BMT Clinical Update
Bone Marrow Transplantation
January 2000

With improvements in both conventional as well as transplant therapies, recommendation as to when a patient is an appropriate candidate for transplant have changed considerably in the last few years. In the next few Transplant Update issues, we will try to bring you up-to-date with transplant outcomes both at our center and nationally and help clarify when transplants should be offered to your patients. We will also highlight the areas still in question or the subject of ongoing clinical trials. We will organize these discussions based on disease with sub-categories including age, stage, and remission status. The first tumor type will be Diffuse Aggressive Non-Hodgkin’s Lymphoma followed by Chronic Myeloid Leukemia in this issue of the newsletter.

Diffuse Aggressive
Non-Hodgkin's Lymphoma

1. First Complete Remission
   The treatment algorithm that we propose for transplants in patients with Diffuse Aggressive Non-Hodgkin’s Lymphoma is shown in Figure 1. As a whole, CHOP chemotherapy is still the standard of care in patients with intermediate and high grade Non-Hodgkin’s Lymphoma producing remissions in 60-70% of patients and cures in 45-50%. There have been a number of Phase III trials comparing transplant to chemotherapy for patients in first remission or as part of initial therapy. In general, these trials have not shown a benefit for transplant as compared to conventional therapy with one exception. In retrospective analyses in many of these trials, the outcome is better for high risk patients defined by IPI (International Prognostic Index) as being in the high intermediate or high risk groups: two or three of the following: > Stage II disease at presentation, LDH > normal at presentation, and impaired performance status such that patients are unable to work full-time. In these retrospective analyses, an improvement in both progression-free and overall survival has been seen. In the most complete data to date, presented by Dr. Haioun at this year’s ASH meeting, was the eight year outcome of patients treated on the GELA LNH87 Trial. The eight year disease-free survivals for those transplanted in first complete remission was 55% vs. 39% for those receiving chemotherapy only (P is .02). The survival was also improved and was 64% vs. 49% retrospectively (P is .04). Validation of this data is currently underway with the recent re-opening of the inter-group trial SWOG 9704, with participation by SWOG, ECOG, and CALGB. This important trial headed by SWOG has Loyola as it’s lead institution. The trial design is shown in Figure 2. Patients can receive one cycle of CHOP before registration. However, they must be registered before the second cycle of therapy. The CHOP chemotherapy for the entire protocol can be given in the community, thus preventing any disruption of traditional conventional therapy for these patients. In addition, funding is being provided by Bristol Meyer Squibb for each enrollee in this trial to be paid by the physician initiating the therapy. As shown in Figure 2, randomization occurs after five cycles of CHOP and is between an additional three cycles of CHOP followed by observation (control arm) vs. one cycle of CHOP followed by transplant. Until the results of this trial are known, there is no rationale for transplanting patients with Diffuse Intermediate Grade Non-Hodgkin’s Lymphoma in first complete remission.
   



First Partial Remission
Patients who do not enter a CR with CHOP chemotherapy are unlikely to be cured with consolidation chemotherapy or radiation therapy. The definition of PR is important here as residual masses may not indeed by residual disease. In general, a PR is defined as biopsy proven disease or disease that is gallium avid. While newer therapy such as Rituxin or Radidubelled MoAb immunotherapy can be tried for this patient population, they are as yet unproven therapies in this particular setting. Transplants are associated with a 70% long-term progression-free survival and are generally accepted as a treatment of choice for this patient group.


2. Induction Failures
   Patients who progress during initial therapy in general have a dismal prognosis. In the past, only palliative chemotherapy has been recommended. However, there does seem to be a sub-group of these patients who may benefit from an aggressive approach. As first reported by us in the JCO in January of 1998, as part of a SWOG trial, we discovered that if a patient who progresses during induction therapy (induction failure) and later responds to an initial salvage chemotherapy regimen such as DHAP, ESHAP, or EPOCH, transplants can then provide long-term survival in at least 50% of patients. Conversely, if patients do not respond to salvage therapy in this setting, transplants including allogeneic transplants offer only a 10-15% chance of long term survival and are frequently not performed. We have found that Rituxin may actually aid in increasing the chances of a remission when given with salvage chemotherapy for this patient population and this strategy will be studied in an upcoming intergroup trial that will be CALGB led.
   
   To summarize, then, a patient who fails induction chemotherapy should be given aggressive salvage therapy; and, if he/she responds, should be referred for transplant.
   
3. Relapsed Disease
   Nearly six years ago, the PARMA trial validated the use of BMT for relapse intermediate grade Non-Hodgkin’s Lymphoma. Longer follow-up data continues to confirm that transplant patients have a 50% long-term survival vs. 20% for patients receiving only conventional therapy and then offered transplant as third line therapy. SWOG has shown in the trial mentioned above (JCO, January 1998) that the more aggressive the preparative regimen, the better the outcome and we continue to evaluate in the Southwest Oncology Group and here at Loyola in a randomized fashion the value of post transplant InterLeukin 2 given for a 19 day cycle after transplant (SWOG 9438). This trial is more than 50% completed and toxicity is not unexpectedly high. In fact, there have been no treatment related deaths due to the IL-2 therapy. Similar to that for induction failures, studies are underway to evaluate the value of Rituxin given with salvage chemotherapy, i.e., pre-BMT to improve outcome as relapse remains the largest cause of failure in this patient population. Not only might this therapy debulk the disease, but it also might, in  vivo, purge patients’ peripheral blood stem cell transplant concentrates. Despite the intensity of the preparative regimens that we recommend, we perform these transplants, including those involving TBI in our new outpatient BMT Unit. Our mortality rate for all lymphoma transplants done over the last 5-6 years here at Loyola is approximately 1%, significantly less than the 6-8% national average such as that seen in the SWOG trials. We continue to lead SWOG in lymphoma BMT trial accruals and feel that this is the best vehicle for answering these important questions.
   
4. Mantle Cell Lymphomas
   We frequently get calls about when to advise transplants for Mantle Cell Lymphoma. With a median progression-free survival of only 15 months and a very low long-term curability rate with conventional chemotherapy, this sub-type of Non-Hodgkin’s Lymphoma has a very dismal prognosis. We and others have found that transplants (autologous) in first remission offers patients at least a 40-50% long-term survival and appears to be superior to that expected as stated above with conventional chemotherapy. Several features appear to be important in this patient population, the first being an aggressive upfront regimen such as that reported recently in JCO by the M. D. Anderson group, the hyper CVAD regimen. This involves a very aggressive CHOP-like regimen combined with high dose ARA-C and high dose methotrexate. Transplants are then performed in first remission. Data both from the United States as well as abroad strongly suggests that TBI as part of the preparative regimen is critical in improving the long-term survival. Chemotherapy only regimens do not appear to be as successful in producing these long-term survivals as TBI based regimens. Because of this interesting data and the dismal prognosis for conventional therapy, this subtype of lymphoma is not eligible for the inter-group trial, and again, is being studied in a Phase II fashion with induction chemotherapy followed by transplant. Thus, as you treat patients with Mantle Cell Lymphoma, if they enter a first complete remission or an excellent PR, transplant should be strongly considered as transplants for relapse disease, while occasionally effective, are not as effective as they are in first remission.
   
   A final comment about allogeneic transplants for intermediate grade lymphoma: in general, and this has been looked at in registry data both in the United States and in Europe, autologous transplants produce the same outcome as allogeneic transplants. Obviously, there are fewer relapses associated with allogeneic transplant, but the morbidity costs and mortality related to regimen related toxicities and graft vs. host disease are much higher for allogeneic transplant. Thus, while the five year survival rates are similar, the one year and two year survival rates are much higher for patients undergoing autologous transplants. Thus, in general, we as well as other centers do not recommend consideration of allogeneic transplant for patients who are responding to upfront or salvage chemotherapy and have a bone marrow uninvolved with disease. However, for these later two categories, allogeneic transplants can and should be considered especially for patients under the age of 40.
   

Chronic Myeloid Leukemia

1. Chronic Phase, Age Less than 40
   The treatment algorithm for CML in chronic phase for patients under 40 is shown in Figure 3. This algorithm has changed a bit over the last several years, but fundamentally offers patients not only the best chance for cure, but also the best chance for long-term survival. Data continues to show that patients, especially those under the age of 40 who have access to an HLA matched sibling donor, should undergo an allogeneic transplant in the first year following diagnosis. In fact, data would suggest in this period that the first six months may actually be optimal. Results from large centers including our own suggest that 60-70% of these patients are alive at 5 years following transplant without evidence of disease. If an HLA matched sibling donor is not available, in the under age 40 group, we do next access the national and international data bases to look for a matched unrelated donor transplant. If we find a donor that is matched at A, B, C, DR loci including DNA matching at Class II antigens, we would pursue a matched unrelated donor transplant as being not only a curative therapy but also less toxic in the last few years with DNA typing and matching at all eight loci. Previously matching occurred at only A, B, and DR. However, recent data from several centers confirms that matching at C loci is important for MUD transplants. Again, transplants should be performed in the first 6 – 12 months and patients should not receive interferon therapy as this seems to increase the complications associated with transplants both from a related as well as unrelated donor. If an unrelated donor transplant (bone marrow donor) is not found, then patients should be treated with aggressive interferon therapy " ARA-C and have bone marrow analysis done at 6 – 9 months. In general, we treat aggressively looking for a white count in the range of 2,500 – 3,000 as being an indicator of full and effective therapy. If patients enter a major cytogenetic remission, i.e., have less than 30% abnormal metaphases, then they should continue on this therapy with bone marrow follow-ups every 6 – 9 months. If there is no cytogenetic remission or if a patient has a remission and then progresses, then evaluation for a cord blood allogeneic transplant would be appropriate. We would look for a 4/6, a 5/6, or a 6/6 matched cord blood unit. We continue to be one of only 2 centers in the United States that has the ability to expand umbilical cord cells for allogeneic transplants to be used in adults. Thus we would consider an adult patient based on the size of the cord blood if the patient meets eligibility for our ongoing FDA approved clinical trial. If a cord blood unit is not available that is matched, then we would pursue an autologous transplant as this therapy appears to be superior to that of the only other option available at that time, that being hydroxyurea therapy.
   
   In summary then, for patients under the age of 40, we look for curative therapy initially that is associated with a reasonably low risk of fatal complications. If that is unavailable, then interferon therapy is the prime therapy of choice. If this is ineffective, then transplants with a lesser chance of long-term progression free or overall survival are considered in lieu of hydroxyurea therapy.
   
   
2. Chronic Phase, Age 40-55
   In general, the algorithm is approximately the same as those under the age of 40. There are, however, exceptions primarily related to whether or not a patient should be transplanted with a matched unrelated donor transplant. If patients have an HLA matched sibling donor available, they should undergo an allogeneic transplant in the first year. If such a donor is not available, we would access the computer registries looking for a MUD transplant. For patients at the lower end of the age group, we would consider very carefully a matched unrelated donor transplant using co-morbid conditions as a discriminating factor. However, in general, patients above the age of 40 should be treated with alpha interferon therapy initially and considered for a MUD transplant only if they do not respond with a major cytogenetic remission or progress after that therapy. At that point, a MUD transplant or autologous transplant under the scenario discussed above would be appropriate therapy. In summary, we would not pursue a MUD transplant for a patient newly diagnosed above the age of 40 before we would consider alpha interferon therapy. The rationale for this is that a MUD transplant in this age population is associated with a one year survival rate of less than 40%. Alpha interferon therapy at 1 – 5 years is associated with a superior survival. Thus, we would be risking a patient’s life by doing a MUD transplant in lieu of alpha interferon therapy; or, for that matter, hydroxyurea therapy which would be associated with improvements in survival relative to MUD transplants for up to five years from diagnosis. With new therapy such as the new tyrosive kwase inhibitor, again, we would think very carefully about recommending a MUD transplant and in general would not pursue this at this institution. While patients might like to have definitive therapy done and done quickly, we believe that the 60%+ mortality in the first year following a MUD transplant in this patient population needs to be very carefully considered before a recommendation for a transplant is given. These mortality rates are data from the National Marrow Donor Program.
   
3. Chronic Phase, Age Above 55
   In general allogeneic transplants would not be considered until recently for patients above the age of 55. However, with the advent of mini-transplants, an allogeneic sub-myeloblative transplant is now appropriate to consider for patients with CML in chronic phase above the age of 50. Encouraging preliminary results show that as many as 40 – 50% of these patients are alive and progression free at one year; and, while longer term follow-up is not available, many of these patients are in pathologic remission as well. Thus, we would assess a donor situation up to age 70 as part of a national protocol that looks at CD8 depleted donor lymphocyte infusions if there is full chimerism with the mini-transplant. If there is no HLA compatible sibling donor, alpha interferon therapy would be administered. If there is no cytogenetic remission or a patient relapses, we would consider an autologous transplant up to age 65.
   
4. Accelerated or Blast Transformation
   In general patients with CML in accelerated or Blast Transformation who obviously have a very dismal prognosis are appropriate candidates for any form of allogeneic transplant. Autologous transplants, even if a patient is induced back into second chronic phase are not associated with improvement in survival as compared to conventional therapy. That is, all patients will ultimately succumb to their disease, usually in a very short period of time. Thus, an allogeneic transplant up to age 55 + would be appropriate to consider from either a matched sibling donor, a matched unrelated donor (up to age 40-45), a cord blood ex vivo expanded allogeneic transplant (up to age 55) or a mini transplant (up to age 55-65) would be appropriate to consider for a patient with this otherwise dismal prognosis.

Next Newsletter:

• Indolent Lymphomas
• Multiple Myeloma

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