The Gift of Blood and Marrow

by Mary Jane Schier

 

More effective blood and bone marrow transplantation techniques developed at M. D. Anderson mean more cancer patients are enjoying longer survival.

 

Almost 600 blood stem cell and bone marrow transplant procedures were performed last year for patients ranging in age from 10 months to 75 years. The number of transplants done annually at M. D. Anderson has doubled in the past five years.

 

"We are in an increasingly productive period. Many of our recent improvements are the result of better laboratory methods to prepare the stem cells and bone marrow for transplantation as well as to enhance our ability to predict - and often minimize - serious complications," says Dr. Richard E. Champlin, chairman of the Department of Blood and Marrow Transplantation.

 

In the Blood and Marrow Transplantation Cell Processing Laboratory, Dr. Richard E. Champlin (left) and Dr. Adrian Gee remove frozen bone marrow for use in transplantation.

Ongoing progress in the laboratory combined with insightful clinical observations allow the majority of M. D. Anderson patients to receive individualized transplant support therapies that offer increasing hope for positive outcomes. Newer approaches permit safer, less-debilitating treatment of more cancer types for patients across a wider age spectrum.

 

Many patients also can be treated as outpatients, thus reducing costs and improving their

quality of life.

 

Transplantation Past, Present, Future

 

The first bone marrow transplant at M. D. Anderson was performed shortly before Christmas in 1975, the same year Dr. Champlin graduated from medical school. Over the next 15 years, he became an international leader in the field through research that extended transplant options to more cancer patients.

 

One of Dr. Champlin's contributions while at the University of California at Los Angeles Center for the Health Sciences was supervising the start of a matched unrelated donor (MUD) program to find suitable donors for patients who had no compatible relatives to give marrow. Since coming to M. D. Anderson in 1990, he has incorporated aggressive unrelated transplant options while building the world's largest Blood and Marrow Transplantation Program.

 

Dr. Jeffrey J. Molldrem is developing a vaccine for acute and chronic leukemias.

Today, his transplantation team includes 13 physicians dedicated solely to providing optimal blood and marrow support for a growing group of cancer patients. They work closely with more than 50 clinical colleagues and diverse research collaborators from throughout M. D. Anderson and several other medical centers. Creating a separate Department of Blood and Marrow Transplantation in 1997 illustrated the institution's commitment to this specialty field.

 

Transplantation support nearly always involves intensive chemotherapy and some patients may receive total body irradiation prior to undergoing a transplant. Dr. Champlin and his colleagues now consider blood and marrow transplantation earlier in the course of most cancers, thereby boosting patients' abilities to overcome complications.

 

"Probably our biggest change in recent years has been the dramatic growth of peripheral blood stem cell transplants, which are easier for donors and generally better for most patients than conventional bone marrow transplants," Dr. Champlin says.

 

Using stem cells when possible in lieu of bone marrow has turned into a big advantage for donors. Instead of a surgical procedure to harvest bone marrow, stem cell donors have their blood removed by a special machine that separates the essential component in a three-hour outpatient procedure. That compares to the need for being hospitalized and receiving anesthesia while having bone marrow excised from their pelvic area. For many recipients, the peripheral blood stem cells engraft quicker and produce fewer complications.

 

Bone marrow now accounts for only about 15 percent of the transplants at M. D. Anderson, while blood stem cells comprise nearly 85 percent of the procedures. Umbilical cord blood transplants also are performed for selected pediatric patients.

 

The major diseases treated with transplant support include malignancies of the blood-forming organs (acute and chronic leukemias, lymphoma, multiple myeloma and myelodsyplastic syndrome) plus such solid tumors as breast and ovarian cancers and sarcomas. Pilot studies have begun for colon cancer and malignant melanoma.

 

Transplants also may be indicated for aplastic anemia, sickle cell anemia and immunodeficiency disorders.

 

Among the types of transplants are:

 

· Autologous, which uses a patient's own blood stem cells or marrow that is removed during remission, cleansed as needed in the laboratory to eliminate cancer cells, stored frozen and then returned to the patient after chemotherapy.

 

· Related allogeneic, in which histologically tissue-matching relatives - usually brothers and sisters but sometimes parents or cousins - donate blood or marrow for immediate or later use as patients need it.

 

· Unrelated allogeneic, which depends on total strangers registered in the United States and other countries to give blood or marrow when it matches patients whose own relatives are unsuitable donors.

 

· Umbilical cord blood, which usually is discarded with the placenta after a baby's birth but can be saved and stored by registries for young cancer patients who have no matched donors.

 

Dr. Adrian Gee, a noted authority on preparing blood and marrow for optimal transplant results, was recruited to M. D. Anderson in early 1997 to direct and expand the Blood and Marrow Transplantation Cell Processing Laboratory.

 

"Coming here was an incredible opportunity to work in the world's leading Blood and Marrow Transplantation Program. Our laboratory has a critical role in processing all types of donor cells and marrow to assure these are in the best possible condition when given to patients," Dr. Gee says.

 

For autologous transplants, his group employs intricate methods to purge patients' own blood and marrow of any lingering cancer cells. The blood separator collects the potentially health-restoring blood so it will rescue patients from the ravages of their cancers - and do so without causing life-threatening complications.

 

The odds are best for any type of transplant if the blood cells or bone marrow genetically matches the patients' tissues. An ideal donor is one whose marrow or blood cells contain the same six cell markers, called human leukocyte antigens (HLAs), as a patient has. Everyone inherits two sets of these proteins, one set from each parent. Only patients who undergo autologous transplants and identical twins have perfectly matching major and minor HLAs.

 

"Obviously, we want tissues that are as closely matched as possible. When the match is very good, we don't have to manipulate the blood cells or bone marrow as much in the laboratory," Dr. Gee says.

 

The most serious complication in allogenic transplants is graft-versus-host-disease (GVHD), an immune system phenomenon in which donor marrow or cells attack the recipient and cause severe skin rash, liver damage and diarrhea. Dr. Champlin's observation that a specific type of white blood cell is most responsible for GVHD has changed the prognosis for many patients.

 

The CD8-positive T-lymphocyte is the offending white blood cell most responsible for producing GVHD. Laboratory techniques to remove these cells, together with the use of several drugs to prevent GVHD, are yielding increasingly good results. Another frequent problem for transplant recipients with compromised immune systems is cytomegalovirus, but more powerful antibiotics have largely controlled this and other infections.

 

"In addition to improving procedures to negate the impact of the T-lymphocytes, we use methods to insert genes into white blood cells given to patients to destroy any remaining signs of GVHD. These same cells, however, may cause the complication. The genes allow more cells to be inactivated when a particular antibiotic is administered to patients," Dr. Gee explains.

 

Other laboratory studies focus on:

 

· Designing new ways to train donor T-lymphocytes to seek out and destroy patients' leukemic cells more rapidly.

 

· Expanding the small number of stem or progenitor cells obtained from donors' peripheral blood by as much as 10-fold to improve transplant outcomes.

 

· Implementing better assays to detect microscopic malignant cells in time to institute transplant-salvage treatments.

 

· Developing genetic therapy support to alter donor blood cells and marrow and prevent serious complications after transplants.

 

Numerous contributions from the laboratory have led to trends that Dr. Champlin believes are revolutionizing blood and marrow transplantation.

 

First, he cites the broader use of non-ablative chemotherapy, which is less toxic than the high-dose anti-cancer drugs administered to transplant recipients in the past. Much better results from manipulating blood stem cells in the laboratory allow transplant patients to recover faster with fewer adverse problems.

 

Second, Dr. Champlin credits the intensive laboratory support throughout patients' transplant experiences with boosting the clinicians' tracking of patients and helping them

take steps earlier to reduce complications.

 

"Among the recent accomplishments at M. D. Anderson, I am particularly proud of our program that provides blood and marrow transplants along with supportive care in a predominantly outpatient arena. We started this service several years ago primarily to reduce costs, but we're seeing enormous emotional benefits to patients who don't want to spend prolonged periods in the hospital," Dr. Champlin says.

 

Several hundred transplant recipients have participated in the outpatient program, in which they usually are hospitalized only to receive intensive chemotherapy, then get their transplants as outpatients and are followed in ambulatory care centers. They are required to live or stay within about 30 miles of M. D. Anderson in order to come in for frequent evaluations and such supportive therapies as fluid replenishment and blood transfusions.

 

"We have not seen a single major complication related to outpatient care," Dr. Champlin says.

 

The transplant leader most involved in insurance reimbursement issues is Dr. James Gajewski, co-medical director of M. D. Anderson's Hematology Center and associate medical director for Managed Care Programs. He is an authority on unrelated and mismatched donor transplants and for applying transplant technology to breast cancer patients.

 

"Some insurers still consider transplants as experimental, so we spend considerable time writing letters and talking with medical directors of managed care plans and other insurance carriers to document the effectiveness of our blood and marrow transplantation services. Overall, we are improving the rate of reimbursement," Dr. Gajewski says.

 

The minimum cost for a transplant regimen provided largely on an outpatient basis is about $60,000. But Dr. Gajewski says the cost can soar to $300,000 for patients who develop severe complications requiring intensive hospitalization and prolonged supportive therapy. The institution aggressively seeks financial support from all possible sources so that a maximum number of patients can undergo transplant procedures.

 

Highly sophisticated multidisciplinary teamwork involving clinical and laboratory scientists is necessary for a successful transplantation program. The complexity and high costs of transplantation point to the need for only tertiary centers offering comprehensive blood and marrow transplantation, he stresses.

 

Dr. Gajewski's first major role in bone marrow transplantation occurred in 1987, when he set up an innovative matched unrelated donor program while a fellow in Dr. Champlin's transplant program at the UCLA Center for Health Sciences. One of their first patients recently celebrated his 10th anniversary of having such a procedure - and is the longest survivor of a matched unrelated donor transplant in the country.

 

About 100 million stem cells -- the equivalent of 20 teaspoons -- are needed for most transplants. Through a mobilization process in the laboratory, the amount of stem cells can be expanded, thereby reducing the number of autologous or donor collections from as many as 10 once required to as few as two or three.

 

Dr. Sergio A. Giralt, an assistant professor of hematology, has helped advance mini-stem cell transplants, especially for patients with multiple myeloma and some leukemias. Patients with well-matching donors receive less-intensive chemotherapy followed by one or more stem cell infusions.

 

"Using mini-transplants lets us treat older and sicker patients who would not be good candidates for high-dose chemotherapy. We've had several patients in their 70s," Dr. Giralt says.

 

Locating the best-matched donor for every patient remains a major challenge.

 

Dr. Champlin says only 20 percent of allogeneic transplant candidates will have suitably matching relatives. Another 30 percent of patients may find compatible donors through the National Marrow Donor Program and other registries. The chances of locating matched unrelated donors is best among individuals of the same racial and ethnic origins.

 

Finding matched unrelated donors is usually difficult for ethnic minority patients due to the small number of people in the registries.

 

"Right now, we're finding unrelated matches for about one-third of our patients. Donor marrow and blood have come from across the United States, Europe and as far away as Australia. But searches for acceptable donor tissue is a time-consuming process. We also have a program to use mismatched related donors for some patients when matching donors are not available," Dr. Champlin says.

 

Good results are reported from two relatively recent innovations for children with

several cancers and women with ovarian cancer.

 

Ten umbilical cord blood transplants have been performed at M. D. Anderson over the past two years. Eight of the patients - ranging in age from 10 months to almost 15 years - were alive and disease-free at the start of the summer.

 

"We hope to increase the use of cord blood for transplantation in the future, particularly for younger leukemia patients at high risk for relapse. But we offer our kids all types of transplants, including autologous and mismatched related donor procedures," says Dr. Ka-Wah Chan, professor and chief of the Bone Marrow Transplant Section in the Division of Pediatrics.

 

Dr. Chan's short-range goal is to perform about 30 transplants annually for the younger patients. He is optimistic that tests of newer drug combinations will lead to less-toxic chemotherapy prior to transplant. He also is pleased about a new clinical study using blood stem cell transplants for children with brain tumors.

 

The outlook for selected ovarian cancer patients is improving through a combination of more-effective chemotherapy and autologous blood stem cell transplants.

 

"We are heartened about several protocols that enhance the patients' likelihood for longer disease-free survival," says Dr. Michele Donato, an instructor of medicine.

 

After completing a two-year fellowship at M. D. Anderson, Dr. Donato was appointed to the faculty in 1997 to help develop a new service of blood and marrow transplant support for women with ovarian cancer. Nearly 30 patients have had transplants in the last year.

Dr. Donato cites two encouraging studies:

 

· A regimen for newly diagnosed ovarian cancer patients, who are referred to M. D. Anderson before any treatment. They receive three cycles of Taxol and cisplatin, donate their own stem cells and then take four cycles of high-dose Taxol and carboplatin. After each high-dose treatment, they get an infusion of their stem cells. These patients receive most of their therapy in an ambulatory environment.

 

· A protocol for ovarian cancer patients found to have residual disease during second-look surgery. Appropriate patients receive one or two cycles of high-dose etoposide and ifosfamide, followed by an intensive three-drug combination of topotecan, cytoxan and melphalan and stem cell transplant.

 

"Many ovarian cancer patients respond well to chemotherapy. We are able to give some of them much higher doses, knowing we can rescue their compromised immune systems with stem cell infusions," Dr. Donato notes.

 

In looking to the near future, Dr. Champlin says he is encouraged about the possibility of a vaccine developed by Drs. Raja Choudhury and David F. Claxton to enhance transplants for both acute and chronic leukemias. Dr. Jeffrey J. Molldrem also was recently recruited from the National Institutes of Health to head another translational research project aimed at designing a vaccine against leukemia.

 

Dr. Molldrem, an assistant professor of medicine, discovered a peptide labeled PR1 that is over-expressed in the myeloid cells responsible for most types of leukemia. In his laboratory at M. D. Anderson, he is manipulating the donors' T-lymphocytes to suppress GVHD while strengthening the cells' ability to destroy the problem.

 

"Our goal is to train the T-cells through laboratory enhancement to better recognize the bad myeloid cells and attack them vigorously. We do this by making use of the target molecules like PR1 that the T-cells recognize, then using those molecules as a vaccine against the leukemia. With time, we plan to expand this technique to vaccinate allogeneic donors, whose T-cells will then be trained to destroy the leukemia without producing complications," Dr. Molldrem explains.

 

A new study involving 60 leukemia patients aims to evaluate the efficacy of three different doses of the PR1 vaccine. Dr. Molldrem and colleagues will be the first to seek approval from the U.S. Food and Drug Administration to use this approach for patients with myeloid leukemias.

 

Presently, he says chemotherapy alone does not cure patients with chronic myelogenous leukemia and produces durable remissions in only 20 percent of acute myelogenous leukemias. Patients who relapse after chemotherapy are candidates for blood and bone marrow transplants.

 

Dr. Champlin says another important area of interest involves targeted radiotherapy to the site of malignancy in patients with multiple myeloma and breast cancer that has spread to their bones. This study seeks to show the role of a bone-seeking radioisotope in selectively killing cancer in the bones. This agent goes to the bone like a bone scan and delivers a high dose of localized radiation with minimal side effects.

 

"These and many other efforts to apply all types of blood and marrow transplantation to more patients are producing major advances. At M. D. Anderson, transplantation has long ceased to be experimental. In fact, I view transplantation support as an essential part of our high-quality patient care," Dr. Champlin emphasizes.