all - trans - retinoic acid ( a relatively new observation as of that writing ) . however , the second patient that they described in that report carried a diagnosis of mds , and experienced a sustained hematologic response to treatment using the combination of prednisone with 1 alpha,25-dihydroxyvitamin d3 ( 1 alpha,25d3 ) as well as 13-cis - retinoic acid . in this paper , 1 alpha,25d3 was administered at a dose of 0.25  micrograms by mouth three times per day for 30 days , in combination with prednisone 40  mg per day for the first 15 days and cis - retinoic acid 20  mg by mouth daily for 30 days . this patient continued the vitamin d for an 8-month period and the retinoic acid for a total of two and one - half years , apparently with a sustained response .   in 2007 , the finnish leukemia group reported the results of a phase ii clinical trial of the combination of valproic acid together with 13-cis - retinoic acid and 1,25-dihydroxyvitamin d3 in the treatment of mds , including several cases chronic myelomonocytic leukemia and several cases of refractory anemia with excess blasts-2 ( raeb-2 ) . valproic acid , an antiseizure medication , has pleotropic effects , including inhibition of the p - glycoprotein ; however , it was chosen in this instance because of the observation that valproic acid can inhibit histone deacetylase activity . oral valproic acid was titrated to achieve serum concentrations between 500 and 700  micromolar , and 13-cis - retinoic acid was administered at a dose of 10  mg by mouth twice daily . the vdd used in this study was etalpha at a dose of 13  microgram by mouth daily . there were no episodes of hypercalcemia observed , although the majority of patients experienced the hypertriglyceridemia associated with the use of 13-cis - retinoic acid . three of the nineteen patients experienced some hematologic improvement  a rise in hemoglobin and neutrophil count in one patient with chronic myelomonocytic leukemia , an improvement in platelet count in one patient with raeb-2 , and an improvement in hemoglobin level in one patient with refractory cytopenias with multilineage dysplasia . a number of groups have attempted to combine vitamin d or its analogs with low - dose conventional antineoplastic chemotherapy in an effort to improve blood counts in patients with either aml , mds , or both . most commonly , cytarabine has been used in combination with a vdd , sometimes with additional agents added to the regimen . in 1988 , hellstrm and colleagues in sweden reported a series of 62 evaluable patients with either mds or aml who were treated with various combinations of lowdose cytarabine , alpha - interferon ( ifn ) , 1 alpha - hydroxyvitamin d3 ( vit d3 ) , and retinoic acid . the cytarabine was dosed initially at 15  mg / meter squared body surface area subcutaneously daily , and the interferon was administered initially at 3 million units subcutaneously daily . the 1 alpha - hydroxyvitamin d3 was dosed at 1  microgram per day by mouth in two divided doses , escalated until mild hypercalcemia was noted , with the dose then adjusted to maintain a serum calcium below 2.90 millimoles / liter . of these , 50% responded favorably to the combination of ifn , vitamin d3 , and retinoic acid , a combination that they termed idr . this was felt by the authors to be comparable to the response rate of 43% for low - dose cytarabine alone . the same group then performed a prospective , randomized phase iii clinical trial , in which 63 evaluable patients with myelodysplastic syndromes and 15 with acute myeloid leukemia were randomized between low - dose cytarabine ( arm a ) as a single agent , and low - dose cytarabine in combination with 13-cis - retinoic acid ( 13-cra ) and 1 alpha - hydroxy - vitamin d3 ( 1 alpha d3 ) ( arm b ) . the doses of these agents were the same as used in their prior report described above ( , op cit ) . the authors stated that 69 patients were evaluable and of these 18 ( 26.1% ) responded to therapy . the addition of 13-cra and 1 alpha d3 had no significant favorable influence on neither survival of the patients , remission rates , nor duration of remissions . 12/27 patients ( 44% ) in arm a and 6/29 patients ( 20% ) in arm b progressed from mds to aml during the course of the study ( p = 0.0527 ) . the authors concluded that a clear cut therapeutic effect of the addition of 13-cra and 1 alpha d3 to cytarabine on mds was not supported by this study . however , they also stated their interpretation that an inhibitory effect on aml development  that is , progression from mds to aml  in some mds subgroups could not be excluded by their data . de rosa and colleagues in italy reported , in 1992 , their experience treating forty - four patients with high - risk primary myelodysplastic syndromes . this cohort was treated with a combination of low - dose cytarabine , retinoic acid , and vitamin d3 . morphological subtypes , using the fab classification schema , were refractory anemia with excess of blasts ( raeb ) in 16 , raeb in transformation ( raeb - t ) in 20 , and chronic myelomonocytic leukemia ( cmml ) in eight patients . in this series , cytarabine was administered at a dose of 10  mg per meter squared body surface area twice daily for 15 consecutive days . the 13-cis - retinoic acid was given at a dose of 20  mg per meter squared body surface area for 21 days by mouth , and vitamin d3 was given at 0.75  microgram per day in three divided doses of 0.25  microgram per oral dose , also for 21 days . the results were compared to those of a matched control group of 44 patients given supportive care only . in the treated group the overall response rate was 50% ( 75% in raeb , 50% in raeb - t , and 0% in cmml ) and the survival was significantly better in the control group ( p < 0.025 ) . comparing separately each fab subgroup suggested that the treatment prolonged the survival in the raeb - t subgroup ( p < 0.002 ) , but not the other two groups . the median duration of response was 15 months and the survival in responders was statistically better than in nonresponders ( p < 0.0001 ) . myelosuppression was the most important side effect ; however , no deaths related to treatment were noted . these authors concluded that this approach was useful for treatment of patients with high - risk myelodysplasia . several years later , ferrero and colleagues from italy described their results in treating 53 mds patients with a combination of cis - retinoic acid ( cra , 20 to 40  mg / day ) and 1,25 alpha ( oh)2 cholecalciferol [ ( oh)2d3 , 11.5  micrograms / day ] with or without intermittent 6-thioguanine ( 30  mg / m / day ) . the 6-thioguanine was administered only to patients with bone marrow blast counts greater than or equal to 5% . the authors reported that treatment was well tolerated , without major toxicity . among 25 patients with bone marrow blasts less than 5% , they observed one complete response , eight partial responses , and four minor responses ( overall response rate 52% ) with a median response duration of 8 months ( 2  24 ) . median survival , which did not correlate with response , was projected by the authors , as of the time of publication , to be 76 months overall . thirty - one patients with bm blast excess ( > or = 5% ) , including three of the previous group who progressed to refractory anemia with excess of blasts ( raeb ) , were treated with the three - drug protocol . one complete , 12-partial , and six minor responses were obtained ( response rate 61% ) with a median response duration of 6 months ( 229 + ) . 0.005 ) was observed between the 19 responders ( median 25 months ) and the 12 nonresponders ( median 9 months ) . a reduction in the transfusion need was observed in 41% of the transfusion - dependent patients with blast excess and in 53% of those without blast excess . therefore , these authors did conclude that combined differentiating therapy seems more effective than single - agent treatments . the same group subsequently reported their experience treating 26 patients with a diagnosis of aml , as well as 4 patients with mds ineligible for standard chemotherapy . the regimen used was a combination of 13-cis - retinoic acid at 20 to 40  mg by mouth daily , together with dihydroxy - vitamin d3 ( rocaltrol ) 1  microgram by mouth daily , along with 6-thioguanine 40  mg by mouth daily , and cytarabine 8  mg per meter squared body surface area twice weekly by subcutaneous injection . the median age of this group of patients was 72.5 years , and they had been deemed ineligible for standard chemotherapy . the median survival of the whole group and responders was 7.5 ( 147 + ) and 16.5 months ( 3.547 + ) , respectively . in a somewhat similar approach , slapek and colleagues at tufts university medical center published their experience in treating a series of twenty - nine patients , ranging from 62 to 82 years of age , all with a diagnosis of aml , treated using a 21-day course of continuous infusion cytarabine at 20  mg per meter squared body surface area per day , together with 1,25-dihydroxyvitamin d3 ( calcitriol ) at a dose of 0.25  microgram by mouth twice daily . the calcitriol was continued until progression of disease or until the patient went off study . hydrea was also given daily by mouth at a dose of 500  mg , started one day prior to the initiation of the cytarabine infusion , and continued for 21 days as well . thirteen patients ( 45% ) obtained a complete remission , and 10 patients ( 34% ) had a partial response for an overall 79% response rate . overall median survival was 12 months for all patients and 14 months for responding patients . these authors concluded that this regimen had acceptable toxicity and can result in prolonged remissions in elderly , high - risk patients with aml . building upon work described above , ferrero and colleagues in europe recently reported on the use of recombinant human erythropoietin in combination with the previously investigated regimen of 13-cis - retinoic acid and dihydroxy - vitamin d3 in the management of anemia in mds patients . they treated 63 mds patients ( excluding refractory anaemia with excess blasts , type 2 ( raeb2 ) ) with the combination of 13-cis - retinoic acid and dihydroxy - vitamin d3 with , or without , the further addition of 6-thioguanine . most patients were categorized as refractory cytopenia with multilineage dysplasia and raeb1 , in the who classification scheme , with intermediate 1 international prognostic scoring system ( ipss ) score . all patients had , at baseline , a hemoglobin of < 9.5  gm / dl , and 70% required regular erythrocyte transfusions prior to beginning this therapy . the treatment dosing schedule included 13-cis - retinoic acid at 20  mg / day by mouth , and 1,25 di(oh ) vitamin d3 at 1  microgram / day by mouth . eleven of the 16 raeb1 patients also received intermittent , low - dose 6-thioguanine ( 40  mg / d for 21 days every 5 weeks ) . rhuepo ( alpha epoetin in the majority , beta epoetin in a minority of patients ) was added at different dosages and schedules according to practices of the different participating institutions and different time periods of treatment . until 2002 , 10,000 unit formulations only were available , and patients received weekly doses ranging from 10,000 units subcutaneously three times weekly up to 10,000 units subcutaneously daily . from 2002 onwards , 40,000 unit formulations of alpha erythropoietin became available , and dosages ranged from 40,000 units / week to 40,000  u every 3 to 4 days . median weekly dose overall was 60,000 units per week ( range : 30,00080,000 units / week ) . all patients were treated for at least 6 months , and in the case of response , until disease progression or death . the treatment started within 12 months from diagnosis in 52 patients and between 15 and 48 months ( median : 21 ) from diagnosis in 11 patients was well tolerated , and erythroid response rate according to new international working group criteria   was 60%:50% in raeb1 and 64% in non - raeb patients . the weekly recombinant human erythropoietin dose administered ranged from 30,000 units per week to as much as 80,000 units per week . median response duration was 16 months , and median survival reached 14 months for raeb1 and 55 months for non - raeb patients , with a significant difference in the latter between responders and nonresponders ( median 82 months versus 44 months ; p = 0.036 ) . no patient experienced clinically significant hypercalcemia .   in a recent novel approach , akiyama and colleagues in japan recently reported the results of a phase ii trial of the combination of either vitamin k monotherapy , or vitamin k in combination with 1-alpha hydroxy - vitamin d3 for the treatment of patients with either low or intermediate-1 risks mds . . the overall response rate to vitamin k monotherapy ( 45  mg / day ) after 16 weeks was 13% ( 5/38 ) including 4 cases with improvement of both anemia and thrombocytopenia and improvement in 1 case with thrombocytopenia . they then enrolled and evaluated 20 out of 33 vitamin k - monotherapy nonresponders for vitamin k plus vitamin d3 ( 0.75  microg / day ) combination therapy . the overall response rate at 16 weeks after initiation of vitamin k plus vitamin d3 was 30% ( 6/20 ) . hematologic improvement for hemoglobin ( hb ) was observed in 6 out of 11 patients ( 55% ) and hematologic improvement for thrombocytopenia in 3 out of 11 patients ( 27% ) , respectively . no hematologic improvement was observed for neutropenia in vitamin k monotherapy , nor in response to vitamin k plus vitamin d3 combination therapy . there was a suggestion in the data that international prognostic scoring system for mds scores and absolute neutrophil counts positively correlated with favorable response , and hemoglobin levels inversely correlated with the response to vitamin k plus vitamin d3 combination therapy . these authors concluded that vitamin k plus vitamin d3 combination therapy appears to be a promising treatment approach for improving anemia and thrombocytopenia in mds patients with low / intermediate-1 mds . a summation of the numbers of patients treated in the reports cited above documents that more than 85 patients with a diagnosis of aml , and a total of more than 350 patients with a diagnosis of mds , have been treated using a vitamin d derivative either alone , or in combination with additional agents  as is evident from table 1 . among this population , response rates have been highly variable , and this may be attributed to several factors . aml is a heterogeneous disease , with dramatic differences in the biologic subtypes , both with respect to the mutational events that drive the disease , as well as the prognosis of the disease based upon cytogenetics , molecular features , and the treatment paradigm employed . at one end of the spectrum , aml with core binding factor mutations generally have a very favorable prognosis when treated using high - dose cytarabine as a part of therapy ; at the other end of the spectrum , aml with mll-1 gene mutations generally have an abysmal prognosis in the absence of allogeneic hematopoietic transplantation . many of the reports reviewed herein were published prior to the recognition in the late 1990 's of the core - binding factor mutations and their prognostic and treatment implications ; this is similarly so for the impact of the mll-1 gene , to identify just two of many important observations regarding aml . the heterogeneity of mds is even greater with respect to biologic features , disease natural history , and prognosis , as compared to aml . how the biologic heterogeneity of these diseases impacts upon the clinical responsiveness of an individual patient has not been investigated to date , but it is very likely that adverse molecular events play a role in the relative unresponsiveness of some patients disease to vitamin d therapy . it is clear that some patients described in the clinical treatment reports above have benefited from vitamin d , or vitamin d analog therapy ; however , dissecting the specific features that could predict responsiveness is difficult based on the relatively limited biologic data provided in the reports above . a priori , one might expect that patients with lower - grade ( low ipss score ) mds would be more likely to benefit from vitamin d therapy than patients with higher risk mds ; however , in the report of de rosa and colleagues ( , op cit ) , that was not the case , and patients with raeb - t appeared more likely to benefit from vitamin d therapy , when compared to historical controls . however , this has not been formally tested to date in a prospective , randomized clinical trial with fully matched controls . the only prospective , randomized clinical trial summarized above was a small study , not powered to detect a modest impact of vitamin d , and randomized patients between low - dose cytarabine ( arm a ) as a single agent , and low - dose cytarabine in combination with 13-cis - retinoic acid ( 13-cra ) and 1 alpha - hydroxy - vitamin d3 ( , op cit ) . consequently , the effects , if any , of the vitamin d agent would have been obscured by the use of 13-cra even if the numbers of patients had been larger . a further issue in determining the efficacy of a vdd in the treatment of aml and mds is the heterogeneity in the vitamin d agent chosen , which has varied from one report to another , as well as the dose and dosing schedule variations . the heterogeneity in the choice of vitamin d agent and the dosing schedule makes aggregating the data from the disparate trials extremely difficult . in order to glean more meaningful insight into the potential role for vdd in the treatment of aml and mds , an optimal vdd , as well as an optimal dosing regimen , will ideally need to be defined in formal phase i and phase ii studies , and then subjected to testing in a large , randomized phase iii clinical trial . in vitro , concentrations of vitamin d that induce differentiation are typically in the range of 1 nanomolar 1,25(oh)2 vitamin d3 ; however , conventional vdd administered in a dose that would achieve such a blood level carries a significant risk of inducing clinically significant hypercalcemia . noncalcemic vdd agents have been developed , but to date have not been tested in patients with mds or aml . there is extensive preclinical data establishing the ability of vitamin d and its analogs to induce immature myeloid hematopoietic cells to terminally differentiate into mature monocytic cells , at which point these cells are no longer able to proliferate . however , in the 19 reports summarized in this paper , only a minority of patients experienced either a transient or a persistent improvement in blood counts in response to vdd - based therapy . the observation that a meaningful number of patients did experience some degree of objective , favorable response demonstrates the potential for clinical use of vdd as differentiation therapy in the management of mds and aml . however , substantial progress remains to be made before this approach can be included in the formal armamentarium of treatments for mds and aml .
despite progress in understanding the biology of acute myeloid leukemia ( aml ) , and despite advances in treatment , the majority of patients with aml die from the disease . 
 the observation that vitamin d can induce aml blast cells in vitro to differentiate along the monocytic lineage was made 30 years ago ; however , it remains to translate this into a clinically meaningful strategy . 
 this is a review of published clinical experience regarding the use of vitamin d and its analogs , either alone or in combination with other agents , to treat aml . in many of these reports , investigators included patients with myelodysplasia ( mds ) as well as aml patients in their treatment cohorts ; therefore reports of vitamin d and its analogs in treating mds are included . this review documents heterogeneity in selection criteria for patients treated in these studies , the spectrum of vitamin d analogs used in various studies , and the differing dosing strategies employed by investigators . despite examples of occasional clinical efficacy , barriers remain to the successful application of vitamin d in the treatment of mds and aml . 
 these include the lack of definition of a particularly sensitive target population , and the as yet unknown optimal choice of vitamin d analog and dosing schedule .