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Keywords:

  • thalidomide;
  • arsenic trioxide;
  • dexamethasone;
  • and ascorbic acid;
  • myelodysplastic/myeloproliferative neoplasms;
  • primary myelofibrosis;
  • myelofibrosis;
  • trial

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND.

Primary myelofibrosis (PMF) and overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal hematopoietic disorders that share similar clinical features and molecular abnormalities, such as the Janus kinase 2 (JAK2) valine to phenylalanine mutation at codon 617 (V617F) and the tet methylcytosine dioxygenase 2 (TET2) mutation. There are limited therapeutic options available for these diseases, and single agents have only modest efficacy. In this phase 2 study, the authors combined multiple active agents (thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid [TADA]) to treat patients with these disorders.

METHODS.

This multicenter trial was conducted from January 2005 to July 2007. The primary endpoint was to evaluate the efficacy of TADA therapy. Patients received the combination for one 12-week cycle followed by maintenance thalidomide for an additional 3 months. Response was assessed using International Working Group criteria.

RESULTS.

Among 28 enrolled patients, the median age was 66.5 years; 15 patients had MDS/MPN-unclassifiable, 8 patients had chronic myelomonocytic leukemia type 1, and 5 patients had PMF. Approximately 60% of the patients had normal cytogenetics. The JAK2V617F mutation was detected in 5 of 14 tested patients, and TET2 mutations were detected in 2 of 8 tested patients. Almost half of the patients had splenomegaly. With a median on-study follow-up of 5.7 months, 21 patients (75%) completed the entire 12-week course of therapy, and 6 patients (29%) responded to TADA. With a median extended follow-up of 24.1 months for 15 evaluable patients, the median progression-free survival was 14.4 months, and the median overall survival was 21.4 months.

CONCLUSIONS.

The TADA regimen yielded clinical responses in patients with PMF and MDS/MPN. To the authors' knowledge, this study represents the first trial targeting this patient population. The results indicated that it is reasonable to incorporate multiple novel agents in the treatment of these rare diseases. Cancer 2012. © 2011 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Primary myelofibrosis (PMF) and overlap myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are clonal disorders of hematopoietic stem cell origin associated with a variable clinical course. On the basis of the 2008 World Health Organization (WHO) classification of myeloid and lymphoid neoplasms, MDS/MPN encompasses chronic myelomonocytic leukemia (CMML)-1 and CMML-2; atypical chronic myeloid leukemia, breakpoint cluster region—v-abl Abelson murine leukemia viral oncogene homolog 1 (BCR/ABL1)-negative (atypical chronic myeloid leukemia [aCML]); juvenile myelomonocytic leukemia (JMML); and MDS/MPN-unclassifiable (MDS/MPN-u), which includes refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) as a provisional entity.1 These overlap syndromes have pathobiologic and clinical evidence of both MDS and MPN, characterized by bone marrow hypercellularity, various myeloid lineage dysplastic and proliferative features, ineffective hematopoiesis, and frequent association with hepatosplenomegaly.

PMF is a myeloproliferative neoplasm that often presents with upfront bone marrow fibrosis, dysplastic megakaryocytes, extramedullary hematopoiesis, and elevated leukocyte and platelet counts. Patients with PMF and overlap MDS/MPN frequently develop progressive cytopenias and may evolve into acute myeloid leukemia. The development of cytopenia, particularly anemia, is recognized as an adverse prognostic feature in several prognostic scoring systems of PMF (Lille, Mayo, Dynamic International Prognostic Scoring System [DIPSS], and DIPSS-Plus classifications) and CMML (M. D. Anderson classification).2-5 Multiple new molecular abnormalities that play an important role in the pathogenesis of myeloproliferative and myelodysplastic disorders have been identified within the past decade, including the Janus kinase 2 (JAK2) valine to phenylalanine mutation at codon 617 (V617F) mutation, which is identified in 40% to 65% patients with of PMF and in 26% to 60% of patients with MDS/MPN.6-10 The tet methylcytosine dioxygenase 2 (TET2) mutation is the second most prevalent molecular abnormality, seen in 17% of PMF cases and 22%-58% of MDS/MPN.9, 11-13 Additional molecular abnormalities known to be associated with MPN and MDS/MPN include myeloproliferative virus oncogene (MPL), additional sex combs like 1 (ASXL1), isocitrate dehydrogenase 1 and 2 (IDH1/IDH2), Cas-Br-M (murine) ecotropic retroviral transforming sequence (CBL), enhancer of zeste homolog 2 (EZH2), lymphocyte-specific adapter protein Lnk (LNK), and IKAROS family zinc finger 1 (IKZF1).9, 13-19

Despite advances in understanding the underlying genetic alterations in PMF and MDS/MPN, patients with these diseases continue to face limited treatment options, and no current clinical trials specifically target patients with overlap MDS/MPN. Allogeneic stem cell transplantation is the only potential curative modality, yet most patients are not suitable candidates. Alternatives are used either to treat symptoms or to attempt to treat the disease, largely by cross-applying therapeutic principles from MDS therapies: response rates, however, usually are <20% to 25% and are of short duration.20-39 Thalidomide and its successor lenalidomide are antiangiogenesis agents with cytokine-modulating activity that have been used in combination with steroids in PMF patients and produce response rates from 40% to 50%.23, 24 Arsenic trioxide (ATO), which works through apoptotic and prodifferentiating mechanisms, inhibits the production of vascular endothelial growth factor40, 41 and has been used as a single agent and in combination with gemtuzumab ozogamicin in patients with MDS, producing response rates from 20% to 30%.38

For the current study, we investigated the efficacy of 4-agent combination therapy with thalidomide, ATO, dexamethasone, and ascorbic acid (AA) (TADA) in patients with PMF and overlap MDS/MPN. This combination was chosen to target mechanisms of disease development for both MDS and MPN, because it is believed that patients with overlap MDS/MPN have disease characteristics of both disorders. AA depletes intracellular glutathione, thereby enhancing the activity of ATO.42-44

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patients and Setting

Patients aged ≥18 years who had a diagnosis of MDS/MPN or PMF, an Eastern Cooperative Oncology Group performance status of 0 to 2, and no previous thalidomide or ATO therapy were enrolled from January 2005 to July 2007. Before patients were enrolled, all diagnoses of MDS/MPN (including MDS/MPD-u and CMML-1 and CMML-2) and PMF were confirmed by bone marrow analysis at 1 of the 3 participating institutions (Cleveland Clinic, University Hospitals in Cleveland, or University of Massachusetts) based on 2001 WHO pathologic classification.45 Negative BCR/ABL testing was required for study enrollment in patients with a diagnosis of MPN. On the basis of the 2002 M. D. Andersen prognostic scoring system for CMML, our study patients with CMML (n = 8) were distributed in the following risk categories: low risk, 5 patients; intermediate-1 risk, 2 patients; and intermediate-2 risk, 1 patient.5 In addition, the prognostic grouping of PMF patients (n = 5) was as follows: based on the Lille classification, there were 2 low-risk patients, 2 intermediate-risk patients, and 1 high-risk patient; based on the Mayo classification, there were 2 low-risk patients, 1 intermediate-risk patient, and 2 high-risk patients; and, based on the DIPSS classification, there was 1 low-risk patient, 2 intermediate-1-risk patients, and 2 intermediate-2-risk patients.4 Patients had to have a life expectancy of at least 3 months, a platelet count >10,000/mm3, and normal organ function.

All patients who participated in this study provided written informed consent. In addition, the majority of patients treated at Cleveland Clinic provided consent for blood and bone marrow aspirate draw for correlative molecular analyses. This study was registered with ClinicalTrials.gov as National Clinical Trial NCT00274820.

Study Design

This was a single-arm, open-label, multicenter, phase 2 study and was approved by the institutional review of boards at the study centers where patients were enrolled. Enrollment occurred from January, 2005 through July, 2007. The primary endpoint of the study was to evaluate response to the TADA combination, as defined below. Secondary endpoints included safety and disease transformation.

Patients received oral thalidomide 50 mg daily for 2 weeks, then 100 mg daily, ATO based on the phase 2 European Union MDS regimen31 (0.25 mg/kg intravenously on days 1-5 of week 1 then twice weekly during weeks 2-12), oral dexamethasone 4 mg daily for 5 days every 4 weeks, and oral AA 1000 mg 2 to 3 hours before each ATO infusion over a 12-week cycle. (Fig. 1) Thalidomide maintenance was continued for an additional 3 months in responding patients as tolerated. Patients received no growth factors during the study. Study protocol required bone marrow evaluation and spleen size assessment at baseline and after week 12 to assess for treatment response. To monitor for ATO cardiac toxicity, a 12-lead electrocardiogram was obtained at baseline and weekly thereafter to assess QTc interval. The serum potassium level was kept ≥4.0 mEq/dL, and the magnesium level was kept at >1.8 mg/dL with electrolyte supplementation as needed at the time of each electrocardiogram screening. Laboratory evaluations and study visits occurred weekly for the first 4 weeks then every 4 weeks thereafter for each cycle. Adverse events were assessed using National Cancer Institute Common Terminology Criteria version 3.0. If grade 2 or 3 treatment-related adverse events occurred, then the next dose of the drug was delayed for up to 4 weeks until symptom improvement. Adverse events that persisted for >4 weeks resulted in patient withdrawal from study, as did disease progression. Patients were followed for at least 4 weeks after discontinuation of the study drugs or study completion.

thumbnail image

Figure 1. The thalidomide (Thal), arsenic trioxide (ATO), dexamethasone (Dex), and ascorbic acid (AA) regimen (TADA) is illustrated.

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Statistics and Efficacy Assessment

Because the TADA regimen had never been tested before this study, interim toxicity assessment was performed after enrollment of the first 6 patients with the intention to discontinue the study if 2 or more patients experienced grade ≥2 nonhematologic toxicity. Patients who received any amount of study drug were included in the efficacy analysis. Survival and follow-up were calculated from the time of study enrollment and were complete for all patients through the completion of maintenance thalidomide and through May, 2011 for 15 patients. The overall response rate (ORR) was defined as achieving complete remission (CR), partial remission (PR), and/or clinical improvement based on 2006 International Working Group (IWG) criteria for PMF for all study participants; in addition, CR, PR, and/or hematologic improvement (HI) were defined based on 2006 IWG response criteria for MDS in patients with overlap MDS/MPN, because there are no specific response criteria to address this diagnostic entity.46, 47 Disease progression also was assessed based on 2006 criteria for PMF in all study participants and based on 2006 IWG response criteria for MDS in patients with overlap MDS/MPN. Baseline characteristics are presented as medians with ranges, and the Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Baseline Characteristics

Twenty-eight patients were enrolled on the study, and 21 of those patients (75%) completed the full 12-week cycle of therapy. The remaining patients (n = 7) did not complete therapy for the following reasons: patient choice and withdrawal of consent (n = 3; 11%), nonhematologic adverse events (n = 2; 7%), thrombocytopenia (n = 1; 4%) and no response (n = 1; 4%). Baseline characteristics of all patients are presented in Table 1. The median age was 66.5 years (range, 49-82 years). Fifteen patients (54%) had a diagnosis of MDS/MPN-u, 8 patients (29%) had a diagnosis of CMML-1, and 5 patients (18%) had a diagnosis of PMF. Almost half (46%) presented with either palpable or radiographically evident splenomegaly. Fifteen patients (54%) had received previous therapy for their disease; most (n = 9; 60%) had received erythropoiesis-stimulating agents, 2 (13%) had received azacitidine, and 1 (7%) had received an investigational therapy. Other therapies included prednisone (13%), anagrelide (13%), and hydroxyurea (7%). The results of cytogenetic analysis were available for 25 patients (89%). A normal karyotype was detected in 13 patients (57%) with MDS/MPN and in 3 patients (60%) with PMF. Complex cytogenetics were observed in 2 patients (7%), both of whom had MDS/MPN. There were no patients with isolated deletion 5q, deletion 20q, or deletion 7 chromosomal abnormalities. Five patients were positive for the JAK2V617F mutation of 14 patients who were tested (36%). TET2 mutational status was assessed later in 8 patients with MDS/MPN patients who had peripheral blood samples available, 2 of whom were positive (25%). Neither of these 2 patients had concomitant JAK2V617F mutations. Therapy was initiated either for significant cytopenias (61%) or for disease-related symptoms (39%).

Table 1. Patient Characteristics
Baseline CharacteristicNo. of Patients (%)
  1. Abbreviations: CMML-1, chronic myelomonocytic leukemia type 1; JAK2 V617F, Janus kinase valine to phenylalanine mutation at codon 617; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; MPN-u, unclassifiable myeloproliferative neoplasm; ND, not done; PMF, primary myelofibrosis; TET2, tet methylcytosine dioxygenase 2.

Median age, y66.5
Primary diagnosis
  MDS/MPN-u15 (54)
  CMML-18 (29)
  PMF5 (18)
  Splenomegaly13 (46)
Laboratory values
 Lactate dehydrogenase, U/L
  Normal, 100-200
  Median [range]300 [137-903]
 Leukocyte count, K/μL
  Normal, 3.7-11.0
  Median [range]12.1 [0.9-70.5]
 Hemoglobin value, g/dL
  Normal, 12-17
  Median [range]10.3 [6.4-13.4]
 Platelet count, K/μL
  Normal, 150-400
  Median [range]126.5 [15-792]
 Circulating peripheral blast count, %
  Normal limits0
  Median [range]0 [0-5]
Cytogenetics for MDS/MPN
  Normal13 (57)
  +22p1 (4)
  +91 (4)
  +82 (9)
  −Y1 (4)
  −12p1 (4)
  Complex: ≥3 abnormalities2 (9)
  Unknown: no growth2 (9)
Cytogenetics for PMF
  Normal3 (60)
  +61 (20)
  Unknown: no growth1 (20)
Mutational status
  JAK2 V617F, n = 14 tested5 (36)
  MDS/MPN2
  PMF3
  TET2, n = 8 tested2 (25)
  MDS/MPN2
  PMFND
Prior therapies, n = 15
  Erythropoietin-stimulating agents9 (60)
  5-Azacytidine2 (13)
  Hydroxyurea1 (7)
  Anagrelide2 (13)
  Prednisone2 (13)
  Investigational1 (7)
Reason for initiating therapy
  Anemia8 (29)
  Thrombocytopenia9 (32)
  Disease-related symptoms11 (39)

Adverse Events and Patient-Reported Symptoms

The interim toxicity analysis based on the first 6 enrolled patients indicated that the combination regimen was safe for study continuation. Adverse events in most patients were mild (grade 1) to moderate (grade 2) (Table 2). Seven patients (25%) experienced grade ≥3 hematologic toxicities, including thrombocytopenia (n = 3; 11%), neutropenia (n = 3; 11%), and leukocytosis (n = 1; 4%). Fatigue was the most common nonhematologic toxicity and was observed in 82% of patients; only 8 patients (29%) experienced grade ≥3 symptoms. Additional common nonhematologic grade 3/4 adverse events included dyspnea (18%) and infections (14%). Approximately two-thirds of the patients developed neuropathy, although most of these episodes were only mild to moderate in severity, and all resolved. Similarly, approximately 60% of study patients experienced grade 1/2 lower extremity swelling, which was managed successfully with diuretics. Episodes of grade 3/4 fluid overload, including cardiac tamponade and pleural effusions, developed in 1 patient and 2 patients, respectively. Two of the study patients had grade 1/2 QTc prolongation; however, in both patients, these electrocardiographic abnormalities were clinically insignificant. No thrombotic episodes were observed.

Table 2. Adverse Events (n = 28)
EventNo. of Patients (%)
Patients With Any EventsPatients With Grade 3/4 Events
Hematologic adverse events
 Anemia1 (3.6)0 (0)
 Thrombocytopenia3 (10.7)3 (10.7)
 Neutropenia4 (14.3)3 (10.7)
 Leukocytosis1 (3.6)1 (3.6)
Nonhematologic adverse events
 Cardiovascular
  Atrial fibrillation1 (3.6)0 (0)
  QTC prolongation2 (7.1)0 (0)
  Tachycardia2 (7.1)1 (2.5)
  Cardiac tamponade1 (3.6)0 (0)
  Cardiogenic edema17 (60.7)0 (0)
  Hypertension2 (7.1)0 (0)
  Hypotension4 (1.3)2 (7.1)
 Respiratory
  Cough10 (35.7)0 (0)
  Dyspnea16 (57.1)5 (17.9)
  Hypoxia1 (3.6)1 (3.6)
  Pneumonitis7 (25)2 (7.1)
  Pleural effusion2 (7.1)2 (7.1)
 Gastrointestinal
  Anorexia6 (21.4)0 (0)
  Dry mouth1 (3.6)0 (0)
  Dyspepsia10 (35.7)0 (0)
  Nausea8 (28.6)0 (0)
  Vomiting3 (10.7)1 (3.6)
  Diarrhea/constipation12 (46.4)0 (0)
  Transaminitis5 (17.9)0 (0)
 Genitourinary and fluid/electrolyte
  Renal failure2 (7.1)2 (7.1)
  Dehydration1 (3.6)0 (0)
  Hypomagnesaemia1 (3.6)0 (0)
  Urination problem2 (7.1)0 (0)
  Sexual dysfunction2 (7.1)0 (0)
 Neurologic
  Neuropathy18 (64.3)2 (7.1)
  Anxiety/confusion5 (17.1)0 (0)
  Dizziness7 (25)0 (0)
  Headache7 (25)0 (0)
  Hearing problems2 (7.1)0 (0)
  Visual problems6 (21.4)0 (0)
  Sleep disturbances3 (10.7)1 (3.6)
 Infection/fever
  Fever without infection6 (21.4)0 (0)
  Infection11 (39.3)4 (14.3)
 Dermatologic
  Rash13 (46.4)1 (3.6)
  Pruritus2 (7.1)0 (0)
  Pigmentation changes4 (14.3)0 (0)
  Alopecia3 (10.7)0 (0)
 Musculoskeletal
  Myalgia6 (21.4)1 (3.6)
  Bone pain5 (17.9)1 (3.6)
 Bleeding
  Epistaxis1 (3.6)0 (0)
  Brusing5 (17.9)2 (7.1)
 Constitutional/other
  Fatigue23 (82.1)8 (28.6)
  Rigors/chills4 (14.3)1 (3.6)
  Night sweats2 (7.1)0 (0)
  Lymphadenopathy1 (3.6)0 (0)
  Splenomegaly6 (21.4)0 (0)
  Weight changes5 (17.9)0 (0)

Treatment Efficacy

The median follow-up on the study was 5.7 months (range, 3.3-9.0 months). According to IWG myelofibrosis criteria, 6 patients (21%) responded to TADA therapy: 1 patient achieved PR (4%), and the remaining patients (18%) had clinical improvement. Responses were observed only among patients who completed the full 12-week cycle of therapy (Table 3). The patient who achieved PR had CMML-1 and also had evidence of a bone marrow response, with interval improvement of bone marrow fibrosis from 4+ at baseline to 2+ at 12 weeks of therapy. Regression of splenomegaly was observed in 2 patients with overlap MDS/MPN; no spleen size reduction was observed in any of the patients with PMF. One of 5 patients with PMF (20%) responded to therapy with improvement of anemia. When modified IWG-MDS criteria were applied to patients with MDS/MPN, 2 achieved HI-erythroid responses, and 1 achieved a platelet response (ORR, 20%). (Table 3) All 5 patients who had the JAK2V617F mutation continued to have stable disease throughout the study period. One of the 2 patients with a TET2 mutation achieved HI, and the other had stable disease. There were no instances of acute leukemia transformation or death throughout the study.

Table 3. Treatment Responsea
Patient GroupIWG MDS Response CriteriaIWG Myelofibrosis Response Criteria
ResponseNo. of Patients (%)ResponseNo. of Patients (%)
  • Abbreviations: Hb, hemoglobin; HI, hematologic improvement; IWG, International Working Group; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; ORR, overall response rate; PMF, primary myelofibrosis; PR, partial response; SD, stable disease.

  • a

    No patient developed leukemic transformation or disease progression during thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid (TADA) therapy.

  • b

    Seventeen patients with MDS/MPN and 4 patients with PMF completed 1 cycle of therapy.

  • c

    Responses according to IWG MDS response criteria were calculated only for patients with MDS/MPN.

All patients, N = 28
   ORR6 (21.4)
  PR1 (3.6)
  Clinical improvement: Hb, spleen5 (17.9)
  SD14 (50)
MDS/MPN, N = 23
 ORR3 (13)ORR5 (21.7)
HI-erythroid2 (8.7)PR1 (4.3)
HI-platelets1 (4.3)Clinical improvement: Hb, spleen4 (17.4)
SD11 (47.8)SD10 (43.5)
PMF, N = 5
   ORR1 (20)
  PR0 (0)
  Clinical improvement: Hb1 (20)
  SD4 (80)
Patients who completed at least one 12-wk cycle of therapy, N = 21b
 ORRc3 (17.6)ORR6 (28.6)
HI-erythroid2 (11.8)PR1 (4.8)
HI-platelets1 (5.9)Clinical improvement: Hb, spleen5 (23.8)
SD11 (64.7)SD11 (52.4)

Extended Follow-Up Results

Extended follow-up data were available for 15 patents. The median extended follow-up was 24.1 months (range, 5.2-75.8 months) for all evaluable patients, the median PFS was 14.4 months (n = 14), and the median OS was 21.4 months (n = 15). Disease progression with transformation to acute myeloid leukemia was observed in 2 patients, including 1 with CMML-1 and 1 with MDS/MPN-u. Both of these patients presented with myeloid sarcoma, the first at 6 months of follow-up and the second at 20 months of follow-up. Only 2 of 15 patients completed the full 6-month course of therapy with the 12-week cycle of TADA followed by maintenance thalidomide. One of these patients, who remained alive at the time of this report, had PMF with the JAK2V617F mutation and continued with stable disease at 52 months of follow-up. The second patient who completed therapy had CMML-1 and achieved a PR with TADA. He died of suicide at 23 months of follow-up, at which point he was still in remission. At the time this report was in preparation, 4 of 15 evaluable patients remained alive. In addition to the aforementioned patient who had duplication of chromosome 6, 3 other patients had normal karyotypes. Two of those patients had CMML-1 and had stable disease on TADA. One of them carried a TET2 mutation and underwent an allogeneic stem cell transplantation at 5 months of follow-up, and the second patient continued to be transfusion-independent despite receiving no further therapy after the completion of TADA. The fourth patient, who underwent previous renal transplantation, had MDS/MPN-u and did not respond to TADA therapy.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

PMF and overlap MDS/MPN remain considerable therapeutic challenges, because current treatment options are only modestly successful without durable responses. There are no drugs approved by the US Food and Drug Administration specifically for MPNs, whereas the hypomethyating agents (azacitidine and decitabine) include CMML on their label based on limited overlap patients enrolled on pivotal trials. Thus, these patients represent an unmet therapeutic medical need, and only retrospective, subgroup data support treatment approaches.

The drugs included in the TADA combination, both independently and in limited combinations, have demonstrated activity in both MPN and MDS. When used as monotherapies, higher drug doses usually are required to produce a clinical effect, even in previously untreated or lower risk patients.32, 35, 36, 48, 49 Unfortunately, higher doses often cause intolerable medication side effects, requiring discontinuation of effective therapies.23, 48 Therefore, combining several effective agents at lower doses has become a common approach to overcome dose-limiting toxicities, particularly when those drugs have nonoverlapping mechanisms of action.

This study demonstrated that the TADA regimen is safe and tolerable enough that 75% of largely previously treated patients could complete an intensive 12-week therapeutic course. The regimen also was moderately effective and was comparable to recently reported, long-term follow-up data on 50 patients with PMF from the Mayo Clinic27 in which IWG myelofibrosis response criteria were applied retrospectively to assess the response to thalidomide-prednisone alone or in combination with either cyclophosphamide or etanercept. The reported grade 3/4 hematologic and neurologic toxicities were comparable to those observed in our study. In another study, ATO in combination with low-dose thalidomide resulted in clinical responses in 25% of 28 patients with lower risk and higher risk MDS and CMML.37 Overall, the nonhematologic adverse events, again, were comparable to TADA, with fatigue, fluid retention, and dyspnea observed in approximately 50% of patients followed by infections (29%) and neuropathy (21%). In contrast to TADA therapy, hematologic toxicities, such as neutropenia and thrombocytopenia, were twice as common. Thalidomide produces favorable responses selectively among patients with erythroid linage MDS.34

The steroid component of TADA may be responsible for the lower rates of neutropenia and thrombocytopenia in our study. In 1 report, when prednisone was combined with thalidomide, several patients with baseline thrombocytopenia experienced platelet count recovery in addition to a hemoglobin response.22 The addition of dexamethasone to ATO and thalidomide in our study did not seem to adversely affect the toxicity profile of the TADA regimen and, thus, could be considered in combinations as tolerated to improve hematologic responses. More novel combinations with lenalidomide and prednisone demonstrated responses in approximately 33% of patients with PMF.25 However, this effect was compromised by significant myelosuppression, with rates of grade 3/4 neutropenia and anemia of 58% and 42%, respectively. Another study that used single-agent lenalidomide for PMF reported grade 3/4 neutropenia in approximately 33% of enrolled patients.24 Comparing these results with the rates of hematologic toxicity observed using the TADA regimen, neutropenia and thrombocytopenia of any grade were observed in only 14% and 11% of patients, respectively. Only 1 patient in our study had to discontinue the therapy because of hematologic toxicity, which was an episode of thrombocytopenia. Nonhematologic adverse effects were tolerable, and only 2 patients required study withdrawal. Fatigue and fluid retention were the most common side effects, although they were mild to moderate in most patients.

Similar to our observation of responses observed preferentially in patients who received a longer treatment course, other studies have reported the achievement of greater hematologic responses in patients who received at least 3 months of continuous therapy.34, 50 Therefore, to achieve maximal effects and possibly durable responses to therapy, it is essential to find an optimal regimen with acceptable toxicity profile.

No major clinical differences were observed between responders and nonresponders in our TADA study. More than half of the TADA participants had received therapies for their diseases before enrollment on this study. The treatment results did not differ significantly between untreated and previously treated individuals, emphasizing the benefit of combination therapy at any stage of disease. With the current availability of newer agents, such as hypomethylators, immunomodulatory derivatives, and JAK2 inhibitors, further opportunities will emerge for new combination therapies, some of which already have demonstrated promising clinical efficacy.28, 30, 38 One next, obvious step would be to substitute lenalidomide or pomolidomide for thalidomide in the current study design.

In conclusion, TADA appears to be relatively well tolerated and yields clinical responses in patients with PMF and MDS/MPD. The identification of novel predictive biomarkers, such as cytokine profiles and 5-hydroxymethylcytosine levels, may help identify patients who are more likely to respond to this regimen. It is possible to design a tolerable combination regimen and to assess responses specifically for patients with overlap MDS/MPN, an orphan disease group in whom therapeutic options are limited.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

This investigation was supported in part by Cephalon Corporation.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES
  • 1
    Vardiman JW, Brunning RD, Arber DA, et al. Introduction and overview of the classification of the myeloid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008: 18-30.
  • 2
    Dingli D, Schwager SM, Mesa RA, Li CY, Dewald GW, Tefferi A. Presence of unfavorable cytogenetic abnormalities is the strongest predictor of poor survival in secondary myelofibrosis. Cancer. 2006; 106: 1985-1989.
  • 3
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