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In Loving Memory of Barbara GrannyBarb Lackritz
A report on the 2002 Tandem BMT Meetings in Orlando Florida

By Arthur Flatau (flataua@acm.org)

The Annual Participants' Meeting of the International Bone Marrow Transplant Registry (IBMTR) and the Autologous Blood & Marrow Transplant Registry (ABMTR) were held February 22-24, 2002 in Orlando, Florida, which was immediately followed by the Annual Meeting of the American Society for Blood and Marrow Transplantation (ASBMT) were February 24-26, 2002.

The National Marrow Donor Program (NMDP), Research and Publications committee met during this meeting so I was able to attend some of the other sessions on February 22 through February 24. What follows is my summary of the talks and presentations that I went to. Since I am not a medical doctor or researcher in the field, it is possible, in fact quite likely that I have misunderstood or misinterpreted some of what was said. In addition, this is based on my notes at the time and I may not have been able to read them or remember correctly what was said. Generally speaking I found most of the talks on the clinical aspects of the meeting understandable, but much of the laboratory and basic research was much more difficult. A good rule of thumb was, when they started talking about mice, it was time to find another session to go to. Please send me an e-mail (flataua@acm.org) if you have questions, comments, notice a typo or just think that this was useful to you.

I will try to use HSCT (hematopoietic stem cell transplant) as a generic abbreviation for bone marrow, peripheral blood stem cells and cord blood transplants.

I was disappointed that in many sessions the slides were not available. In the sessions in which they were available, I do not think that they are available online. I have tried to put in links to places, where I know that they are available. The slides from the working committees are available online and in fact were only available there (they were not provided at the sessions). In addition, the slides from the Data Management Meetings sesssions are available online [Unfortunately they are no longer available]. I did not attend any of those sessions, although many of them looked interesting, particularily after looking at some of the slides.

Here is a quick list of the sessions that I attended.

Friday, February 22, 2002

Emerging Strategies in Immunosuppressive Therapy in Allogeneic Bone Marrow Transplantation

Sponsered by Fujisawa Healthcare, Inc.

Chair: Joseph H Antin

This session started at about 7:15 a.m., those BMT doctors like to get started early. I had to register and got going a bit late, so I missed a little of the first talk. All these talks dealt with the use of tacrolimus (FK-506) in HSCT, Fujisawa is the manufacturer of tacrolimus.

  1. Cord blood transplantation and immunosuppressive therapy with tacrolimus in pediatric BMT patients -- Ka Wah Chan
  2. Non-myeloablative bone marrow transplantation: pilot study results with tarolimus in adult BMT patients -- Ian W Flinn

    This talk was a report on the use of non-myeloablative transplants for hematological malignancies (mostly leukemia) at Johns Hopkins. There were 20 patients reported on, most of whom were heavily pre-treated and about half had a previous HSCT. There was little severe GVHD in this group, although one patient died of severe GVHD. The long-term survival was about 45%. The prepartive regimen was based on that at Fred Hutchinson, using 200 cGYs of total body irradiation (TBI) and FK-506. However there were some problems with engraftment so fludarabine was added in patients who had previously recieved more then 12 rounds of chemotherapy.

  3. Tacrolimus and rapamycin therapy in allogeneic bone marrow transplantation: pilot study results -- Joseph H Antin

    Rapamycin (Sirolimus, Wyeth-Ayerst) is an experimental drug that is being used to treat GVHD. The use of rapamycin can decrease the amount of FK-506 (or cyclosporin, which has been demonstrated in solid organ transplants) with perhaps better GVHD prophalaysis, it may be possible to do away with treating with methotrexate. This appears to be quite promising.

    Possible advantages are:

    • It may inhibit GVHD better

    Possible disadvantages are:

    • It tastes worse then cyclosporine (hard to believe) and was only available as an oral liquid, although pills are now available. Oral drugs are usually not the best choice early after HSCT.
    • Since much less FK-506 (or cyclosporin) needs to be taken, it is more difficult to taper these drugs later. For instance, if you are taken 100 mgs of cyclosporin, it is hard to taper this 5%/week as you can not get cyclosporin in pills of mg.

PLENARY: Stem Cell Plasticity

Session Chair: Irving Weisman, MD

This was quite an interesting session, looking at stem cells to treat diseases that I do not normally think of being treated with HSCT, for instance heart problems. They are not using transplants typically, but using the stem cells themselves.

  1. Transdifferentiation and differentiation by purified stem and progenitor cells - Irving Weisman, MD, Stanford University School of Medicine Talked a lot about mice.
  2. Cytokine mobilized stem cell repair of myocardial infarcts - Donald Orlic, PhD, National Institutes of Health This study was in mice, but much of it I did understand. They used G-CSF (Neupogen) and stem cell factor (I think) to repair heart problems (infarcts) in mice. They also used bone marrow cells and G-CSF mobilized peripheral blood stem cells. Survival of mice that were treated with G-CSF was 80% versus about 20% in mice that were not treated.
  3. Stem cell plasticity: the blood of Prometheus - Neil Theise, MD, New York University Stem cells can be grown and turned into many other types of cells. In animals with severe liver injury approximately 40% of the cells in the liver appear to be derived from the bone marrow versus about 1% under normal conditions.

    Proposed some axioms of genomic uncertainty

    • Can turn any cell into any other cell.
    • Like the Heisenburg Uncertainly Princicpal in Physcis, attempting to determine what kind of cell you are looking at can change the cell.
    • You can not tell what a cell will become, only that it is probable that it will become a cell of a certain type.

CONCURRENT 1: Solid Tumors: Where Do We Stand?

Session Chair: Giovanni Rosti, MD

  1. EBMT Registry and European activity - Giovanni Rosti, MD, - Ospedale Civile He talked very quickly and in addition had some problems with slides, so I likely missed some things. He gave a quick overview of transplants for solid tumors in Europe. Some points:
    1. The age limits for transplants are increasing
    2. There appears to be about 2% mortality at 100 days for auto HSCT
    3. Breast cancer
      • The number of HSCTs for breast cancer has decreased dramatically.
      • An Italian study showed benefit for HSCT for patients under 35 who had 4-9 positive lymph nodes.
      • Dutch study showed some benefit for HSCT.
      • Other trials are ongoing -- particularily looking at long term survivial
    4. Testicular cancer -- auto HSCT are used more often in Europe then in the North America for relapsed disease.
    5. Small Cell Lung Cancer (SCLC) proceeding with a random study comparing with chemotherapy (ICE).
    6. Ewing's Sarcoma -- patients recieving Busulfan do much better
    7. Doing non-myeloablative stem cell transplants for many solid tumors
    8. Renal Cell Carcinoma. A small study at Huddinge did non-myeloablative stem cell transplants for 10 patients (age 47-65) with 5 related donors and 5 unrelated donors. 6 patients died from the treatment.
  2. High-dose chemotherapy for ovarian carcinoma - Thomas Shea, MD, University of North Carolina This was an overview of various studies on autologous HSCT for ovarian cancer. A study he did did autologous HSCT in complete remission (based on "second look" surgery) on 33 patients, overall survival at 5 years was about 30-40%.

    Donato reported at ASCO 2001 on 102 patients, half of whom were stage 3 or in second complete remission the other half were more refractory. They were treated with autologous HSCT, using various regimens. There was no treatment related mortality and overall survival at six years was 55%.

    Stiff et. al, ( High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: a multivariate analysis of survival for 100 consecutively treated patients (article abstract), J Clin Oncol 1997 Apr;15(4):1309-17 reported that younger age, less bulky disease and platinum sensistivity predicted better overall survival.

    Stiff et. al, in a report based on ABMTR data ( High-dose chemotherapy and autologous stem-cell transplantation for ovarian cancer: an autologous blood and marrow transplant registry report.(article abstract) Ann Intern Med 2000 Oct 3;133(7):504-15 looked at 421 patients and came to the same conclusion as the above study.

    There has been some work on vaccine therapy with Theratope in Breast Cancer and Ovarian Cancer (Holmberg, et. al. Clinical outcome of breast and ovarian cancer patients treated with high-dose chemotherapy, autologous stem cell rescue and THERATOPE STn-KLH cancer vaccine (article abstract) Bone Marrow Transplant 2000 Jun;25(12):1233-41 which is still a work in progress.

    At ASCO 2001, Gineco reported on a randomized trial with patients who had a low tumor burden. There was 1 treated related death in 102 patients. With a median follow-up of 3 years there was a disease free survival of 22 months in the autologous HSCT group vs. 11 months in the group treated with conventional therapy.

    A Phase III randomized trial (where? UNC?) of carboplatin + pacitaxel (8 totol doses) vs. the same regimen (6 total doses) plus auto HSCT is continuing with the hope of accruing and randomizing 200 patients.

  3. High-dose chemotherapy for metastatic breast cancer: do we know everything? - Michael Crump, MD, University of Toronto This was a review of various studies looking at high dose chemotherapy (HDC) with HSCT for Breast Cancer.

    Standmayer showed no difference between standard CMF and autologous HSCT.

    In 1996, Breast Cancer was the most common reason for autologous HSCT. However the Intergroup (randomized trial ??) study was accruing slowly. A Canadian study showed no difference in overall survival between HDC and standard dose chemo. Disease free survival (DFS) was better with HDC, but toxicity was worse.

    Berry et. al ( High-Dose Versus Standard Chemotherapy in Metastatic Breast Cancer: Comparison of Cancer and Leukemia Group B Trials With Data From the Autologous Blood and Marrow Transplant Registry, Journal of Clinical Oncology, Vol 20, Issue 3 (February), 2002: 743-750) show no difference between HDC and standard chemo and the regimen does not effect overall survival.

    Immunotherapy, faster engraftment means better overall survival. Adding IL-2 to G-CSF during mobilization before harvesting enhances Natural Killer (NK) cells.

    Conclusion: High Dose Chemotherapy should only be used in scientifically valid trials.


Luncheon Satellite Symposium (American Red Cross)
Dendritic Cell Immunotherapy: Towards Clinical Reality

Chair: Kerry Atkinson

As I recall this session was very technical.

  1. Recent advances in human dendritic cell biology -- Derek N J Hart, Mater Medical Research Institute, Brisbane, Australia Definition of a Dendritic Cell:
    1. Ability to take up and process antigen
    2. Ability to migrate selectively through tissue
    3. Ability to interact with, stimulate and direct T cells responses
    4. An emerging molecular phenotype
    5. Certain morphological features.

    Conclusions:

    1. Rapid progress is being made in understanding Dendritic Cell Biology
    2. Cancer immunotherapy is a useful new theory that continues to need a lot of work
    3. Dendritic Cell therapies are coming
  2. Use of adenoviral transduced dendritic cells as activators of cytotoxic T-cells for immunotherapy -- Stephen Gottschalk, Baylor College of Medicine, Methodist Hospital and Texas Children's Hospital Using an adenovirsus vector to modify dendritic cells. This has been tried in EBV positive relapsed Hodgkin's disease patients with promising results.
  3. Dendritic cell vaccines for cancer: clinical experience -- John Timmerman Dendritic cells have been studies in clinical trials for B cell lymphoma, melanoma, renal cell carcinoma, carcinoembyronic antigen (CEA)+ carcinomas, prostate carcinoma and pediatric solid tumors.

    Idiotype-pulse dendritic cell vaccination (to be published in Blood, May 1, 2002). 23 patients in first remission with residual disease and antibody/T cell responses in 65% and tumor regression in 4/18 (22%). After boosting with ld-KLH protient, tumor regression was seen in 3/6 (50%) of patients, 2 with a complete response and 1 with a partial.

    Nestle et. al ( Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. (article abstract), Nataure Medicine, March, 1998;4(3):p 328-32) treated 16 patients with monocyte derived dendritic cells pulsed with several melanoma antigen peptides. There was little toxicity and 2 complete responses (lasting 15+ months) and 3 partial responses.

    Thurner, et. al. ( Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. (article abstract) Journal of Experimental Medicine, December 1999 6;190(11): pp. 1669-78.) Also little toxicity and produced "mixed responses" (complete regression of individual metastases) in 6/11 patients.

    Banchereau, et al, ( Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. (article abstract), Cancer Research, September 2001 1;61(17):6451-8), tried a different dendritic vaccine. Again little toxicity, but 3 complete remissions, 4 mixed responses and 3 patients with stable disease.

    There have been some results in renal cell carcinoma 7/17 patients with some response, although there is some controversy about the results. In carcinoembyronic antigen (CEA) expressing cancers, results have been mostly poor (Morse, et. al., A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen. , Clinical Cancer Research Vol. 5, 1331-1338, June 1999 and Weber from USC).

    However Fong, et. al ( Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy , Proceeding National Academy Sciences. USA, Vol. 98, Issue 15, 8809-8814, July 17, 2001) had 2 complete responses and 1 mixed response and 2 patients with stable disease out of 12 people treated.

    In pediatric solid tumors (neuroblastoma, sarcomas and renal tumors), Geiger, et. al. ( Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. (article abstract), Cancer Research December 2001 1;61(23): pp 8513-9), 10 patients were treated, there was one partial response and 5 patients with stable disease.

    In summary, dendritic cell vaccination appears to have clinical activity in a number of cancers but a lot of research is still needed.


WORKSHOP 3: GVHD - Can We Improve Grading and Diagnosis?

Co-Chairs: Nelson Chao, MD, Duke University Medical Center;
Edmund Waller, MD,PhD, Emory University

First Kenneth Cooke from University of Michigan gave an overview of Graft versus Host Disease (GVHD). The requirements for GVHD (Billingham Postulates ??) are that the T-cells from the donor have some HLA mismatch and the host is immuno-suppressed.

GVHD is hypothesized to begin because of toxicity of the conditioning causing tissue damage. The immune system attempts to "fix" this damage which starts an inflammatory response (from cytokines, including IL-1, IL-2 and Tumor Neucrosis Factor alpha -- TNF-alpha).

TNF-alpha levels correlate with GVHD.

Dr. Cooke then went on to talk about lung injuries post-BMT and whether these might be associated with GVHD. Idiopathic pneumonia syndrome (IPS) has a 50% mortality soon after an HSCT. There is an association between acute GVHD and IPS, similarily there is an association between chronic GVHD and BOOP (Bronchiolitis Obliterans Organizing Pneumonia).

There is much disagreement between experts in what constitutes GVHD stage II, most agree on stage 0 (no GVHD) and stage I as well as more advanced disease (stage III and IV). When it comes to chronic versus acute GVHD, the dividing line of 100 days is entirely arbitrary. This is becoming more and more apparent with Non-myeloablative HSCT and more Donor Leukocyte Infusions (DLI). Whether it is chronic or acute really depends more on the symptoms. What should be reported to the registery is what the symptoms show. Pathology is not always reliable.


WORKSHOP 4: Cord Blood Transplants

Co-Chairs: Joanne Kurtzberg, MD, Duke University Medical Center;
Vanderson Rocha, MD, Hopital St Louis

This was a discussion of cord blood transplants, with an emphasis on cord blood banking issues. Although the co-chairs were as above, Pablo Rubinstein of the New York City Blood Bank contributed quite a bit of data.

There is good evidence that the higher the number of cells in the cord blood unit, the better the outcome. This does present something of a dilemma when looking at multiple units of differing size for a particular patient. Should the larger unit always been chosen (within reason) or does it make sense to choose a smaller unit, but sufficiently big in order not to deprive some future hypotheical patient who might need it and not be able to use the smaller unit.

Although there does not seem to be a known minimum acceptable dose, there is good evidence that there is very high mortality when units with less then 1 x 10 7 cells/kg are used. Increasing the cell dose significantly lowers the mortality. However after 50x10 7 there is a point of diminishing returns. Larger cell doses result in somewhat faster engraftmetn, but otherwise similar results.

For these reasons most doctors will opt for a larger unit.

Rubinstein ( Outcomes among 562 Recipients of Placental-Blood Transplants from Unrelated Donors, Pablo Rubinstein, et. al., New England Journal of Medicine, Volume 339, Number 22, pages 1565-1577, November 26, 1998) showed the importance of cell dose. Since 1998 at the New York City Blood Center, there has been an increase in cell dose among patients but no improvement in survival. This is probably because less well matched HLA units were used more often. A guideline is that a HLA mismatch is worth about 2.5x10 7 cells/kg.

What threshold (in terms of number of cells in a unit) should there be for banking. It is clear that smaller units are less useful, should they not be saved? The goal is to have at least 1.5x10 7 leukocytes/kg (after thawing). For an adult (70 kg) this means that 1.4x10 9 cells are needed at collection. Approximately half of all units are this large.

How a unit is stored at the transplant center also appears to be important. There was a fair amount of discussion on freezers. The bottom line, in my view, is that hospitals that do more cord blood transplants will, I hope have better procedures in place to handle cord blood units.

As for directed donations, this is different then public banking. There are more relapses with sibling transplants in malignant diseases, but there are good outcomes in other diseases.


Tandem BMT Meetings Welcome Reception

Those BMT doctors can really party!! I did meet and talk to a few folks here, but to be honest I was tired at the end of the day and soon went to bed.


Saturday, February 23, 2002

IBMTR/ABMTR Acute Leukemia Working Committee Meeting

Co-Chairs: AML: Armand Keating,MD-Princess Margaret Hospital
ALL: Daniel J. Weisdorf,MD-University of Minnesota
Statistician: Waleska Perez, MPH

The slides from this meeting are available are online. There were various presentation on research projects that are being done using data from the IBMTR/ABMTR.

4. Studies in progress

a. Optimal timing of BMT for MDS , Corey Cutler, Dana-Farber Cancer Institute. For the lowest risk patients (i.e. more or less stable) the best stradegy appears to wait to do HSCT until after progression to AML, otherwise HSCT should be done as soon after diagnosis as possible. They are trying to determine a good algorithm for when to do a BMT for MDS, using the data from the IBMTR and hopefully the data from Seattle as well.

b. Vp16/TBI vs CyTBI for HLA-identical sibling BMT for ALL , David I. Marks PhD Bristol Adult BMT Unit. Not much was added to the manuscipt [ Unfortunately no longer available ].

d. Transplant vs chemo for relapsed AML Marcos de Lima, M. D. Anderson Cancer Center. Not much was added to the manuscipt [ Unfortunately no longer available ].

5. Proposed Studies

b. Outcome of Ethnic Minorities with Malignancies Treated with Hematopoietic Stem Cell Transplantation . K. Scott Baker, M.D, University of Minnesota.

  • To determine if ethnic minorities have similar outcomes to whites

  • Is race an independent risk factor?

Probably only sufficient data to look at black vs. white vs. all others, although perhaps Hispanics have enough data. There are other conflicting factors, e.g. socio-economic status, education.

c. Busulphan and melphalan conditioning for BMT in AML , Peter J Shaw, MD; Marie Bleakley, MD, Sydney, Australia.

There is limited data on the use of Busulphan and melphalan in AML patients, there are only 102 patients in the IBMTR database (for AML, ALL and MDS).

d. Comparison of autologous hematopoietic stem cell transplantation with or without reinfusion of molecularly negative stem cells and allogeneic hematopoietic stem cell transplantation (HSCT) for patients with acute promyelocytic leukemia (APL) in second complete remission . Martin Tallman, MD, Northwestern University, Chicago, IL.

Compared auto-HSCT versus allogeneic HSC for patients with APL in second complete remission. There is 75% disease free survival (7 year) with ATRA and chemo with ATRA maintenance. Using arsenic to induce a second remission appears to result in about 60% DFS after no further treatment. In a small study harvesting molecularily negative cells results in high DFS. e. Allogeneic Stem Cell transplantation for the Treatment of Therapy-Related Myelodysplastic syndrome and Acute Myelogenous Leukemia . MR Litzow, Mayo Clinic & Foundation, Rochester, Minnesota.

There are about 400 patients in the IBMTR from 1996 through 2000.


PLENARY: Immunopharmacology

Session Chair: Barbara E Bierer, MD

  1. Molecular immunopharmacology of immunophilin binding reagents -- Barbara E Bierer, MD, National Heart, Lung and Blood Institute, NIH
  2. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies in transplant patients - Leslie M Shaw, PhD, University of Pennsylvania Medical Center Mycophenolate Mofetil (MMF or CellCept) breaks down into Mycophenolic acid (MPA) in the body. In kidney transplants, there is a big improvement in one year graft survival in patients who recieve MMF, but after that the rates of organ rejection are about the same (MMF has mostly been used in solid organ transplants and only recently been used in HSCT patients).

    There have only been small trials of MMF in HSCT patients, but it is still widely used.

  3. Immunopharmacology of novel biologic agents: IMiDs and PS341 -- Nikhil C Munshi, MD, Dana-Farber Cancer Institute A high level of microvessel denisty in multiple myeloma patients has predicted lower survival. This was the rational for the use of thalidomide -- to inhibit the growth of new blood vessels. Thalidomide worked on many patients but in patients taking thalidomide microvessel density did not predict survival.

    This lead to the development of IMiDs - immuno modulating agents. IMiDS are similar chemically to thalidomide however they are more potent T-cell stimulators then thalidomide.


CONCURRENT 3: Roles of Apoptosis in BMT

Session Chair: Scott Kaufmann, MD, PhD

I went to this session after talking to Sue Stewart from the BMT InfoNet as she was going to go the Quality of Life session. However after the first talk, I realized that most of the talks dealt with mice and did not understand many of them, so I then went next door to the Quality of Life session.

  1. Overview of apoptotic pathways and their activation during bone marrow transplantation -- Scott Kaufmann, MD,PhD, Mayo Clinic As indicated above, this talk was largely on mice and I did not understand much of it.
  2. The marrow microenvironment and resistance to drug-induced apoptosis -- William Dalton, MD,PhD, H Lee Moffitt Cancer Center I did not go to this talk.
  3. Cell death induced by cytotoxic lymphocytes -- Pierre Henkart, PhD, National Cancer Institute I did not go to this talk.


CONCURRENT 4: Quality of Life

Session chair: John Wingard, MD;

I missed the first talk, below in an optimistic attempt at understanding apotosis. It was surprising to me that there appeared to be many more people in the Quality of Life session then in the apotosis session.

  1. QOL and relationships after BMT: preliminary results -- Michelle M Bishop, PhD - University of Florida HSC I missed this talk.
  2. The problem of fatigue after high-dose chemotherapy -- Paul Jacobson, PhD, H Lee Moffitt Cancer Research Institute; The causes of fatigue in cancer patients (who have completed treatment) is poorly understood. Possible causes of fatigue include:
    • Anemia -- certainly a cause in patients under treatment, but should not be a major cause of fatigue after treatment
    • Physical inactivity and deconditioning
    • Sleep disturbance
    • Depression - fatigue is a symptom
    • Central Nervous System (CNS) toxicity -- Perhaps? There is higher cognitive impairment in Breast Cancer patients treated with HDC (autologous HSCT) then those treated with standard chemotherapy.
    • Reduced heart and/or lung function ??
    • Altered immune or endocrine function ??
      • There is significant fatigue in patients recieving Interferon-alpha
      • Chemotherapy reduces estrogen and testorone levels
    • Insights into post transplant quality of life from the Unrelated-Donor Transplant Trial -- Shelly Carter, PhD, The EMMES Corporation; She reported on a study of patients entered into a T-cell depletion study. The primary end-point of the study was 3 year Disease Free Survival (DFS). However they also did an assessment of patients' optimism before treatment and after treatment. This was done by telephone interviews at baseline, 100 days post HSCT, 6 months, 1 year and 3 years. There were 400 questions at the baseline and it took 45-60 minutes to complete. Fewer questions were used on followup. 81% of the surviving patients completed the study.

      The conclusion was the social support, optimism and coping were associated with a higher quality of life, while pessimism, and aviodance were associated with a lower quality of life.

    • What these studies teach us and what we need to learn -- John Wingard, MD, University of Florida HSC


NMDP RAP Meeting

This is the meeting what I was supposed to go to Orlando for. The NMDP maintains a database of all the transplants that it has facilitated. This database is a useful resource in trying to ascertain what are the best treatment approaches for different populations of patients (difference diseases, race, age, etc.). They provide assistance in acquiring this data from the database and statistical analysis of the data. The job of the RAP committee, at least as I understand it, is to oversee this activity.

The closed meeting focused mostly on how we were supposed to evaluate different proposals. We decided that we should evaluate them based on scientific merit and importance.

The other interesting item at this meeting was the use of peripheral blood stem cells in unrelated HSCT. NMDP has a Investigational New Drug (IND) application with the FDA for the use of G-CSF (Neupogen) mobilized peripheral blood stem cells (PBSC) with unrelated donors. NMDP has conducted a Phase II (non-randomized) trial using PBSC and there was not a statistical significant different (it is still too early to tell if this is true for chronic GVHD). NMDP wants to conduct a Phase III randomized trial comparing bone marrow with PBSC. Scientifically, they would like to force centers to enter patients in this trials, patients who are not entered in the trial would only be able to get bone marrow (unless the donor for some reason could not donate bone marrow, only PBSC). It was felt by many of the doctors on the committee that this would not work, centers would not want to be told that they could not recieve PBSC. It is certainly important to find out which is better PBSC or bone marrow and in what situations (it is not unreasonable to expect that this might differ depending on the disease being treated). It was also felt that this trial needed to start as soon as possible, otherwise centers will be making decisions on which they think is better and not be willing to participate in the trials.


NMDP Open Research & Publications Session

NMDP's Research and Publications (RAP) Committee is hosting this open session for presentation of selected study proposals. There were 5 oral presentations at this session.

  1. Unrelated Donor Stem Cell Transplantation in Patients Who Failed an Autologous Transplant presented by Steven Pavletic, University of Nebraska, with Chatchada Karnes, NMDP

    This study would look at the results of unrelated transplants who had an unrelated HSCT after recieving an autologous HSCT and then relapsing. According to the NMDP database, there are 543 patients with hematological cancers in this group (188 patients with AML, 41 with ALL, 42 with CML, 42 with MDS, 167 with NHL, 53 with Hodgkin's disease and 63 with plasma cell disorder). At the time of this survey 31% were surviving, about half are 1 year post-HSCT. The study proposing to look at prognostic factors that might predict better or worse survival.

  2. Evaluation of Unrelated Donor Leukocytes Infusions to Treat Relapse after Unrelated Donor Stem Cell Transplantion , David L. Porter, University of Pennslyvania, with Alison Wakoff, University of Pennslyvania and Jose Leis, Oregon Health and Science University

    Although Donor Leukocyte Infusions (DLI) have been used quite extenisively in patients with relapsed leukemia after matching sibling HSCT, there has not been nearly as much experience with unrelated transplants. The same authors published a study looking at DLIs in unrelated transplants before 1996 ( Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions, David Porter, et. al. Blood, Vol. 95 No. 4, February 15, 2000: pp. 1214-1221 ). There were only 61 patients identified in the NMDP database, 58 were included in the study. Although the original study was small, it showed that DLIs from unrelated donors in patients with CML was about as effective as in siblings, while it was more effective in acute leukemia (AML and ALL). This new study would look at patients who were treated with DLIs between 1997 and 2001. There are surprisingly few patients in the NMDP database who have recieved DLIs. There are 642 patients who have relapsed, but only 89 who recieved DLIs (25 for CML, 49 for AML and 15 for ALL). This is a surprisingly low number.

  3. HLA Disparity: Defining Allogeneic Potential through Outcomes Analysis , Lee Ann Baxter-Lowe, University of California, San Francisco

    Frankly I did not understand this proposal. It is attempting to look more closely at HLA types and see if these can predict patients who will get more or less GVHD after a transplant. I felt a little better after Dan Weisdorf, from University of Minnesota, who asked a question starting with, there are probably only three people in the room who understood the proposal.

  4. Unrelated Hematopoetic Stem Cell Transplantation for Severe Combined Immunodeficieincy Syndrome and Wiskott-Aldrich Syndrome: Analysis of Outcome by Graft Type , Mary Eapen, IBMTR/ABMTR Statistical Center with Alexandra H. Filipovich, Children's Hospital Medical Center

    This study is designed to look at whether it is better to use unrelated donors or umbilical cord blood (UCB) in treating children with severe combined immunodeficiency (SCID) and Wiskott-Aldrich syndrome (WAS).

  5. The Effect of Natural Killer Cell Killer Immunoglobulin Receptir (KIR) Class I Epitope Mismatching on Outcome of Volunteer Unrelated Donor Hematopoietic Cell Transplantation , Sherif S. Farag, Ohio State University.

    Mismatching for a particular Epitope (Killer Immunoglobulin Receptir -- KIR) may have an effect on graft failure, GVHD and relapse, this has been claimed in at least one study ( Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation., by Ruggeri L, Blood Vol 94, No 1, July 1, 1999, pages 333-339). This study intends to look back at the NMDP database and try to retrospectively look at KIR and see how it effects patients outcomes.


ORAL ABSTRACTS: Session 3

The abstracts have been published in the February, 2002 issue of Biology of Blood and Marrow Transplantation. The abstract numbers refer to that issue.

Six oral presentations selected from submitted abstracts for GVH/GVL and Solid Tumors, moderated by Joanne Kurtzberg.

  1. IL-18 reduces acute GVHD but preserves GVL effect after allogeneic BMT . P Reddy, et al.
  2. Regulatory T-cells actively suppress GVHD and promote lymphoid reconstitution in a MHC class I/II disparate murine BMT model . L Marks, et al.
  3. T-cells from CCR5 knockout mice induce accelerated acute GVHD lethality after allogeneic BMT in mice . WJ Murphy, et al.
  4. Salvage treatment with high-dose chemotherapy followed by hematopoietic stem cell support in germ cell tumor patients . G Rosti, et al.
  5. The CXCR4-SDF-1 axis regulates metastatic rhabdomyosarcoma cell behavior . MZ Ratajcza, et al.
  6. Long follow-up of patients with primary breast cancer and ¡Ý 10 involved axillary lymph nodes after high-dose chemotherapy and autologous hematopoietic stem cell transplant . LE Damon, et al. Abstract 39. There are few results at 10 years. Convetional chemotherapy results in about 40% survival in this group (the range is 17 to 56%). These patients are considered stage II-A or II-B or III-A. The 5 year,7 year,and 10 year overall survivals (OS) were 68%, 65%,and 59%. Overall Survival was better in patient who were Estrogen Receptor Positive (ER+), however there were no events in ER- patients after 3 years. There was one death due to treatment (2%), there were no deaths with the use of peripheral stem cells.


ORAL ABSTRACTS: Session 4

Six oral presentations selected from submitted abstracts for Late Effects/QOL and Immune Reconstitution, moderated by Catherine Verfaillie.

  1. Growth hormone accelerates immune recovery following allogeneic BMT . BJ Chen, et al.
  2. TREC expression by human CD4+ CD25+ T-cell subsets with regulatory activity . J Woodliff, et al.
  3. Recovery of CD8+ T-cell populations posttransplant . FT Hakim, et al.
  4. The thymic stromal gene spatial regulates the size of thymocyte cell populations . FA Flomerfelt, et al.
  5. Immunologic effects of recombinant human growth hormone after congeneic BMT in young versus aged mice . R Sun, et al.
  6. Optimism and the outcome of hematopoietic SCT . SJ Lee, et al. In patients who were considered optimistic before HSCT, there appeared to be a survival advantage after 2 months. However after 6 months this survival advantage disappeared.


Dinner

I skipped the dinner Symposium and instead went to dinner with Daniel Weisdorf who is on the NMDP RAP committee, his wife Pam who is the Directory of Patient Adovcacy at NMDP and Linda Burns, also BMT doctor at the University of Minnesota. Quite an interesting time, although I did not take notes and I am not sure what of interest I can report.


Friday, February 24, 2002

Graft-versus-Host Disease and Non-Myeloablative Transplantation: An Update

Sponsered by SuperGen

Chair: Richard J O'Reilly;

  1. Non-myeloablative transplants: an update - Steven Pavletic; The number of Non-myeloablative transplants (NSTs) is increasing rapidly. Many of the patients recieving NSTs are significantly older then those recieving traditional high dose allo-HSCT. About half older then 50, some older then 70. It is not clear whether NST is as effective as convential allo-HSCT in younger healther patients. There are many different preparative regimens with differing intensities.
  2. Non-myeloablative transplants: does the regimen matter? - Kenneth Miller; Tufts University School of Medicine Reduced Intensity Stem Cell Transplantation Incorrect Principles
    1. All regimens are basically the same.
    2. All reduced intensity transplants have reduced toxicity.
    3. All reduced intensity transplants are associated with similar rates of engraftment and GVHD.
    4. There is a best regimen.
    5. Reduced intensity transplants will replace all conventional allogeneic transplants.

      Ideally a prepartive regimen should have a high engraftment rate, low morbidity and mortality, with low incidence of GVHD but good graft versus disease effect.

    At New England Medical Center, the transplant regimin includes photopheresis (to alter host reponse to donor cells), pentostatin and medium intensity Total Body Irradiation (TBI, 600 cGy). Cyclosporine and short course of Methotrexate and then MMF (CellCept) are used to prevent GVHD. In 56 patients treated since January, 2000 (all ineligible for standard HSCT) with various hematological malignacies, 98% engrafted, there were 12% transplanted deaths. Survival at 100 days was 84% and 96% achieved full donor chimerism.

    Comparing Very High Risk patients (had a prior HSCT or been treated with 3 or more prior regimens), overall survival about 50% (more then a year) compared with about 75% in other (high risk) patients.

  3. Preparative regimen and GVHD - Daniel Couriel; M.D. Anderson Cancer Center Compared various regimens used in patients at MDACC. There were 168 patients treated with NST. NST resulted in a lower incidence of acute GVHD, chronic GVHD does not appear to depend on the prepartive regimen. De novo chronic GVHD (i.e. without prior acute GVHD) is more common in NST.

  4. New directions in therapy for chronic GVHD - David A Jacobsohn, Johns Hopkins School of Medicine Discussed new drugs being used to treat GVHD. The standards are cyclosporine and prednisone, long term use of prednisone is associated with a lot of bad side effects. Mycophenolate Mofetil (MMF) has been studied for chronic GVHD since 1997, used with cyclosporine and FK-506. There is an ongoing Phase III trial of MMF.

    New drugs include hydroxychloroquine. Gilman, et. al. used hydroxychloroquine in a Phase II trial of 40 patients ( Hydroxychloroquine for the treatment of chronic graft-versus-host disease. (article abstract), Biology of Blood and Marrow Transplant 2000;6(3A): pp 327-34). 17 of 32 evaluable patients (53%) had a partial or complete response and most were able to lower their steriod dose.

    Pentostatin has had a good response in acute GVHD. In a study at JHU, 23 patients were treated with pentostatin, 17 were evaluable. 8/17 had a major response and 3/17 had a minor response. It was well tolerated, although 2 patients withdrew from the study because of side effects and there was one death, although it did not appear to be related to pentostatin. Optimal schedule and dose remain unknown.

    Conclusion: The goal should be to move these newer agents into first line therapy in order to avoid steriods and their toxicity.


PLENARY: Myeloma

Session Chair: Kenneth Anderson, MD;

  1. Novel biologically based therapies -- Kenneth Anderson, MD, Dana-Farber Cancer Institute; IMiDs are related to Thalidomide, but are 1000% - 5000% more potent. They inhibit binding of the myeloma cells to stromal cells (once the myeloma cells bind they are less sensitive to chemotherapy).

    Cytokins (IL-6, VEGF are produced much more often in myeloma cells with stomal cells, but not in the presence of IMiDs.

    A Phase I trial of CC-5013 (an IMiD) in high risk patients (heavily pre-treated), had low side effects, only grade IV toxicity was neutropenia at the highest dose. There was stable disease or better in 79% of patients, with durable remissions. A Phase II trial is starting in newly diagnosed patients, relapsed patients and for maintenance.

    Proteasome Inhibition -- PS-341. In a Phase II trial in refractory or relapsed disese, in patients who were heavily pre-treated there was a response rate of 50% (a decrease in protein of at least 25%). 10% of patients had a "close to complete" remission. 33% of patients had stable disease. There were many durable responses and no Grade IV toxicity. There was improvements in Quality Of Life over time with more treatments. The drugs (CC-5013 and PS-341) appear to be synergistic and will soon be tried together in humans.

  2. Role of autografting in myeloma -- Jean-Luc Harousseau, MD, Hotel-Dieu; High Dose Chemotherapy resulted in 7 year Overall Survival (OS) of 43% with a median of 57 months compered to 7 year OS of 25% and median survival of 44 months with conventional chmeotherapy.

    In a comparison of single versus double PBST and BMT, there were 3 treatment related deaths in the first group, versus 5 in the second. 85% of first group completed the BMT, while 88% of the second group completed the first BMT and 78% completed both.
        Single BMT group Double PSCT and BMT group
      Complete Remission   34%   35%
      Overal Remission   42%   49%
      6 year Overall Survival   26%   40%
      Median Survival   50 months   58 months

    Survial was the same until 42 months, when the double PSCT and BMT group showed better survival.

  3. Role of post transplant therapies -- Nikhil Munshi, MD, Dana Farber Cancer Institute Using a vaccination stradegy with 2 transplants, after 2nd transplant results look better.

    Dendritic cell vaccination yields poor responses. Subcutaneous injection resulted in no toxicity, but response is not huge in a small group of patients (5 patients).


CONCURRENT 5: Biologic Modification in vivo & in vitro

Session Chair: Robert Korngold, PhD;

This session talked a lot about mice, so much of it I did not understand. However even though I should understand some of the statistical methods used in studies (which was the other session) this one seemed more worthwhile then the others going on.

  1. Effect of anti-TNFa mAb treatment on GVHD and GVL responses -- Robert Korngold, PhD, Kimmel Cancer Institute Jefferson Medical College; Cytokines are involved in GVHD including TNF-alpha and IL-12. This study looked at whether blocking the action of TNF-alpha and IL-12 is useful in treating acute GVHD. Anti-IL-12 haa no effect in mice, while anti-TNF-alpha has a modes effect -- benefiting about 40% of mice. Combining both treatments does not help.

    When CD-4 selected T-cells are transplanted (instead of unselected stem cells), anti-IL-12 has no effect, however anti-TNF-alpha has a major effect.

    Using CD-8 selected cells, anti-IL-12 has a modest effect.

    What about GVL (graft versus Leukemia)? Using a DLI after HSCT, with anti-TNF-alpha does not interfer with GVL.

  2. The role of regulatory cells in allogeneic BMT -- Bruce Blazar, MD, University of Minnesota; CD4+ and CD25+ t-cells can reduce mortality from GVHD, adding these cells to graft inhibits GVHD in mice.


  3. Mobilization and potential clinical uses of dendritic cells -- Edgar Engleman, MD, Stanford University Colon and lung cancer patients with significant pre-treatment. Harvest dendritic cells with FLT-3 ligand and "vaccinate" them with a peptide related to CEA (an antigen expressed by these tumors) in 12 patients. 5 experienced some effect, 2 a complete remission and 3 a partial remission.

    FLT-3 ligand increases dendritic (immature) cells and can induce a tumor response. However it is difficult to grow these cells, expensive in time and labor intensive. Dendritic cells can be targeted in vivo to induce anti tumor immunity.


Luncheon Satellite Symposium (SangStat)
Expanding the Promise of Hematopoietic Stem Cell Transplantation (HSCT) in Autoimmune Disease

Chair: Richard Burt;

This was quite an interesting sessions. Most of the transplants (auto) have been done for Lupus and result in many remissions. Care must be taken here as almost any treatment related mortality would make many doctors hesitant to use these treatments. However early indications are that (at least in SLE) many patients benefit, having their disease significantly improve for long periods.

  1. Stem Cell Transplant for Systemic Lupus -- Ann Traynor, Northwesten University Medical School;
    Five years and fifteen patients later: The groundwork of a Phase III trial. Patients that have been transplanted have advanced disease. Cyclophosphamide (Cytoxan) is given before harvesting, followed by Neupogen (G-CSF). The Cyclophosphamide is necessary to get the ANC ≤ then 1000 as G-CSF is known to stimulate Lupus.

    Most patients -- 8 out of 10 are on no immune suppression after 18 months. HSCT is cost effective compared to standard therapy. Some patients are able to return to work or school and care for children without assistance.

  2. HSCT for Crohn's Disease -- Robert Craig, Northwesten University Medical School; Again the worry is whether the cure is worse then the disease. Mortality from Crohn's Disease is about 6%, although there can be serious morbidity (fistulae, abscesses, eye, skin, joint and liver complications, may surgeries and pain).

    Six patients (in remission from Crohn's ??) with Crohn's have been treated with HSCT for other reasons. One has been in remission from Crohn's for 15 years. Nine patients with active disease at time of HSCT, 5 have been in remission from Crohn's for 6-10 years. Similar restrictions and protocol to Lupus. Two patients have been treated at Northwestern, one age 16 and the other 22, both had continuous disease for 6-10 years. One has significantly reduced medication (steriods) and the other is now asymptomatic.

  3. HSCT for multiple sclerosis -- Richard Burt, Northwesten University Medical School; More transplants have been done for MS then Lupus or Crohn's. In the Chicago/Milwaukee experience, after followup of 1 to 60 months, 24/25 patients have no evidence of disease progressing. In ambulatory patients, 90% do not progress after HSCT, in non-ambulatory patients 40% do not progress. In conclusiong: HSCT for MS can be preformed safely with proper mobilizatoin and conditioning regimen. Tests suggest arrest of the disease.
  4. Will HSCT finally defeat severe autoimmune diseases? -- Alberto Marmont, S. Martino's Hospital, Genoa, Italy There was not much new here. Alberto Marmont was the first to propose auto-HSCT for treating auto-immune diseases.


WORKSHOP 9: Donor Leukocyte Infusion

Co-Chairs: Christopher Bredeson, MD,MSc, Medical College of Wisconsin;
Esperanza Papadopoulous, MD, Memorial Sloan-Kettering Cancer Center

This session was scheduled from 2:00 to 3:30. I had to leave this session early, at about 2:50, to catch the shuttle back to the airport. I am not sure how much I missed though, as the US-Canada gold medal hockey game was beginning at 3:00 and some people wanted to go see that (including one of the co-chairs).

The first question that they tried to get a handle on was the definition of what is a Donor Leukocyte Infusion (DLI) versus what is a HSCT. The hope is to create a systemic way of viewing the data in order to be able to analyze it.

  1. Does the type of graft matter? If mobilization is used (i.e. the donor gets G-CSF or other drugs to mobilize the stem cells into the bloodstream) then that is considered another transplant (DLI's do not usually use mobilized cells).
  2. Does the intent matter?
  3. Indication? Is the intent to induce a graft versus tumor effect or to help reconstitute the immune system or because of graft failure (and in this case does it matter if it is post Non-myeloablative stem cells transplant -- NST or a conventional HSCT).

    One school of thought is that if it is the same donor to the same patient then it is a DLI (except perhaps if it is to treat a different disease).

    Much of the rest of the workshop (at least the part I was in) discussed a hypothetical case of a patient with CML who was treated at MSKCC using a T-cell depleted transplant (which is their standard protocol) and how and when they would use a DLI, when there is no hematological or cytogenetic evidence of disease, but there is molecular evidence of Minimal Resistant Disease (MRD). This was compared to other institional practice (from members in the audience).

    At 3 months post HSCT if there was evidence of MRD they would not treat (in the absence of hematological or cytogenetic evidence of disease). This is because it is thought the treatment is worse then the (possible) disease. If at 6 months there is still MRD then they would do a DLI, using a small cell dose (it was noted from the audience that in the case of CML many places were using Gleevec with good results, there were many papers on this at ASH 2001, MSKCC has not had success with Gleevec in relapsed CML post-HSCT, perhaps because of the T-cell depleted graft). One doctor in the audience said that in the case of T-cell depleted grafts, almost everyone needs DLIs for CML. A higher dose of T-cells (with sibling donors) leads to more GVHD, earlier DLIs also lead to GVHD more often. It was also noted that in early relapse for AML, a DLI (with a sibling donor) does not work well.



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