Burkitt Lymphoma and Burkitt-like Lymphoma Treatment & Management: Approach Considerations, Chemotherapy Overview, CODOX-M/IVAC Regimen (Magrath Regimen) (original) (raw)

Approach Considerations

Burkitt lymphoma (BL) is a very fast growing tumor. Patients should be admitted to the hospital for rapid workup and diagnostic measures. Chemotherapy is the mainstay of treatment for this disease; consultation with a hematologist and oncologist should be obtained as soon as possible. No role exists for surgery or radiation therapy in the treatment of Burkitt lymphoma.

It is critical to closely monitor serum chemistries in patients with Burkitt lymphoma (BL), especially during chemotherapy because of the high risk of tumor lysis syndrome and uric acid nephropathy. Prophylactic allopurinol and aggressive hydration with urine alkalinization should be administered.

Intravenous antibiotics should be administered for neutropenic fevers. Growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] or granulocyte colony-stimulating factor [G-CSF]) are administered to help decrease the duration of neutropenia.

Transfusions (red blood cells or platelets) are administered as clinically indicated for anemia and thrombocytopenia. All blood products should be leukodepleted and irradiated.

Measures to prevent tumor lysis syndrome

Maintain adequate hydration through intravenous (IV) fluids, ideally starting 24 hours before administering chemotherapy. Note, however, that many patients require chemotherapy emergently and, in these patients, therapy should not be delayed.

Maintain high urine outflow (200-250 mL/m2/h), and monitor renal function closely.

Most patients with Burkitt lymphoma are considered at high risk for tumor lysis and meet the criteria for upfront treatment with rasburicase, which should be administered at a dose of 0.20 mg/kg IV daily for 5 days. Note that patients receiving rasburicase should not have alkalinization of the urine and that this agent is contraindicated in patients with glucose-6-phospate deficiency (G6PD). Lower-risk patients and those who cannot tolerate rasburicase can receive allopurinol, 300 mg twice daily

Close monitoring of the complete blood cell (CBC) count, coagulation studies, and at least twice-daily measurement of serum uric acid, potassium, calcium, phosphorus, magnesium, and creatinine levels is necessary for the first several days of treatment. Consider placing the patient on a cardiac monitor for the first few days. Liver function results should also be monitored.

Treatment should be performed at a facility where renal dialysis is available should it be necessary, particularly for patients with extensive disease.

Consultations

In addition to obtaining a consultation with a hematologist and hematopathologist should as soon as possible, various subspecialty consultations may be required as indicated by clinical situations, such as renal consultation for patients presenting with, or developing, renal failure (uric acid nephropathy) that may require dialysis and surgical consultation for excisional lymph node or tissue biopsy and central line/port placement

Transfer

Patients should be treated in a facility where the physicians are familiar with the use of intensive chemotherapy regimens. The facility should have access to hematopathology and physicians experienced in the prevention and treatment of renal failure from tumor lysis. Adequate blood product support should be available.

Diet and activity restrictions

Most centers advise a neutropenic diet, and patients with significant renal dysfunction should receive a renal diet.

Most patients with Burkitt lymphoma are acutely ill and in the hospital at diagnosis. Their activities will be extremely limited at this time. As the patient responds to therapy, they can increase their activity appropriately. Patients with significant anemia will be limited by fatigue. These patients should appropriately restrict activities that require intense concentration. Patients with significant thrombocytopenia should not perform strenuous activities.

Chemotherapy Overview

Intensive systemic chemotherapy is the treatment of choice for this aggressive disease in all its stages. [34] All clinical variants of Burkitt lymphoma are treated generally the same. The overall survival rate associated with Burkitt lymphoma depends upon the stage of the disease at initial diagnosis. Patients with localized disease respond well to chemotherapy and have an excellent survival rate. Patients with disseminated disease respond less well to chemotherapy and have a less favorable survival rate. Increasing age has also been associated with inferior outcome in most clinical trials. [6, 55] (See Staging and Prognosis.)

For patients who refuse, or are not candidates for clinical trials, short-duration, intensive, alkylator-based, multiagent chemotherapy regimens with adequate central nervous system (CNS) prophylaxis are necessary. Administration of less intensive chemotherapy regimens used in other non-Hodgkin lymphomas (NHL) (eg, CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine and prednisone]) usually results in frequent relapses and inferior survival. Of particular importance is the rapid administration of successive cycles of intensive multidrug therapy to prevent tumor regrowth. Dose reduction should also be avoided if possible. [56]

Most adult Burkitt lymphoma regimens were initially adopted from the pediatric study protocols that used several known active agents, including cyclophosphamide, vincristine, methotrexate, doxorubicin, and cytarabine. The French (LMB 81, 84, 86, and 89) and the German (B-NHL 83, B-NHL 86) protocols as well as the CODOX-M/IVAC regimen (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate / ifosfamide, etoposide, high-dose cytarabine) were modified and used in adult patients with acceptable outcomes (2-y overall survival: 40-74%). Other protocols (hyper-CVAD [modified fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone], Cancer and Leukemia Group B [CALGB] 9251, etc) were evaluated primarily in adults.

A study by Todeschini et al found that intensive pediatric-based chemotherapy regimen increased remission and survival rates in both children and adults with Burtkitt lymphoma. [57]

Even though a standard regimen is not available yet, in general, three treatment approaches are available:

• Intensive, short-duration regimens like CODOX-M/IVAC (Magrath regimen) and the CALGB 9251 protocol
• Long-duration chemotherapy similar to acute lymphoblastic leukemia (ALL) treatment, like hyper-CVAD and the CALGB 8811 protocol
• Combination regimens followed by autologous stem cell transplantation (SCT)
• Most current regimens have added rituximab to previously established chemotherapy regimens

Despite the fact that no direct comparison has been done among these different approaches, the short-duration, more intense regimens are usually preferred in most US institutions, because they are faster to administer (ALL-type treatment may take up to 2 y and usually involves a maintenance arm) and less complicated than ALL-type treatment or SCT. The regimen most frequently used is CODOX-M/IVAC.

Toxicity

Each of the above mentioned regimens carries a 60-70% chance of prolonged progression-free and overall survival, but that is unfortunately associated with a significant toxicity profile. No toxic deaths were reported in the initial study by Magrath (CODOX-M/IVAC), but the rate of grade 3/4 neutropenia was 100%; thrombocytopenia, 96%; mucositis, 61%; and sepsis, 22%. Similar toxicities were seen on the CALGB 9251 protocol.

CNS prophylaxis

CNS prophylaxis using intrathecal methotrexate with or without cytarabine and hydrocortisone is included in most regimens. Without CNS prophylaxis, 30-50% of patients will develop CNS relapse. With the above mentioned regimens, the rate of CNS relapse drops to about 6-11%. [58] Use of prophylactic cranial irradiation causes increased neurologic toxicity; in the 2004 update of the CALGB 9251, the protocol was amended to restrict its use to patients with bone marrow involvement only. This did not significantly affect the rate of CNS relapse.

CODOX-M/IVAC Regimen (Magrath Regimen)

The CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate / ifosfamide, etoposide, high-dose cytarabine) regimen consists of 4 cycles, each cycle lasting until blood counts recover (absolute neutrophil count [ANC] > 1000/μL; platelets > 100,000/μL). Cycles 1 and 3 involve CODOX-M, and cycles 2 and 4 involve IVAC. Three cycles of CODOX-M are usually enough for low-risk patients, whereas high-risk patients receive 4 total cycles (2 cycles of CODOX-M, alternating with 2 cycles of IVAC). [30]

CODOX-M

The CODOX-M regimen is as follows:

• Cyclophosphamide 800mg/m2 IV on day 1, followed by 200 mg/m2 IV on days 2-5
• Doxorubicin 40 mg/m2 IV on day 1
• Vincristine 1.5 mg/m2 IV (no capping of dose) on days 1 and 8 (cycle 1), as well as on days 1, 8, and 15 (cycle 3)
• Methotrexate 1200 mg/m2 IV over 1 hour on day 10; then 240 mg/m2/h for the next 23 hours; leucovorin rescue begins 36 hours from the start of the methotrexate infusion
• Intrathecal cytarabine 70 mg (patient older than age 3 y) on days 1 and 3
• Intrathecal methotrexate 12 mg (patient older than age 3 y) on day 15

IVAC

The IVAC regimen is as follows:

• Ifosfamide 1500 mg/m2 IV on days 1-5, with mesna protection
• Etoposide 60 mg/m2 IV on days 1-5
• Cytarabine 2 g/m2 IV every 12 hours on days 1-2
• Intrathecal methotrexate 12 mg (patient older than age 3 y) on day 5

Administration of colony-stimulating factors is usually started 24 hours after completion of chemotherapy and continues until the ANC >1000/μL. See the Absolute Neutrophil Count calculator.

CNS involvement

If central nervous system (CNS) involvement is documented, patients are treated with a more intense intrathecal regimen during cycles 1 and 2. Cytarabine 70 mg (15 mg if administered into an Ommaya reservoir) is given on days 1, 3, and 5 of cycle 1 as well as on days 7 and 9 of cycle 2; in addition, intrathecal methotrexate 12.5 mg (2 mg if via Ommaya reservoir) on days 15 and 17 (cycle 1) and day 5 (cycle 2). For cycles 3 and 4, the usual prophylactic intrathecal doses of cytosine arabinoside (Ara-C) and methotrexate are given.

The MRC/NCRI LY1O trial investigated a modified dose of methotrexate (3 g/m2) and showed an overall survival of 67%, with decreased toxicity compared with the previous LY06 trial with full-dose methotrexate (6.7 g/m2). [59]

CALGB 9251 Regimen

The Cancer and Leukemia Group B (CALGB) launched a multidrug regimen pilot study (9251) of high-intensity, brief-duration chemotherapy. A brief schema of this protocol is discussed in this section. [60, 61]

Note: Courses II, IV, and VI and courses III, V, and VII are similar and described together. Courses II-VI are administered at 21-day intervals

Course I consists of cyclophosphamide 200 mg/m2/d IV on days 1-5; prednisone 60 mg/m2/d by mouth (PO) on days 1-7.

Courses II, IV, and VI comprise the following:

• Ifosfamide 800 mg/m2 IV over 1 hour on days 1-5
• Mesna 200 mg/m2 IV on days 1-5 (at 0, 4, and 8 h after ifosfamide)
• Methotrexate 150 mg/m2 IV over 30 minutes on day 1, followed by 1.35 g/m2 IV over the next 23.5 hours (total dose: 1.5 g/m2)
• Leucovorin 50 mg/m2 IV starting 36 hours after methotrexate, then 15 mg/m2 every 6 hours until serum methotrexate levels are < 5 × 10-8 M (0.05 μM)
• Vincristine 2 mg IV bolus on day 1
• Cytarabine (Ara-C) 150 mg/m2/day by continuous infusion over 48 hours (days 4-5)
• Etoposide 80 mg/m2 IV over 1 hour on days 4-5
• Dexamethasone 10 mg/m2 PO per day on days 1-5

Courses III, V, and VII comprise the following:

• Cyclophosphamide 200 mg/m2 IV daily on days 1-5
• Methotrexate 150 mg/m2 IV over 30 minutes on day 1, followed by 1.35 g/m2 IV over the next 23.5 hours (total dose: 1.5 g/m2)
• Leucovorin 50 mg/m2 IV starting 36 hours after methotrexate, then 15 mg/m2 every 6 hours until serum methotrexate levels are < 5 × 10-8 M (0.05 μM)
• Vincristine 2 mg IV bolus on day 1
• Doxorubicin 25 mg/m2 IV bolus on days 4-5
• Dexamethasone 10 mg/m2 PO daily on days 1-5

Intrathecal chemotherapy consists of methotrexate 15 mg plus cytarabine 40 mg plus hydrocortisone 50 mg, all administered on day 1 of each course (II-VII).

Cranial radiation (amended in the 2004 update of the CALGB 9251: Only for those patients with previous bone marrow involvement): 2400 cGy in 12 fractions, administered at least 21 days after course VII.

Hyper-CVAD Regimen

The hyper-CVAD (modified fractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) regimen consists of alternating A (days 1, 3, 5, and 7) and B (days 2, 4, 6, and 8) cycles. The second and subsequent cycles are administered when the patient's white blood cell (WBC) count is more than 3000/mm3, and the platelet count is higher than 60,000/mm3 (between 14 and 21 d).

Cycle A comprises the following:

• Cyclophosphamide 300 mg/m2 intravenously (IV) over 2 hours every 12 hours for 6 doses, on days 1-3
• Mesna 600 mg/m2 by continuous IV infusion over 24 hours, starting 1 hour before cyclophosphamide and continuing for 12 hours after the last dose of cyclophosphamide
• Vincristine 2 mg/dose IV push over 2-3 minutes for 2 doses on days 4 and 11
• Doxorubicin 50 mg/m2 IV over 2 hours on day 4
• Dexamethasone 40 mg/day orally (PO) or IV for 8 doses on days 1-4 and on days 11-14
• Filgrastim 10 mcg/kg/day subcutaneously (SC) starting 24 hours after the last dose of chemotherapy and continuing until the WBC count is >3000/mm3

Cycle B comprises the following:

• Methotrexate 1000 mg/m2 by continuous IV infusion over 24 hours on day 1
• Cytarabine 3,000 mg/m2 IV over 2 hours every 12 hours for 4 doses, on days 2-3
• Calcium leucovorin 50 mg IV over 20 minutes administered 12 hours after methotrexate infusion is completed, followed 6 hours later by leucovorin 15 mg IV every 6 hours for 8 total doses or until blood methotrexate concentration is < 0.1 µmol/L
• Filgrastim 10 mcg/kg/day SC starting 24 hours after the last dose of chemotherapy and continuing until the WBC count is > 3000/mm3

Calcium leucovorin doses should be escalated to 50 mg IV every 6 hours if serum methotrexate concentrations are the following:

• Greater than 20 µmol/L at the end of the methotrexate infusion (hour 24)
• Greater than 1 µmol/L at 24 hours after the end of the methotrexate infusion (hour 48)
• Greater than 0.1 µmol/L at 48 hours after the end of the methotrexate infusion (hour 72)

CNS prophylaxis

See the list below:

• Methotrexate intrathecally on day 2 of each cycle, 12 mg/dose via lumbar puncture or 6 mg/dose via Ommaya reservoir
• Cytarabine 100 mg/dose intrathecally via lumbar puncture or Ommaya reservoir administered on day 7 for 8 cycles

Rituximab

Rituximab is a recombinant antibody that targets CD20 on the surface of B lymphocytes. Many studies have incorporated rituximab into the treatment of Burkitt lymphoma. When Oriol et al investigated the addition of rituximab to an intense chemotherapy regimen containing methotrexate, cyclophosphamide, vincristine, ifosfamide, and teniposide (NHL2002 protocol from GMALL [German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia] study) in treating 36 patients, 19 (53%) of whom were HIV positive, complete remission (CR) rates were 88% for HIV-negative patients and 84% for HIV-positive patients. [62]

HIV-positive patients had a higher rate of mucositis and infectious diarrhea, but there was no statistically significant difference in 2-year overall survival between the 2 groups of patients. [62] The HIV-positive patients were all treated concurrently with highly active anti-retroviral therapy (HAART). [62] An improvement in the 3-year estimated survival, disease-free survival (DFS), and event-free survival (EFS) rates, particularly for the elderly, were seen in patients with Burkitt lymphoma receiving rituximab compared with historical controls who did not receive rituximab.

Rituximab has also been evaluated prospectively in small studies, in combination with hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) [29] and dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone). [63] Complete remissions were seen in 86-100% of patients. Rituximab is therefore recommended in the treatment of BL patients, probably to be started with cycle 2, in order to decrease the risk of tumor lysis with the first cycle. CALGB is currently recruiting for a trial looking specifically at the role of rituximab (CALGB 10002).

Evaluation of Treatment Response

After completion of chemotherapy, the response to treatment should be investigated. This should include patient history, physical examination, laboratory studies (complete blood cell (CBC) count, renal/liver profiles, and lactate dehydrogenase [LDH] levels) ,and posttherapy imaging, preferably computed tomography (CT) scans (see Workup).

A complete remission is achieved if the patient has no evidence of disease or disease-related symptoms and if all the masses or lymph nodes that were previously present have resolved on the posttreatment CT scan. If the bone marrow was involved before treatment, a repeat bone marrow biopsy should be normal.

Relapsed/Refractory Burkitt Lymphoma

The majority of relapses occur during the first year of treatment for Burkitt lymphoma. Failure to achieve complete remission is a very poor prognostic sign. Those who remain free from disease at 10-12 months are considered cured, although reports of delayed relapses have been described in the African population and in patients with concurrent human immunodeficiency virus (HIV) infection.

The best management approach to these patients is not well defined. Most patients in this group respond poorly to salvage therapy, although some patients are reported to have long-term survival.

The salvage regimen typically incorporates chemotherapeutic agents to which the patient has had no previous exposure. The DHAP (dexamethasone at 40 mg PO for 4 d, high-dose cytarabine [Ara-C] at 2000 mg/m2 IV q12h for 2 doses, and cisplatin at 100 mg/m2 IV for 1 dose) regimen is often used as salvage therapy. Among these patients, those whose disease demonstrates some chemosensitivity are then referred for high-dose chemotherapy and autologous stem cell transplantation (SCT)/bone marrow transplantation (or allogeneic SCT in clinical trials). Patients with chemoresistant disease are usually referred for best supportive care (see Sweetenham et al [64] ).

Wu et al reported on two preliminary trials of chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed and refractory Burkitt lymphoma in adults. One trial evaluated the clinical efficacy and toxicity of CD19/CD22 CAR T-cell therapy alone, and the other evaluated it in combination with autologous stem cell transplantation. Complete responses were observed in 16 (57.1%) of the 28 patients enrolled. Grade 2–4 cytokine release syndrome occurred in 39.3% of patients, and immune effector cell–associated neurotoxicity syndrome in 10.7%. Estimated 1-year progression-free and overall survival rates were 55.6%. [65]

Stem Cell Transplantation

The use of high-dose chemotherapy plus stem cell transplantation (SCT) has decreased because of the high rate of remission achieved with current treatment regimens.

High-dose chemotherapy plus autologous SCT may be considered for patients whose condition has not responded to (primary refractory) or who have relapsed after first-line conventional chemotherapy. The outcome for adult patients treated with a short, intensive regimen is less favorable than the outcome in children. Up to 40% of the patients treated on the LMB81 and LMB84 regimens experienced relapse; this rate is lower in patients treated with CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine). [30] Current indications for treatment of these patients with high-dose chemotherapy plus autologous SCT remain similar to those of the pediatric group.

Primary refractory disease

Patients with primary refractory disease do not respond well to high-dose chemotherapy plus autologous SCT. The duration of responses in these patients is often short, with eventual relapse in most reported series. Alternative approaches, including allogeneic SCT/bone marrow transplantation or salvage regimens in the setting of a clinical trial, should be considered in these cases. [6, 66]

Partial remission

Patients in first partial remission should be considered for high-dose chemotherapy plus autologous SCT. The outcome of treatment in these patients with conventional chemotherapy regimens is usually poor. In a report by Philip and Biron, the results of bone marrow transplantation in patients with Burkitt lymphoma (BL) in partial remission was a 70% survival rate at 2 years. [67]

Subsequent randomized studies in aggressive non-Hodgkin lymphoma (NHL) have failed to clearly show an advantage for high-dose chemotherapy plus autologous SCT. Currently, patients with Burkitt lymphoma (BL) whose disease demonstrates chemosensitivity and who achieve a good partial remission after front-line therapy should be considered for high-dose chemotherapy plus autologous SCT. [28]

Clinical remission

Patients in first clinical remission with poor prognostic features have been considered for consolidation therapy with high-dose chemotherapy plus autologous SCT. Published data to date do not support the use of this approach outside of a clinical trial. [68]

Relapse

A French group has reported improved survival rates in patients with relapsed aggressive NHL who were treated with high-dose chemotherapy plus autologous SCT. [69] The only significant prognostic factor noted was sensitivity to reinduction chemotherapy at the time of relapse. A 3-year survival rate of 36% in sensitive relapse (SR) versus 14% in resistant relapse (RR) was reported. [69] Subsequent studies have reported similar outcomes.

Patients with relapsed Burkitt lymphoma (BL) with chemosensitive disease should be considered for high-dose chemotherapy plus autologous SCT; alternative therapies should be considered for those with RR (see the Sweetenham et al reference [64] ).

SCT and graft vs leukemia effect

The role of allogeneic SCT and graft versus leukemia effect in Burkitt lymphom or Burkitt-like lymphoma remains investigational. [70, 71] Many transplant centers consider this option for patients at high risk and for those with refractory disease. There have also been case reports that suggested a possible role for nonablative and cord blood transplantation in relapsed heavily treated patients. [72]

Surgical Intervention

In current clinical practice, effective and durable responses are observed with combination chemotherapy, obviating the role of surgical debulking. Historically, most patients with Burkitt lymphoma who presented with large masses, particularly abdominal disease, underwent an exploratory laparotomy, at which time an effort was made to debulk as well. With newer, sophisticated interventional radiology approaches, an adequate diagnosis can be reached in almost all patients without major surgical intervention.

Surgical indications include the following:

• Palliative surgery is considered only for patients with obstruction who cannot begin chemotherapy immediately.
• Tracheotomy is indicated if the patient's airway is compromised from the physical pressure of a large tumor mass.
• Exploratory laparotomy may be performed for bowel obstruction (often before the diagnosis is made). Patients with uncontrolled gastrointestinal bleeding may also need exploratory laparotomy or endoscopic procedures for hemostasis.
• Pericardiocentesis is indicated for patients presenting with cardiac tamponade.
• Paracentesis is indicated if large ascites is one of the presenting complaints.
• An excisional lymph node biopsy is usually necessary to reach an accurate diagnosis.

A semi-permanent intravenous catheter such as a peripherally inserted central catheter (PICC) line or medicine port should be arranged with interventional radiology or surgery to aid administration of chemotherapy, medications, and blood products and for fluid management.

Long-Term Monitoring

When patients with Burkitt lymphoma receive treatment in the clinic, close monitoring of their white blood cell (WBC) count, hemoglobin, platelet count, serum chemistry levels, and liver functions is needed.

After chemotherapy is completed, patients should be monitored at least every 2 months during the first year, then every 3 months the following year, and every 6 months thereafter.

During follow-up visits, a complete physical examination should be performed, and CBC count and serum electrolyte levels should be obtained. Lactate dehydrogenase (LDH) and beta2 microglobulin studies may be helpful in detecting early relapse.

Repeat staging with computed tomography (CT) scanning is performed during and after completion of treatment to ascertain disease response and document achievement of complete remission.

Special Considerations

Burkitt lymphoma and Burkitt-like lymphoma have an aggressive clinical course; therefore, management should be directed toward an expeditious diagnosis, followed by prompt institution of definitive therapy. Initial treatment should be started in an inpatient setting.

Patients with Burkitt lymphoma presenting with B symptoms should have a thorough examination, and a biopsy should be obtained immediately for any suspicious mass. Failure to diagnose this high-grade lymphoma can lead to long-term sequelae and, possibly, death.

Kidney failure as a result of tumor lysis syndrome from therapy is a potential risk in all patients, especially those with a high tumor burden. Aggressive management of this potentially life-threatening complication should be clearly addressed. Early hemodialysis should be considered in these patients to prevent long-term renal dysfunction.

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Author

Coauthor(s)

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Patturajah Anbumani, MD, MBBS, MS, MCh Associate Medical Director, Best Medical Care; Former Associate Medical Director, Jeanes Hospital, Temple University Health System; Former Adjunct Clinical Assistant Professor, New York College of Osteopathic Medicine; Former Clinical Assistant Professor, Department of Medicine, State University of New York-Downstate

Patturajah Anbumani, MD, MBBS, MS, MCh is a member of the following medical societies: American College of Physicians, American Medical Association, and American Medical Women’s Association

Disclosure: Nothing to disclose.

Samer A Bleibel, MD Staff Physician, Department of Internal Medicine, Wayne State University School of Medicine, St John's Hospital and Medical Centers

Samer A Bleibel, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Asher A Chanan-Khan, MD Assistant Professor, Department of Medicine, Division of Lymphoma and Bone Marrow Transplantation, Roswell Park Cancer Institute, State University of New York at Buffalo

Asher A Chanan-Khan, MD is a member of the following medical societies: American College of Physicians, American Medical Association, and American Society of Hematology

Disclosure: Nothing to disclose.

Hanxian Huang, MD, PhD Staff Physician, Department of Internal Medicine, Leesburg Regional Medical Center, The Villages Regional Hospital

Hanxian Huang, MD, PhD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine

Disclosure: Nothing to disclose.

Anand B Karnad, MBBS Program Director, Fellowship Programs in Hematology-Oncology, Professor of Medicine, Division of Medical Oncology, Department of Medicine, University of Texas Health Sciences Center, San Antonio

Anand B Karnad, MBBS is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Osler Society, American Society of Hematology, Assocation of Subspecialty Professors, and Massachusetts Medical Society

Disclosure: Nothing to disclose.

Olga Kozyreva, MD Attending Physician, Division of Hematology-Oncology, St Elizabeth's Medical Center; Assistant Professor, Tufts University School of Medicine

Disclosure: Nothing to disclose.

Sarah K May, MD Consulting Staff, Department of Hematology-Oncology, Caritas Carney Hospital, Commonwealth Hematology-Oncology PC

Disclosure: Nothing to disclose.

from Memorial Sloan-Kettering - Philip Schulman, MD Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Clinical Professor, Department of Medicine, New York University School of Medicine

Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, and Medical Society of the State of New York

Disclosure: Nothing to disclose.

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology

Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Yubao Wang, MD, PhD Fellow, Division of Hematology/Medical Oncology, University of Texas Health Science Center, San Antonio

Yubao Wang, MD, PhD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Nothing to disclose.