Stem Cell Transplantation

Conditioning Regimen for Hematopoietic Stem Cell Transplation (HSCT)

February 18, 2013 Chemotherapy, Hematology, Pharmacokinetics, Therapeutics No comments ,

There are two categories of HSCT, autologous HSCT (ASCT) and allogeneic HSCT (allo-SCT). For patients being considered for ASCT, the most common reason for choosing a particular conditioning regimen is the disease for which transplantation is being considered. For patients being considered for allo-SCT, the initial choice of a conditioning regimen is based on the disease and the condition of the recipient at the time of transplantation. And a major consideration for allo-SCT is whether to administer a myeloblative conditioning regimen or a reduced-intensity regimen.

When choosing between myeloablative or reduced-intensity conditioning, providers analyze a number of factors, including the age, the comorbidities, the disease and its stage at the time of transplantation, the source of stem cells being used, the degree to which human leukocyte antigen matches, and the preference of the patient.

To evaluate the efficacy and safety of different conditioning regimens, five aspects should be considered, including toxicity, risk of relapse, hematopoietic engraftment, treatment-related mortality, and overall survival.

Conditioning Regimens for ASCT

Table 1 Conditioning Regimens and Specific Malignancy

Conditioning RegimenSpecific Malignancy
1Gemcitabine plus busulfan plus melphalanRelapsed non-Hodgkin lymphoma
2Gemcitabine plus busulfan plus melphalanRefractory Hodgkin lymphoma
3Busulfan plus cyclophosphamide plus etoposidenon-Hodgkin or Hodgkin lymphoma
4Busulfan plus bortezomibMultiple myeloma (relapse after first ASCT)
5MelphalanMultiple myeloma

 

1. Gemcitabine/Busulfan/Melphalan for relapsed non-Hodgkin lymphoma

Gemcitabine, intravenous infusion over 4.5 hrs per day with a total dose of 2550 mg/m2 per day (maximum tolerated dose). Busulfan, intravenously in 4 daily doses targeted to an area under the curve (AUC) of 4000 μM*min per day. Melphalan, on days minus 3 and minus 2, 60 mg/m2 per day.

2. Gemcitabine/Busulfan/Melphalan for refractory Hodgkin lymphoma

Gemcitabine, intravenous infusion for 10 mg/m2 per minute over 4.5 hrs on days minus 8 and minus 3. Busulfan, intravenously targeted to an AUC of 4000 μM*min per day for 4 daily doses. Melphalan, given at 60 mg/m2 per day for 2 days on days minus 3 and minus 2.

3. Busulfan/Cyclophosphamide/Etoposide for non-Hodgkin or Hodgkin lymphoma

Busulfan, infusion at a test dose of 0.8 mg/kg for 2 hrs between days minus 14 and minus 11. The test dose is used for pharmacokinetic testing. The remaining busulfan dose is calculated to achieve a total AUC of 20,000 μM*min. One-fourth of this dose is given as a 3-hour infusion on day minus 8, during which a second pharmacokinetic analysis is done. The same daily busulfan dose is administered on days minus 7, minus 6, and minus 5, unless the pharmacokinetic results for day minus 8 showed total AUC outside the target range plus or minus 20%. Etoposide is administered at a dose of 1400 mg/m2 on day minus 4 followed by cyclophosphamide 2.5 g/m2 per day on days minus 3 and minus 2.

4. Busulfan/Bortezomib for mutiple myeloma

Busulfan, infusion at a test dose of 0.8 mg/kg for 2 hrs between days minus 12 and minus 9. Following pharmacokinetic sampling, individualized pharmacokinetic-directed dosing of busulfan is recommended to achieve a total AUC for the regimen of 20,000 μM*min, with intravenous infusion over 3 hrs each day from days minus 5 to minus 2. Bortezomib is administered 1.3 mg/m2 intravenously on day minus 1.

5. Melphalan for mutiple myeloma

High-dose melphalan forms the backbone of the conditioning regimen for the vast majority of patients undergoing ASCT for multiple myeloma. However, patients given the same elevated dose of melphalan may experience up to 5-fold variation in total exposure as measured by AUC. The median dose of melphalan is 192 mg/m2.

Conditioning Regimens for allo-SCT

Table 2 Conditioning Regimens and Specific Diseases

Conditioning RegimenSpecific Diseases
1Busulfan plus fludarabineVariety of hematological malignancies
2Fludarabine plus busulfanMalignant and non-malignant diseases (pediatric)
3Fludarabine plus busulfanLymphoma

 

1. Busulfan/Fludarabine for variety of hematological malignancies

Busulfan, a test dose of intravenous busulfan 0.8 mg/kg is administered approximately 1 week prior to the start of conditioning, and a desired AUC is calculated from the busulfan clearance dose levels. Dose levels are escalated in 20% increments from 4800 to 5766 to 7603 and finally to 8663 μM*min per 24 hours, from days minus 7 to day minus 3. The infusion is given over 90 hours all together. Fludarabine is administered 30 mg/m2 per day on days minus 7 to minus 3.

2. Fludarabine/Busulfan for malignant and non-malignant diseases (pediatric)

3. Fludarabine/Busulfan for lymphoma

Busulfan is targeted to three levels of AUC of 3500 μM*min per day, 5300 μM*min per day, and over 5300 μM*min per day. All three groups are along with intravenous fludarabine.

Reduced-Intensity Conditioning Regimen

1. Fludarabine plus cyclophosphamide, with or without anti-thymocyte globulin for severe aplastic anemia.

2. 2 Gy total body irradiation alone or with fludarabine for hematological malignancies.

3. Clofarabine plus total lymphocyte irradiation plus anti-thymocyte globulin for variety of hematological malignancies.

4. Alemtuzumab alone for relapsed/refractory chronic lymphocytic leukemia.

Novel Approaches to the Treatment of Acute Myeloid Leukemia

August 14, 2012 Chemotherapy, Cytogenetics, Hematology, Therapeutics No comments , , , , , ,

Morphology of AML.

Yesterday and today I read an literature by Gail J. Roboz in the Education Program Book by American Society of Hematology (ASH), which is named “Hematology” and published annually by the ASH in one volume per year. The name is “Novel Approaches to the Treatment of Acute Myeloid Leukemia”. In this article the author discussed several aspects of Acute Myeloid Leukemia (AML) including: the general, the chemotherapy regimen, the stem cell transplantation, and the prognostic of AML. Now let’s get into this article.

In the introduction section. Approximately 12,000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, with a median age of 67 years. Despite advances in therapeutics and supportive care, the majority of patients with AML die from their disease. But among the subtypes acute promyelocytic leukemia (APL) is an important exception to the general statement of AML. In this subtype >75% of patients are cured with a combination of anthracycline-based chemotherapy, all-trans retinoic acid, and arsenic trioxide. For some APL patients, it is possible to eliminate cytotoxic chemotherapy altogether and to achieve cure with arsenic and all-trans retinoic acid alone. In this article we don’t discuss this subtype of AML in detail.

For all other subtypes of AML, the mainstay of initial treatment was developed nearly 40 years ago as a combination of cytosine arabinoside (ara-C) with an anthracycline, and this regimen remains the worldwide standard of care. Without stem cell transplantation, the age of patients is an in dependent major determinant indicator of the prognostic. For patients <60 years of age approximately 70%-80% of those will achieve complete remission, but most ultimately relapse and overall survival is only 40%-45% at 5 years. Among patients >60 years of age, 40%-50% of those with a good performance status can achieve complete remission, but cure rates are <10% and median survival is <1 year. Later in another section we will discuss the older AML patients in detail.

Advances in genomics technologies have identified AML as a genetically highly heterogeneous disease. As the technologies is well developed today, we are able to assign AML patients to many subgroups based on their molecular genetic defects. First we can assign AML patients to two subgroups which are cytogenetically normal and cytogenetically abnormal.

Cytogenetically normal patients comprise the largest subgroup of AML. This subgroup can now be further divided into a myriad of molecular subgroups too. Some subtypes of molecular genetic defects are know to have significant prognostic implications. For example, mutations in FLT3-ITD have been associated with an aggressive disease phenotype and poor outcomes. In contrast, patients with biallelic mutations in CEBPA and NPM1 without concomitant mutations in FLT3-ITD have significantly more favorable outcomes.

Also there is subgroup with abnormal cytogenetics. For example, mutations in KIT may negate the “favorable” classification previously associated with t(8;21).

Treatment of Acute Myeloid Leukemia

The treatment paradigm for AML generally includes remission induction, followed by consolidation with either 1-4 cycles of chemotherapy or stem cell transplantation.

The drugs for remission and consolidation have been variations on a theme of ara-C combined with an anthracycline or anthracenedione. In 1973 Yates et al first reported the result of a pilot trial of infusional cytarabine combined with daunorubicin in AML. The treatment was called “7&3 DNR 45” to indicate the dose of daunorubicin, 45 mg/m2. And there are many former studies to show the effects of the anthracyclines. There are five recommands for the treatment of AML.

  • Cumulative anthracycline dose for induction should be at least 180 mg/m2 of daunorubicin or 36 mg/m2 of idarubicin and consider daunorubicin 270 mg/m2 (It’s called intensive therapy, we will discuss about it later) for patients up to 65 years of age with a good performance status and adequate cardiac function.
  • Consider carefully if offering intensive consolidation to patients >60 years of age because this has not been shown to prolong survival and is associated with significant toxicity.
  • Refer potential transplantation candidates immediately at time of diagnosis to allow adequate time for donor identification and transplantation planning.
  • Age is not a major determinant of outcome after reduced intensity allogeneic transplantation; do not exclude patients on the basis of chronological age alone and refer older patients with good performance status early.
  • Almost every patient with AML should be considered for a clinical trial, including those who are already in remission. (more…)

Top docs provide free online advice for rare leukemia

July 14, 2012 Hematology, Pharmacy Education No comments , ,

July 11, 2012 — Seven hematologists from leading cancer centers have volunteered to provide free medical advice to patients with myeloproliferative neoplasms (MPNs), a rare form of leukemia, and to their healthcare providers.

The physicians have signed on with the online MPNforum Magazine, which is published monthly by an MPN patient collective. They offer help to patients and caregivers on MPN Clinic, an online roundtable hosted by the publication.

The term MPN covers a rare set of disorders occurring in about 5 people per million, according to a press release from the publication, which operates on a shoestring budget. This rarity means that community-based clinicians may never see a case and if one comes along, help is needed.

The initial volunteers for the project are Richard Silver, MD (Weill-Cornell in New York City), Srdan Verstovsek, MD (M.D. Anderson in Houston, Texas), Ruben Mesa, MD (Mayo Clinic in Scottsdale, Arizona), Claire Harrison, DM (Guy’s and St. Thomas’ in London, United Kingdom), Jason Gotlib, MD (Stanford Medical Center in Palo Alto, California), Ross Levine, MD (Sloan-Kettering in New York City), and Attilio Orazi, MD (Weill-Cornell).

“It’s amazing that we have this group of doctors,” said Zhenya Senyak, the founder and editor of MPNforum, about the eminence of the participating experts. “They are really concerned about getting this information out,” he told Medscape Medical News in an interview. Senyak, who lives in Asheville, North Carolina, is a writer who has myelofibrosis.

I’ve never waited more than a day for a response.

The service is free. Patients, caregivers, and healthcare providers can email questions to MPNclinic@gmail.com, which are then forwarded to all members of the panel. One of the experts responds, and circulates that response among the other panel members for review and comment. The final response is then forwarded to the individual who submitted the question. “I’ve never waited more than a day for a response,” said Senyak. The volunteer experts have even responded while on vacation, he said, adding that the answers are highly detailed and “powerful.”

All the questions, answers, and comments will eventually be published in the monthly MPN Clinic section of MPNforum Magazine. The entries will be archived in a searchable, publicly available online database.

The first MPN Clinic report will be published on September 15. However, Senyak said that responses to 27 questions have already been received and forwarded to patients in the United States and England. He is delighted by the volunteer experts’ helpfulness. “They have nothing to gain. It is purely altruistic of them,” he said.

MPNforum is financed by small donations, which, to date, amount to about $2000.

More About MPNs

MPNs are caused by one or more mutations, usually acquired after middle age. However, increasing numbers of younger adults and children are being diagnosed with the disorder, according to an MPNforum press statement. In MPNs, an overproduction of blood cells disrupts normal hematopoiesis. The various MPNs are differentiated by what is overproduced, such as erythrocytes in polycythemia vera or platelets in essential thrombocythemia.

If treated properly, many patients can live a normal life span with minimal suffering, according to the organization; however, some forms, such as myelofibrosis, can be debilitating and even fatal.

Myelofibrosis is associated with the dysregulation of 2 enzymes — janus-associated kinase (JAK)1 and 2 — which are involved in regulating blood and immunologic functioning. As the disease progresses, bone marrow is replaced with scar tissue, leading to anemia and thrombocytopenia. However, the scarred bone marrow tissue accumulates in other organs, most notably the spleen and liver. This collagen fibrosis can also cause bone pain, intense fatigue, and loss of appetite.

The only cure for myelofibrosis has been stem cell transplantation. However, since the implication of a genetic mutation in this disease was discovered, there have been developments in drug treatment. In 2011, the first drug treatment ever for myelofibrosis, ruxolitinib (Jakafi, Incyte Corp.), was approved by the US Food and Drug Administration.

Ruxolitinib has shown results that are “unprecedented” in the treatment of this disorder, according to Dr. Harrison, who is one of the volunteers and one of the drug’s principal investigators.

While research continues, access to MPN specialists remains the surest means of securing optimal treatment, said Senyak.