Publications by authors named "Mahran Shoukier"

12 Publications

  • Page 1 of 1

Are Pivotal Clinical Trials for Drugs Approved for Leukemias and Multiple Myeloma Representative of the Population at Risk?

J Clin Oncol 2022 Aug 9:JCO2200504. Epub 2022 Aug 9.

Georgia Cancer Center at Augusta University, Augusta, GA.

Purpose: There are significant disparities in care and outcomes for patients with leukemias and multiple myeloma (MM). To evaluate the extent to which clinical trials (CTs) match the demographic and geographic diversity of populations affected by leukemias and MM.

Methods: CTs leading to drug approval were identified from the US Food and Drug Administration databases. Demographic and geographic data were collected from ClinicalTrials.gov and primary manuscripts. Standard descriptive statistics were used to summarize the data in frequencies and proportions, including 95% CIs, by race, ethnicity, sex, and malignancy subtypes.

Results: A total of 41 (67.2%) trials leading to drug approval reported data on race and 20 (48.8%) on ethnicity. These trials included 13,731 patients, of whom 11,209 (81.6%) were White. Among minorities, Asian-Pacific Islanders and Blacks had the highest representation in chronic myeloid leukemia, 147 (12.7%) and 61 (5.3%), and lowest in chronic lymphocytic leukemia, 55 (3%) and 20 (1.1%), respectively. Proportions for Blacks, Native Americans, and Hispanics were significantly low, reflecting under-representation in trials compared with the proportion in the general population. Females were also under-represented in acute myeloid leukemia (44.7% 60.5%, < .0001), and males in MM (55.3% 60.2%, < .0001) and chronic myeloid leukemia (55.2% 62.9%, < .0001). The geographic distribution of trials showed inadequate regional and state participation compared with mortality for all malignancies except MM.

Conclusion: There are significant demographic and geographic under-representation and imbalances in pivotal CTs leading to drug approvals for leukemias and MM compared with the population affected. These disparities need to be addressed to make results applicable to all relevant populations.
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http://dx.doi.org/10.1200/JCO.22.00504DOI Listing
August 2022

Activity of decitabine as maintenance therapy in core binding factor acute myeloid leukemia.

Am J Hematol 2022 05 22;97(5):574-582. Epub 2022 Feb 22.

Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Posttherapy measurable residual disease (MRD) positivity in core binding factor acute myeloid leukemia (CBF-AML) is associated with shorter relapse-free survival (RFS). Elimination of MRD measured via quantitative reverse transcription polymerase chain reaction (qRTPCR) for disease specific transcripts can potentially lead to better outcomes in CBF-AML.

Methods: We prospectively monitored the MRD using qRTPCR and flow cytometry on bone marrow samples in patients with newly diagnosed CBF-AML who received decitabine (DAC) maintenance therapy after fludarabine/cytarabine/G-CSF (FLAG)-based induction/consolidation regimen. Negative qRTPCR (CMR) was defined as fusion transcript <0.01%.

Results: Thirty-one patients with CBF-AML including 14 with t(8;21) and 17 with inv(16) received parenteral DAC as maintenance therapy. Fifteen patients (48.3%) had completed FLAG-based induction/consolidation but with positive MRD (0.35%, range = 0.01%-0.91%) (Group 1). Sixteen patients (51.7%) could not complete recommended consolidations with FLAG-based regimen (due to older age or complications) and were switched to DAC maintenance (Group 2). In Group 2, eight patients (50%) had undetectable MRD (Group 2A) (all had qRTPCR ≤ 0.01%) and the other eight patients (50%) had residual fusion product by qRTPCR (0.1%, range = 0.02%-0.36%) (Group 2B) prior to starting DAC. Amongst the 23 patients who had a PCR ≥ 0.01% before maintenance therapy (Groups 1 and 2B), 12 patients (52%) attained a CMR as their best response (responders). The median pre-DAC qRTPCR amongst responders were 0.03% compared to 0.14% in nonresponders (p = .002). The median estimated molecular RFS amongst responders were 93.9 months. At a median follow-up of 59.3 months (13.2-106 months) from DAC initiation, 16 patients (51.6%) had to be initiated on a second line of therapy (40%, 25%, and 100% patients, respectively, in Groups1, 2A, and 2B). The median estimated time to new treatment between responders was 112.4 versus 5.8 months in nonresponders (hazard ratio = 0.16, 95% confidence interval = 0.04-0.54); however, there were no difference in overall survival between these groups (p = .37).

Conclusion: DAC is an effective maintenance therapy for CBF-AML patients with persistent fusion transcript at a low level after FLAG-based regimen. Attainment of CMR with DAC maintenance can lead to long-term remission in patients who have persistent MRD positive after FLAG-based regimen or are unable to receive the full course of consolidation therapy.
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http://dx.doi.org/10.1002/ajh.26496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303262PMC
May 2022

Sudden Blast Crisis After Excellent Initial Response in Chronic Myeloid Leukemia.

Cureus 2021 Sep 28;13(9):e18368. Epub 2021 Sep 28.

Department of Hematology and Oncology, Georgia Cancer Center at Augusta University, Augusta, USA.

Sudden blast crisis is an uncommon phenomenon in chronic myeloid leukemia (CML) patients who are being treated with tyrosine kinase inhibitors (TKIs). Despite well-defined guidelines to treat and monitor the disease, it is difficult to predict the occurrence of a sudden blast crisis. Research directed towards improving guidelines in choosing the appropriate TKIs and better monitoring protocols could help prevent such unfortunate outcomes. We present a case of a 46-year-old man diagnosed with CML who responded well to imatinib as evidenced by a downtrend in quantitative BCR-ABL mutation to less than 1. He quickly transformed into a blast crisis phase after five months of therapy with imatinib regardless of achieving an excellent initial optimal response. In conclusion, it is possible to transform into a blast phase despite achieving an initial optimal response. Therefore, attention should be focused on the selection of proper tyrosine kinase inhibitors and careful monitoring to allow the early detection of sudden blast crisis.
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http://dx.doi.org/10.7759/cureus.18368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555935PMC
September 2021

Outcomes in patients with newly diagnosed TP53-mutated acute myeloid leukemia with or without venetoclax-based therapy.

Cancer 2021 10 28;127(19):3541-3551. Epub 2021 Jun 28.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53 ) over standard therapy is undefined.

Methods: In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53 AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN-based (n = 58) and non-VEN-based (n = 180) regimens.

Results: Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens. Compared with patients who received non-VEN-based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse-free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN-based regimens, regardless of age or intensity of treatment.

Conclusions: The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53 AML. These data highlight the need for novel therapies beyond VEN to improve the outcome of patients with TP53 AML.
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http://dx.doi.org/10.1002/cncr.33675DOI Listing
October 2021

Review of New-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.

Curr Oncol Rep 2021 06 14;23(8):91. Epub 2021 Jun 14.

Georgia Cancer Center, Augusta University, 1410 Laney Walker Rd., CN2222, Augusta, GA, 30912, USA.

Purpose Of Review: In this review, we analyzed the available data from clinical trials with new tyrosine kinase inhibitors (TKIs) under development and how to consider chronic myeloid leukemia (CML) patients who had either resistance or intolerance to current TKIs for treatment with such agents.

Recent Findings: Nearly 50% of CML patients treated with TKIs frontline have required a change of therapy by 10 years. Second-line therapy is effective (by achievement of complete cytogenetic response) in only approximately 50% of patients, and available third-generation TKI has been marred by concerns of arterio-occlusive events. These facts highlight the need for additional treatment options. New TKIs have shown promising efficacy and tolerance in CML patients with resistance or intolerance to multiple available TKIs. Additional studies will determine their role in the management of CML.
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http://dx.doi.org/10.1007/s11912-021-01087-xDOI Listing
June 2021

Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation.

J Immunother Cancer 2021 02;9(2)

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: Immune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.

Methods: A retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.

Results: Four patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2-4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).

Conclusions: ICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.
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http://dx.doi.org/10.1136/jitc-2020-001818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919586PMC
February 2021

Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors.

Arthritis Rheumatol 2021 05 1;73(5):866-874. Epub 2021 Apr 1.

University of Texas MD Anderson Cancer Center, Houston.

Objective: To estimate the incidence of immune checkpoint inhibitor-related myositis (ICI-myositis) in cancer patients receiving ICIs, and to report associated clinical manifestations, patterns of care, and outcomes.

Methods: We identified a retrospective cohort of patients receiving ICIs between 2016 and 2019 seen at the University of Texas MD Anderson Cancer Center. Cases of ICI-myositis were identified using International Classification of Disease codes and confirmed by reviewing medical records and pathology, as available.

Results: A total of 9,088 patients received an ICI. Thirty-six patients (0.40%) were identified as having ICI-myositis: 17 patients (47%) with ICI-myositis alone and 19 (53%) with overlap manifestations (5 patients with myocarditis, 5 with myasthenia gravis, and 9 with both). The incidence of ICI-myositis was 0.31% in those receiving ICI monotherapy and 0.94% in those receiving combination ICI therapy (relative risk 3.1 [95% confidence interval 1.5-6.1]). Twenty-five patients (69%) received ≥1 treatment in addition to glucocorticoids: plasmapheresis in 17 patients (47%), intravenous immunoglobulin in 12 (33%), and biologics in 11 (31%). Patients with overlap conditions had worse outcomes than those with myositis alone, and 79% of them developed respiratory failure. Eight patients died as a result of ICI-myositis, and all had overlap syndrome with myasthenia gravis or myocarditis (P < 0.05); 75% of these patients had a concomitant infection.

Conclusion: ICI-myositis is a rare but severe adverse event. More than half of the patients presented with overlap manifestations and had deleterious outcomes, including respiratory failure and death. None of the patients with ICI-myositis alone died as a result of adverse events. Optimal treatment strategies have yet to be determined.
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http://dx.doi.org/10.1002/art.41604DOI Listing
May 2021

Clinical characteristics and outcomes in patients with acute myeloid leukemia with concurrent FLT3-ITD and IDH mutations.

Cancer 2021 02 29;127(3):381-390. Epub 2020 Oct 29.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Isocitrate dehydrogenase (IDH1 and IDH2) mutations commonly co-occur with FMS-like tyrosine kinase 3 (FLT3) mutations in patients with acute myeloid leukemia (AML).

Methods: The authors reviewed cases of patients with FLT3-internal tandem duplication (FLT3-ITD)-mutated AML with concurrent IDH mutations diagnosed between January 2011 and December 2018.

Results: A total of 91 patients with FLT3-ITD and IDH1 or IDH2 "double-mutated" AML were identified; 36 patients had concurrent FLT3-ITD/IDH1 mutations (18 in the frontline and 18 in the recurrent and/or refractory [R/R] setting) and 55 patients had concurrent FLT3-ITD/IDH2 mutations (37 in the frontline and 18 in the R/R setting). FLT3 and/or IDH inhibitors (FLT3Is and/or IDHIs) were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low-intensity therapy (LIT). Rates of complete remission (CR) plus CR with incomplete count recovery (CRi) with the use of CCT and FLT3Is were 100% and 64%, respectively, in patients in the frontline and R/R settings. CCT with IDHIs was given in 2 frontline patients and both achieved a CR. LIT with FLT3Is in the frontline and R/R settings demonstrated CR and CRi rates of 67% and 28%, respectively. Single-agent FLT3Is and IDHIs demonstrated limited activity with a CR and/or CRi rate of 14% in patients with disease in the R/R setting.

Conclusions: The combination of FLT3I-based therapy with CCT or LIT appeared to be effective in both the frontline and R/R settings among patients with FLT3-ITD/IDH co-mutated disease. Fewer patients with double-mutated disease received CCT or LIT with IDH1/2 inhibitor in the frontline setting; however, high response rates also were noted with this approach.

Lay Summary: The prognostic influence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and isocitrate dehydrogenase (IDH) co-mutation status on outcomes in patients with acute myeloid leukemia receiving an FLT3 inhibitor, non-FLT3/IDH inhibitor-based regimens, or an IDH inhibitor is unclear. This is an important clinical question because multiple targeted therapies for FLT3 and IDH1/2 mutations have become available. The results of the current study demonstrated that a combination of a FLT3 inhibitor with cytotoxic chemotherapy or low-intensity therapy appears to be an effective approach in patients with FLT3-ITD/IDH co-mutated disease in both the frontline and recurrent and/or refractory settings. Fewer dual-mutated patients received cytotoxic chemotherapy or low-intensity therapy with an IDH1/2 inhibitor in the frontline setting; however, excellent responses also were observed with this approach.
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http://dx.doi.org/10.1002/cncr.33293DOI Listing
February 2021

The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis.

Haematologica 2021 11 1;106(11):2853-2858. Epub 2021 Nov 1.

Georgia Cancer Center at Augusta University (research performed while at MD Anderson Cancer Center).

Approximately 20-50% patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs) or with myelofibrosis (MF) treated with ruxolitinib develop grade ≥3 thrombocytopenia needing treatment interruptions and dose reductions. We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia while on TKI or ruxolitinib. Eltrombopag was initiated at 50 mg/day, with dose escalation up to 300 mg daily allowed every 2 weeks. Twenty-one patients were enrolled (CML=15, MF=6); median age 60 years (range, 31-97 years). The median platelet count was 44x109/L (range, 3-49x109/L) in CML and 62x109/L (range, 21-75x109/L) in MF. After a median of 18 months (range, 5-77 months), 12/15 patients with CML achieved complete platelet response. The median peak platelet count among responders was 154x109/L (range, 74-893x109/L). Among CML patients 5 could re-escalate the TKI dose and 9 improved their response. None of the 6 patients with MF had a sustained response. Therapy was generally well tolerated. One patient discontinued therapy due to toxicity (elevated transaminases). One patient with CML developed significant thrombocytosis (>1000x109/L). Another CML patient developed non occlusive deep venous thrombosis in the right upper extremity without thrombocytosis, and one MF patient had myocardial infarction. Eltrombopag may help improve platelet counts in CML patients receiving TKI with recurrent thrombocytopenia. Further studies are warranted.
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http://dx.doi.org/10.3324/haematol.2020.260125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561288PMC
November 2021

The clinical impact of time to response in de novo accelerated-phase chronic myeloid leukemia.

Am J Hematol 2020 Jun 17. Epub 2020 Jun 17.

Georgia Cancer Center, Augusta, Georgia, USA.

We aimed to describe the impact of time to response on the outcomes of 75 patients with accelerated-phase chronic myeloid leukemia (CML-AP) at diagnosis. Patients had at least 1 feature of AP: blasts ≥15% (n = 2), basophils ≥20% (n = 19), platelets <100 × 10 /L (n = 7), cytogenetic clonal evolution (n = 34), or more than one factor (n = 13). Thirty-three patients received imatinib; 42 received a second-generation tyrosine kinase inhibitor (2GTKI) (19 dasatinib and 23 nilotinib). We used chi-square and Kaplan-Meier analyses to determine the impact of various degrees of molecular and cytogenetic response at early time points (3 and 6 months) on rates of overall cytogenetic and molecular response, overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS). After a median follow-up of 96 months (range: 18-224 months), the overall rate of complete cytogenetic response was 79%, of major molecular response, 71%, and of molecular reponse (MR)4.5, 59%. Patients who achieved a major cytogenetic response (MCyR) (n = 49) at 3 months had significantly better 3-year OS (94% vs 75%; P = .002), TFS (98% vs 73%; P < .001), EFS (93% vs 42%; P < .001), and FFS (83% vs 25%; P < .001) rates than patients who did not have MCyR at 3 months. Most (67%) who eventually achieved sustained MR4.5 had achieved MCyR at 3 months. In de novo CML-AP, early response at 3 and 6 months is a strong determinant of long-term outcome.
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http://dx.doi.org/10.1002/ajh.25907DOI Listing
June 2020

Major Stressful Life Events and Risk of Developing Lung Cancer: A Case-Control Study.

Clin Med Insights Oncol 2019 1;13:1179554919835798. Epub 2019 May 1.

Division of Oncology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Lung cancer is the leading cause of cancer-related mortality and is strongly linked with smoking. We sought to determine whether major stressful life events (e.g. divorce) are also a risk factor for developing lung cancers.

Methods: We performed a matched case-control study. Cases (CA) were lung cancer patients diagnosed within the previous 12 months. Controls (CO) were patients without a prior history of malignancy. Data on major stressful life events were collected using the modified Holmes-Rahe stress scale. The primary endpoint was the odds of having a major stressful life event between CA and CO. A sample of 360 patients (CA = 120, CO = 240) was needed to achieve 80% power to detect an odds ratio (OR) of 2.00 versus the alternative of equal odds using  = 0.05.

Results: Between May 2015 and December 2016, we enrolled 301 patients (CA = 102, CO = 199), matched for median age (CA = 64.4 years, CO = 63.9 years), sex (CA-Male = 48%, CO-Male = 49.2%), and smoking status (ever smoker, CA = 84%, CO = 85%). There was no difference in lifetime stressful life event rate between CA and CO (95% vs 93.9%;  = .68). However, CA were significantly more likely to have had a stressful event within the preceding 5 years than CO (CA = 77.4% vs CO = 65.8%;  = .03, OR = 1.78). β-blocker use was significantly higher among CO (CA = 29.4%, CO = 49.7%;  = .0007, OR = 0.42), suggesting a protective effect.

Conclusion: Patients with lung cancer are significantly more likely to have had a major stressful life event within the preceding 5 years. In addition, use of β-blockers may be protective against lung cancer.
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http://dx.doi.org/10.1177/1179554919835798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495441PMC
May 2019

Azacitidine in fludarabine-refractory chronic lymphocytic leukemia: a phase II study.

Clin Lymphoma Myeloma Leuk 2013 Jun 21;13(3):292-5. Epub 2012 Dec 21.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Background: Treatment of fludarabine-refractory disease in patients with chronic lymphocytic leukemia (CLL) remains a challenge. Because a recent genome-wide methylation analysis of CLL cells suggested that demethylation therapy might be beneficial in CLL, we conducted a phase II trial with the hypomethylating agent azacitidine in patients with recurrent fludarabine-refractory CLL.

Patients And Methods: Nine patients with recurrent fludarabine-refractory Rai stage IV CLL (median age, 74 years; range, 49-81 years) were enrolled. Azacitidine (75 mg/m(2)) was administered by subcutaneous injection daily for 7 consecutive days every 3 to 8 weeks, and the data were analyzed at a median follow-up of 9 months (range 3-47 months).

Results: The trial was prematurely discontinued because of lack of response and slow accrual. The number of cycles administered ranged from 1 to 6. Three patients received 1 cycle, 3 patients received 2 cycles, and the remaining 3 patients received 4, 5, or 6 cycles. Side effects included grade 2 or 3 infectious episodes (resulting from immunosuppression and drug-induced neutropenia), diarrhea, rash, vomiting, anemia, and thrombocytopenia. One patient experienced reduction of hepatosplenomegaly and a substantial increase in platelet count after 4 cycles of therapy. However this response did not qualify as a partial response according to the National Cancer Institute International Workshop on CLL (NCI-IWCLL) criteria. At a median follow-up of 9 months after the start of azacitidine treatment, 3 patients (33%) who went on to receive other treatments were alive.

Conclusions: Although no partial or complete responses occurred in these heavily pretreated patients, the encouraging response in 1 of these patients may warrant further studies to investigate the effects of azacitidine in CLL.
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http://dx.doi.org/10.1016/j.clml.2012.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860181PMC
June 2013
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