CORRESPONDENCE be three million with iron deficiency and RLS, making iron deficiency anemia with RLS an overlooked public health issue which needs to be addressed.
The role of intravenous iron for the treatment of restless legs syndrome To the Editor: This is the 5th article in a series of short articles concerning iron deficiency and the role of intravenous (IV) iron. As the author of this series, for this article on the role of IV iron in restless legs syndrome (RLS), I will take a short license to describe our own experience. RLS, also known as Willis-Ekbom disease, is associated with largely nocturnal, rest-induced, distressing urges to move the legs [1]. Insomnia, interference with partner comfort and cramps are common, resulting in decreased quality of life. Four years ago, two key opinion leaders in sleep medicine specializing in RLS, approached me with the query of infusing a total dose infusion of low molecular weight iron dextran in iron replete, but not overloaded, patients with RLS. Our observed initial clinical benefit was transformative, with an observed immediate clinical benefit of significant magnitude. It is, therefore, not surprising that the role of IV iron as primary therapy for RLS has become a major clinical research interest. Subsequently, in 2013 we began screening anemia referrals with, in addition to standard blood work, a 13-item sleep-vitality questionnaire and the 13-item Cambridge Hopkins RLS diagnostic questionnaire [2]. These scales evaluate tiredness, weakness and energy levels. The remaining items evaluate aspects of sleep. Over a one year period, 343 new patients were screened with 252 meeting inclusion criteria. The results were enlightening, revealing a four to five fold increment, or 35% incidence of RLS in the iron deficient population. Treatment of RLS is suboptimal. Medications such as pregabalin and pramepexole are widely used but associated with significant fatigue. Subsequently, a far more felicitous and seamless, single infusion of IV iron may provide significant therapeutic advantage. This contention is supported by an observational study reporting that the significant majority of RLS sufferers have moderate to severe disease [3]. RLS is associated with reduced brain iron making the total dose infusion of IV iron appealing. Oral iron, in addition to near ubiquitous dietary perturbation has limited benefit [4]. In those with RLS without iron deficiency, iron absorption across the intestinal epithelium into the blood is limited. Two controlled studies using equivalent doses given in a total dose infusion (1,000 mg) but administered as multiple small boluses of iron sucrose revealed marginal and no benefit, respectively [5,6]. The role of total dose infusion is considered controversial. Published evidence reported extraordinary response rates but unacceptable toxicity. Ondo administered 1,000 mg of high molecular weight iron dextran, now no longer available, over 4–5 hr and observed a very high response rate. Unfortunately a 10% incidence of serious adverse events, blunted the enthusiasm for this therapy [7] High molecular weight iron dextran is known to be associated with a marked increase in observed serious adverse events, but now that it is removed from market, the relevancy is moot. In our series of 1,266 infusions of low molecular weight iron dextran in 888 patients, administered as 1,000 mg in 1 hr, no serious adverse events were observed [8]. Of note, 162/888 patients were gravidas in the second or third trimester. Using the clinical paradigm of 1,000 mg of low molecular weight iron dextran in patients with iron deficiency and documented RLS, we observed a 50% complete remission, usually within the first 24–48 hr, with an additional 4% reporting marked improvement and another 16% significant improvement [2]. This was supported by a Korean study reporting IV low molecular weight iron dextran resulted in a significant improvement of RLS symptoms in a majority of patients without any clinical significant adverse events [9]. We are about to begin the first prospective, randomized, double-blind, placebo controlled study comparing oral iron to IV iron in RLS. If the results of this study corroborate previous observations, the infusion of large doses of IV iron in a single setting will offer a considerable improvement over other forms of therapy for RLS. This conclusion will be especially poignant with the approval of three new IV iron formulations which promise to offer complete replacement dosing in 15 min or less. Considering that iron deficiency anemia is estimated to occur in 5% of American adults and 20% of child-bearing aged women [10], in the United States alone there may
MICHAEL AUERBACH* Clinical Professor of Medicine, Georgetown University School of Medicine Conflict of interest: Nothing to report *Correspondence to: Michael Auerbach; Auerbach Hematology and Oncology, 9110 Philadelphia Rd Suite 314, Baltimore, MD 21237. E-mail: [email protected] Received for publication: 30 July 2014; Accepted: 31 July 2014 Published online: 2 August 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.23820
䊏 References 1. Allen R, Chen C, Garcia-Borreguero, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014;370:621–631. 2. Allen R, Auerbach S, Bahrain H, et al. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013;88:261–264. 3. Allen R, Walters A, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–1292. 4. Wang J, O’Reilly B, Venkataraman, et al. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med 2009;10:973–975. 5. Grote L, Leissner L, Hedner J, et al. A randomized double-blind, placebo controlled, multicenter study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 2009;24:1445–1452. 6. Earley C. The importance of oral iron therapy in restless legs syndrome. Sleep Med 2009;10: 945–946. 7. Ondo W. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 2010;11:494–496. 8. Auerbach M, Pappadakis J, Bahrain H, et al. Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia. Am J Hematol 2011;86:860–862. 9. Cho Y, Allen R, Earley C. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med 2013;14:274–277. 10. Control CD. Iron Deficiency—United States, 1999–2000. MMWR 2002;51:897–891.
BCR-ABL1 kinase domain mutational analysis of CD341 stem/ progenitor cells in newly diagnosed CML patients by next-generation sequencing To the Editor: Mutations in the BCR-ABL1 kinase domain (KD) represent one of the most important causes of resistance to tyrosine kinase inhibitors (TKIs) treatment in patients with chronic myeloid leukemia (CML). The resistance-causing mutations are hypothesized to expand directly from the stem and/or progenitor cells and are present in CD341 cells significantly earlier than they occur in bone marrow or peripheral blood. Thus, early detection of these mutations is of great importance, since it can affect the subsequent TKI therapy. We here report on a study performed to analyze the frequency and the spectrum of clinically relevant mutations in the stem cell/progenitor compartment represented by the CD341 cell population at the time of CML diagnosis, using a next-generation sequencing (NGS) mutation screening platform. Sorted CD341 cells obtained from bone marrow at the time of diagnosis of 50 de novo CML patients (median age 58 years; range: 26–92 years) were analyzed for the presence of BCR-ABL1 KD mutations. All samples were investigated using amplicon deep-sequencing during nine runs on a GS Junior Roche instrument. The sequencing steps and ABL1 reference alignment (GenBank accession number X16416.1) were performed with a variant frequency calculation as developed in the framework of the IRON-II (Interlaboratory Robustness of Next-generation sequencing) consortium. The lower detection limit of molecular variants was set at 2.0%.
TABLE I. Detected Mutations in CD341 Samples from de novo TKI-Naive CML Patients
Case
Sokal/Hasford score (H/I/L)
Type of first line TKI
Date of diagnosis
Mutation status CD34 1 cells before treatment
1 2 3
H/L H/H AP
IMA IMA IMA
4/17/2012 5/18/2011 1/4/2012
mutated mutated mutated
4
I/H
IMA
11/8/2011
mutated
Deep-sequencing result (mutation load) S446P (3.0%), F497V (12.0%) E255K (82.7%), E255V (1.3 %), T315I (3.5%) V339A (12.1%), G227S (3.1%), G303E (7.0%), Y312C (2.9%) E255D (6.4%)
TKI failure
TKI failure date
no yes yes
8/19/2011 2/22/2012
no
Abbreviations: H, high; I, intermediate; L, low; AP, accelerated phase; IMA, imatinib. C 2014 Wiley Periodicals, Inc. V
1016
American Journal of Hematology, Vol. 89, No. 10, October 2014
doi:10.1002/ajh.23820
The role of intravenous iron for the treatment of restless legs syndrome To the Editor: This is the 5th article in a series of short articles concerning iron deficiency and the role of intravenous (IV) iron. As the author of this series, for this article on the role of IV iron in restless legs syndrome (RLS), I will take a short license to describe our own experience. RLS, also known as Willis-Ekbom disease, is associated with largely nocturnal, rest-induced, distressing urges to move the legs [1]. Insomnia, interference with partner comfort and cramps are common, resulting in decreased quality of life. Four years ago, two key opinion leaders in sleep medicine specializing in RLS, approached me with the query of infusing a total dose infusion of low molecular weight iron dextran in iron replete, but not overloaded, patients with RLS. Our observed initial clinical benefit was transformative, with an observed immediate clinical benefit of significant magnitude. It is, therefore, not surprising that the role of IV iron as primary therapy for RLS has become a major clinical research interest. Subsequently, in 2013 we began screening anemia referrals with, in addition to standard blood work, a 13-item sleep-vitality questionnaire and the 13-item Cambridge Hopkins RLS diagnostic questionnaire [2]. These scales evaluate tiredness, weakness and energy levels. The remaining items evaluate aspects of sleep. Over a one year period, 343 new patients were screened with 252 meeting inclusion criteria. The results were enlightening, revealing a four to five fold increment, or 35% incidence of RLS in the iron deficient population. Treatment of RLS is suboptimal. Medications such as pregabalin and pramepexole are widely used but associated with significant fatigue. Subsequently, a far more felicitous and seamless, single infusion of IV iron may provide significant therapeutic advantage. This contention is supported by an observational study reporting that the significant majority of RLS sufferers have moderate to severe disease [3]. RLS is associated with reduced brain iron making the total dose infusion of IV iron appealing. Oral iron, in addition to near ubiquitous dietary perturbation has limited benefit [4]. In those with RLS without iron deficiency, iron absorption across the intestinal epithelium into the blood is limited. Two controlled studies using equivalent doses given in a total dose infusion (1,000 mg) but administered as multiple small boluses of iron sucrose revealed marginal and no benefit, respectively [5,6]. The role of total dose infusion is considered controversial. Published evidence reported extraordinary response rates but unacceptable toxicity. Ondo administered 1,000 mg of high molecular weight iron dextran, now no longer available, over 4–5 hr and observed a very high response rate. Unfortunately a 10% incidence of serious adverse events, blunted the enthusiasm for this therapy [7] High molecular weight iron dextran is known to be associated with a marked increase in observed serious adverse events, but now that it is removed from market, the relevancy is moot. In our series of 1,266 infusions of low molecular weight iron dextran in 888 patients, administered as 1,000 mg in 1 hr, no serious adverse events were observed [8]. Of note, 162/888 patients were gravidas in the second or third trimester. Using the clinical paradigm of 1,000 mg of low molecular weight iron dextran in patients with iron deficiency and documented RLS, we observed a 50% complete remission, usually within the first 24–48 hr, with an additional 4% reporting marked improvement and another 16% significant improvement [2]. This was supported by a Korean study reporting IV low molecular weight iron dextran resulted in a significant improvement of RLS symptoms in a majority of patients without any clinical significant adverse events [9]. We are about to begin the first prospective, randomized, double-blind, placebo controlled study comparing oral iron to IV iron in RLS. If the results of this study corroborate previous observations, the infusion of large doses of IV iron in a single setting will offer a considerable improvement over other forms of therapy for RLS. This conclusion will be especially poignant with the approval of three new IV iron formulations which promise to offer complete replacement dosing in 15 min or less. Considering that iron deficiency anemia is estimated to occur in 5% of American adults and 20% of child-bearing aged women [10], in the United States alone there may
MICHAEL AUERBACH* Clinical Professor of Medicine, Georgetown University School of Medicine Conflict of interest: Nothing to report *Correspondence to: Michael Auerbach; Auerbach Hematology and Oncology, 9110 Philadelphia Rd Suite 314, Baltimore, MD 21237. E-mail: [email protected] Received for publication: 30 July 2014; Accepted: 31 July 2014 Published online: 2 August 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.23820
䊏 References 1. Allen R, Chen C, Garcia-Borreguero, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014;370:621–631. 2. Allen R, Auerbach S, Bahrain H, et al. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013;88:261–264. 3. Allen R, Walters A, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–1292. 4. Wang J, O’Reilly B, Venkataraman, et al. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med 2009;10:973–975. 5. Grote L, Leissner L, Hedner J, et al. A randomized double-blind, placebo controlled, multicenter study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 2009;24:1445–1452. 6. Earley C. The importance of oral iron therapy in restless legs syndrome. Sleep Med 2009;10: 945–946. 7. Ondo W. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 2010;11:494–496. 8. Auerbach M, Pappadakis J, Bahrain H, et al. Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia. Am J Hematol 2011;86:860–862. 9. Cho Y, Allen R, Earley C. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med 2013;14:274–277. 10. Control CD. Iron Deficiency—United States, 1999–2000. MMWR 2002;51:897–891.
BCR-ABL1 kinase domain mutational analysis of CD341 stem/ progenitor cells in newly diagnosed CML patients by next-generation sequencing To the Editor: Mutations in the BCR-ABL1 kinase domain (KD) represent one of the most important causes of resistance to tyrosine kinase inhibitors (TKIs) treatment in patients with chronic myeloid leukemia (CML). The resistance-causing mutations are hypothesized to expand directly from the stem and/or progenitor cells and are present in CD341 cells significantly earlier than they occur in bone marrow or peripheral blood. Thus, early detection of these mutations is of great importance, since it can affect the subsequent TKI therapy. We here report on a study performed to analyze the frequency and the spectrum of clinically relevant mutations in the stem cell/progenitor compartment represented by the CD341 cell population at the time of CML diagnosis, using a next-generation sequencing (NGS) mutation screening platform. Sorted CD341 cells obtained from bone marrow at the time of diagnosis of 50 de novo CML patients (median age 58 years; range: 26–92 years) were analyzed for the presence of BCR-ABL1 KD mutations. All samples were investigated using amplicon deep-sequencing during nine runs on a GS Junior Roche instrument. The sequencing steps and ABL1 reference alignment (GenBank accession number X16416.1) were performed with a variant frequency calculation as developed in the framework of the IRON-II (Interlaboratory Robustness of Next-generation sequencing) consortium. The lower detection limit of molecular variants was set at 2.0%.
TABLE I. Detected Mutations in CD341 Samples from de novo TKI-Naive CML Patients
Case
Sokal/Hasford score (H/I/L)
Type of first line TKI
Date of diagnosis
Mutation status CD34 1 cells before treatment
1 2 3
H/L H/H AP
IMA IMA IMA
4/17/2012 5/18/2011 1/4/2012
mutated mutated mutated
4
I/H
IMA
11/8/2011
mutated
Deep-sequencing result (mutation load) S446P (3.0%), F497V (12.0%) E255K (82.7%), E255V (1.3 %), T315I (3.5%) V339A (12.1%), G227S (3.1%), G303E (7.0%), Y312C (2.9%) E255D (6.4%)
TKI failure
TKI failure date
no yes yes
8/19/2011 2/22/2012
no
Abbreviations: H, high; I, intermediate; L, low; AP, accelerated phase; IMA, imatinib. C 2014 Wiley Periodicals, Inc. V
1016
American Journal of Hematology, Vol. 89, No. 10, October 2014
doi:10.1002/ajh.23820
