CONTENTS Report from the 2nd International Report from the second iwNST meeting ...... 1 Workshop on NST January 25–28, 2001, St Martin, West Indies Filipovich, Vose assume Registry chairs; Sergio Giralt, MD he inaugural meeting of the International Ringdén, Champlin Working Group on Non-myeloablative Stem- Associate Professor, BMT Unit, T cell Transplantation (iwNST) was held in St Lucia named as University of Texas M.D. Anderson Cancer chairs-elect ...... 1 Center, Houston in 2000. The meeting brought together a small group of international transplantation experts with an interest in the development of non- Perspectives: myeloablative or reduced-intensity preparative – Julie M. Vose regimens for blood and marrow transplantation – Armand Keating ... 2 Shimon Slavin, MD (BMT). Following the success of this meeting, a Professor and Chairman, Department of second iwNST meeting was held with the support BMT and Cancer , Hadassah Tandem BMT meetings of Schering AG in St Martin from January 25–28, University Hospital, 2001. The aims of the second meeting were – in appreciation...... 3 twofold. First to discuss progress made in NST in hematologic malignancies, solid tumors and a Forbeck Forum range of other therapeutic settings, including discusses Christopher N. Bredeson, autoimmune diseases, and second to determine recommendations for areas of consensus suitable for establishing MD, MSc multicenter prospective clinical trials in non- clinical trials in Assistant Scientific Director, IBMTR/ABMTR myeloablative transplantation (NST). Assistant Professor of Medicine, Medical The meeting was divided into three sections: College of Wisconsin, Milwaukee transplantation ...... 9 continued on page 4

Recent peer-reviewed publications from the IBMTR/ABMTR ...... 10 Filipovich, Vose assume Registry chairs; Ringdén, Champlin named as chairs-elect Foundation and corporate support of At the February 2001 Annual Meeting, Dr. Alexandra Dr. Gérard Socié from Hôpital St. Louis in Paris, the IBMTR/ABMTR . 11 Filipovich of Children’s Hospital Medical Center in France (Secretary-Treasurer) and Drs. Sergio Giralt Cincinnati assumed the Chair of the IBMTR Advisory from M.D. Anderson Cancer Center in Houston, Committee. Dr. John Goldman (Imperial College of Texas and Axel Zander from University Hospital IBMTR/ABMTR Medicine, London) will continue to serve on the Eppendorf in Hamburg, Germany (Members-at- Executive Committees Executive Committee for a three-year term as Large). and Statistical Center Immediate Past-Chair. Dr. Olle Ringdén of Huddinge personnel ...... 12 University Hospital, Stockholm, Sweden was chosen For the ABMTR, Dr. Michael Bishop from the US as IBMTR Chair-Elect in the pre-meeting balloting. National Cancer Institute has been elected Dr. Julie Vose of the University of Nebraska, Omaha Nominating Committee Chair, and Dr. Koen van assumed the Chair of the ABMTR Advisory Besien from the University of Chicago Medical Center Committee; Dr. Armand Keating (University of has been named Secretary-Treasurer. New ABMTR Toronto) will continue to serve on the Executive Executive Committee Members-at-Large are Drs. Committee as Immediate Past-Chair. Dr. Richard Elizabeth Reed from the University of Nebraska, Champlin from M.D. Anderson Cancer Center was Omaha and Patrick Stiff from Loyola University This issue of the IBMTR/ chosen as ABMTR Chair-Elect. Medical Center in Maywood, Illinois. ABMTR Newsletter is supported by an unrestricted In other IBMTR election results, Dr. Daniel Weisdorf of We thank Drs. A. John Barrett, Robert Peter Gale, educational grant from the University of Minnesota, Minneapolis was Hans-Jochem Kolb and John Wingard for their past selected as Nominating Committee Chair. Newly service on the IBMTR Executive Committee and Drs. Schering AG elected IBMTR Executive Committee members are James Armitage, Bruce Camitta, Carole Miller and continued on page 4

1 Perspectives

Julie M. Vose, MD ABMTR Advisory Committee Chair Professor of Medicine, University of Nebraska Medical Center, Omaha, NE, USA

It is my distinct pleasure to assume the research groups have ultimately lead to specific issues. Our organization is in an chair of the ABMTR from Armand Keating. many excellent papers in peer-reviewed excellent situation to be able to assist in Over the past three years Dr. Keating, journals. In addition to research the statistical planning, development, and along with Dr. Mary Horowitz and the contributions, the Registry is an invaluable implementation of such studies. With such entire Statistical Center, has led the source of information for patients, efforts, scientific questions can be ABMTR to the forefront of autologous physicians, and healthcare agencies definitely answered in appropriately transplantation research. interested in transplantation. designed clinical trials.

From the inception of the ABMTR in the The future of this outstanding organization Developments in transplantation over the late 1980s, the activity of the organization must include the planning, organization, next several years will shape the future of has continued to grow and prosper. and conduct of prospective clinical trials in transplantation clinical care and research Accomplishments include the collection of transplantation. This can be accomplished and will affect countless patients with data on more than 63,000 patients through a large network of transplant malignancies and other conditions. It is receiving autologous transplantation for centers which collaborate on transplant exciting to be able to assist in the next various malignancies or conditions since clinical trials that have been specifically phase of the ABMTR’s development and 1989. Collaborations on research papers developed to answer important questions to be a part of the future of blood and with multiple investigators and other regarding transplantation and disease- marrow transplantation.

Armand Keating, MD ABMTR Immediate Past-Chair Professor and Chief, Medical Services, Princess Margaret Hospital, University of Toronto, Ontario, Canada

It is indeed gratifying that both the ABMTR in North America and internationally. In A second and important area for further and IBMTR continue to thrive. This is true order to carry this out effectively, it must development is the ongoing need to for registration activity as well as for active adapt, change and grow in new ways. I collaborate with related organizations. The contributions to the field of blood and would like to provide three examples of reasons are obvious: synergy and the marrow transplantation. For example, over how this is already taking place. avoidance of duplication among many 63,000 cases have been registered with others. An excellent example is the the ABMTR, including the approximately The first is a strong interest in participating collaboration with the ASBMT that has 19,000 detailed research reports since in prospective clinical trials. The Registry resulted in the continued success of the 1989 when the Registry began. Perhaps with its large network of participating Tandem BMT Meetings. Another most impressively, during the 2000–2001 transplant centers (including large and successful collaboration is with the EBMT, year there have been 17 papers small, highly academic as well as service- and it is recognized that greater interaction published, with 10 in press and 6 under based programs) is extremely well can only help the field. The IBMTR/ review from the IBMTR and ABMTR. Many positioned to evolve as a hub of a ABMTR is currently exploring the have, and will appear in first rate prospective trials network. Indeed, a possibility of collaborating with the international peer-reviewed journals. network of transplant programs is already Canadian Transplant Group These accomplishments attest to the vigor established through the Statistical Center (CBMTG) to develop a national registry and leadership of the Working Committees by virtue of the data exchange that takes database. This is of some significance and of Mary Horowitz and the Statistical place between them. Because of its broad because the 24 centers in Canada Center. The merging of the IBMTR and constituency of participating transplant perform about 1200 transplants per year. ABMTR roles in the Working Committees programs, the Registry is well placed to The development of such a registry will has been an important and creative force facilitate rapid and large accrual to help facilitate the CBMTG’s goal of in this productivity. important trials. Another major advantage establishing a cohesive national clinical is that Registry studies are hypothesis- trials network. They already have the Vital organizations do not stand still. I generating, enabling key prospective trials advantage that all the centers are believe that the ABMTR (and IBMTR – it is to be quickly developed. Importantly, the associated with teaching hospitals and becoming increasingly difficult to separate feasibility of such trials can be readily their directors are committed to their functions) will have an increasingly tested by analyzing the extensive Registry addressing important transplant-related important role in moving the field forward database. questions.

continued on page 3 2 • Volume 8 • Issue 1 • August 2001 • Tandem BMT Meetings

Tandem BMT Meetings 2001– in appreciation By D’Etta Waldoch, CMP

t is simply time to say thank you – time efficiency next year. Online registration heralded for gathering and nurturing the Ito acknowledge the many people who proved itself worthy with 60% fewer on- quality data without which not one valid contributed to the success of this year’s site registrations at Keystone, resulting in scientific study or presentation could exist. Tandem BMT Meetings. fewer on-site surprises and much less The highly-interactive and well-attended congestion at the registration desk. data management sessions were primarily The 2001 Tandem BMT Meetings were Thanks also to a delightful set-up and orchestrated by Diane Knutson and other held at the newly expanded Keystone registration staff, led by Patty Vespalec, dedicated members of the Statistical Resort and Conference Center in Marmie Kiva and Debbie Schaubel, who Center staff. A special thanks goes out to Colorado. The ASBMT (American Society kept a smile at all times. transplant centers for support of these for Blood and Marrow Transplantation) training efforts. met from February 15–17, and the IBMTR/ It takes an incredible amount of diligence ABMTR Annual Participants’ Meeting was to keep the lively banter of the Working Let it not be said that we aren’t also held February 17–19. Committee meetings humming while the thankful for the exceptional service, hearty alternative for the afternoon could be smiles and professionalism of the So! Thank you! To the 1300+ attendees skiing or basking in the Colorado sunshine Keystone Resort staff. Large meetings can who constitute a significant sample of the with a good book. Thanks to those who produce some very tense moments world’s best in BMT: clinicians, scientists, took the initiative to download materials despite the best planning. Always pharmacists, nurses, clinical research from the IBMTR/ABMTR web site, in courteous and willing to go the extra mile, associates, administrators, pharmaceutical advance preparation for more stimulating Keystone’s Conference Services company representatives, and other allied interaction at the committee meetings. Department works proactively to keep the professionals. Thank you for serving as Thanks also to a dedicated statistical staff, most trying times invisible to meeting planners and organizers, session chairs, whose workload increases exponentially attendees. Thank you for more than speakers, facilitators, poster presenters, each year just keeping up with the number doubling the size of your state-of-the-art judges, educators and (not least of all) of studies proposed and approved, Conference Center, which will allow the sponsors, staff and clean-up crew. Great tempering ambitious plans with reality. Tandem BMT Meetings to return in 2003, strides have been made in integrating the 2005 and beyond. And, oh yeah! the food IBMTR/ABMTR and ASBMT scientific Thanks to 30+ pharmacists and Orphan was spectacular! Now … about building a programs into one complete meeting Medical, Inc. for pioneering the first few more condos …. package, and thank you for noting your BMT pharmacists conference into an appreciation of these efforts on your unqualified success and to Kathy A special thanks to Gérard Socié and evaluation forms. Kovatovic from the Medical College of Donna Reece for serving as IBMTR/ Wisconsin and Harry Hopkins from the ABMTR program chairs at this year’s For its initial effort, the Tandem BMT Ottawa Hospital for organizing the event. Annual Participants’ Meeting, and to Julie Meetings’ online registration and housing Plans are to continue this as a regular part Vose for her service as program chair for program worked well. Many thanks to of the annual Tandem BMT Meetings. ASBMT. Finally, thanks to the many those a little less electronically-inclined, scientists and clinicians who have brought who struggled a bit with the new program BMT clinical research associates and the IBMTR/ABMTR to the forefront of and provided insights into improving our research nurses worldwide are to be clinical research in this exciting field.

continued from page 2 appear to be any existing mechanism to that are likely to vouchsafe the continuing The third area of growth in a new direction monitor, review and report outcomes on all contributions of the Registry to blood and involves the exploration by the ABMTR these patients. A relevant and particularly marrow transplantation. In looking back (and IBMTR) of a Working Committee on unfortunate aspect, given the current over the last few years, I realize that I gene therapy / gene marking. The timing relatively negative climate towards gene have been very fortunate in witnessing for this endeavor is important because of therapy, is the prevailing publication bias from within, the dynamism, growth and the current uncertainty surrounding the in which negative studies are unlikely to maturation of the ABMTR. I have been entire field of gene therapy, especially be reported. The expertise of the Registry truly honored and privileged to be the from the standpoint of government and the enthusiasm of a cadre of Chair and I thank all my colleagues and regulatory agencies. There have been transplant physicians responsible for many friends for their good natured, rigorous over 30 RAC-approved protocols for cell of these gene marking/therapy protocols and unstinting efforts to move the field marking and gene therapy involving more could help to provide much needed data forward. In the challenging times ahead than 200 patients, using predominantly that will better inform scientific and public we will be very ably served by the autotransplants to deliver a variety of policy in this important area of medicine. leadership, already evident, of Julie Vose, gene-modified cells. There does not These are only some of the developments the new ABMTR Chair.

3 Filipovich, Vose assume Registry chairs; Ringdén, Champlin named as chairs-elect – continued from page 1

Donna Reece for their past service on the ABMTR Executive determining the leadership of the Registries. We genuinely Committee. Also, our gratitude goes to Dr. H. Grant Prentice and appreciate your continuing input and suggestions. Please see Dr. Patrick Stiff, for their service as IBMTR and ABMTR page 2 for perspectives on the ABMTR given by incoming Nominating Committee Chairs, respectively. Advisory Committee Chair, Julie M. Vose, MD and Immediate Past-Chair, Armand Keating, MD. The next Newsletter will feature We congratulate our new officers and look forward to working with perspectives on the IBMTR by incoming Chair Alexandra them. We know we speak on behalf of all IBMTR and ABMTR Filipovich, MD and Immediate Past-Chair John M. Goldman, DM. participants when we express our gratitude for the time and effort A complete listing of the membership of the IBMTR and ABMTR these individuals have devoted to Registry activities. We also Executive Committees is shown on page 12, along with a listing thank all IBMTR/ABMTR centers that gave their input in of Statistical Center personnel.

Report from the second iwNST meeting – continued from page 1 1. Update on tolerance and immunotherapy – This included an survival of full-thickness donor skin allografts in mice if they entire day of presentations focusing on basic science issues achieved a mixed chimeric state with 20–50% donor cells in the relevant to NST. This session covered topics such as basic blood. This suggests that, after TLI, additional selective clonal of tolerance and transplantation tolerance, deletion of residual host cells can induce a state of long-lasting induction of immunoregulation and immunotherapy, effector specific tolerance to a wide variety of donor-derived tissues.1 cells of immunotherapy, and induction of self-tolerance in autoimmune diseases. Elimination of self-reactive – “graft 2. Update on clinical experience with NST – The second day versus autoimmunity” potential of NST and DLI included presentations from a dozen clinicians who summarized the NST protocols being studied at their No specific therapy exists for autoimmune diseases caused by respective hospitals and institutions, with details of the types of self-reactive lymphocytes (SRLs). However, as shown in animals patients being treated, treatment outcome and associated and pilot clinical studies, SRLs can be eliminated using high-dose toxicities. chemoradiotherapy, followed by autologous stem cell 3. Protocol development sessions – The final day of the meeting transplantation (SCT).2 These SRLs may also be successfully was dedicated to protocol development. The goal of the eliminated using highly immunosuppressive but not necessarily protocol development sessions was to encourage focused myeloablative conditioning in conjunction with allogeneic SCT. An discussion among all the participants in the meeting, resulting NST protocol including fludarabine 30 mg/m2/day x 6, anti-T- in consensus on a number of possible trial protocols that could globulin (ATG) 10 mg/kg/day x 4, and busulfan 4 mg/ be initiated by them. Separate sessions addressed NST in kg/day x 2 resulted in elimination of all signs of autoimmunity myeloma, solid tumors, myeloid leukemias, lymphoid (psoriasis and arthritis) in a patient with chronic myelogenous malignancies, and pediatrics / non-malignant disorders. The leukemia and severe systemic psoriasis and psoriatic management of graft-versus-host disease (GVHD) in NST was polyarthritis.3 This response of also discussed. manifestations via a “graft versus autoimmunity” (GVA) effect in parallel with the elimination of host-derived hematopoietic cells This report summarizes the experience with NST in a variety of supports the hypothesis that autoimmune diseases caused by settings at both the Hadassah University Hospital and M.D. SRLs may be effectively treated by alloreactive elimination of the Anderson Cancer Center (MDACC), as reported at the workshop. SRLs following induction of host-versus-graft tolerance. This Additionally, a summary of the protocol development sessions approach is analogous to the replacement of malignant or chaired by ourselves and others is included. genetically abnormal host cells following donor lymphocyte infusion (DLI) in patients having previously received an allogeneic transplant. It is therefore suggested that intentional GVA effects Update on tolerance and immunotherapy may be inducible by DLI following NST in recipients with life- threatening autoimmune diseases resistant to conventional modalities. Adoptive immunotherapy of autoimmunity may thus Induction of transplantation tolerance by donor bone involve a two-step procedure: first, inducing host-versus-graft marrow cells (HVG) and graft-versus-host (GVH) transplantation tolerance through a transient stage of mixed chimerism; second, inducing At the Hadassah Hospital conditioning for transplantation using controlled GVA effects, initially by discontinuation of ciclosporin no post-graft immunosuppression has been studied in mice. The (CSA) and then, if indicated, by late outpatient DLI to eradicate regimen consisted of a short course (6 daily fractions of 200 cGy) residual hematopoietic cells of host origin. of total lymphoid irradiation (TLI), followed by selective elimination of those donor-specific alloreactive cells of the host that have survived the low-dose TLI. Donor-specific alloreactive cells were activated by intravenous inoculation with a high dose (3 x 107) of Update on clinical experience with NST donor bone marrow cells (BMC) 1 day after TLI, and eliminated by a single intraperitoneal dose (200 mg/kg) of cyclophosphamide The Hadassah experience in myeloid leukemias given 1 day after cell transfer. Infusion of a low number of T-cell- depleted (TCD) BMC (3 x 106 cells) after this approach to The Hadassah Hospital uses an NST preparative regimen that tolerance induction converted recipients to stable mixed chimeras consists of fludarabine 30 mg/m2/day x 6, busulfan 4 mg/kg/day free of GVHD. This strategy allowed acceptance and life-long x 2 and ATG 5–10 mg/kg/day x 4. Peripheral blood stem cells are

4 • Volume 8 • Issue 1 • August 2001 •

Report on the second iwNST meeting collected from related donors. Posttransplant Table 1. Engraftment after NST with Flag-Ida conditioning in AML/MDS immunosuppression of the host is with CSA from day –1 until patients neutrophil engraftment, when it is rapidly withdrawn. This Count recovery n median days (range) approach has been used in over 120 patients with hematologic ANC > 500 /µL2814.5 (10–38) malignancies. In his presentation, Reuven Or focused on patients platelets > 20,000/µL25 18 (10–78) with acute myeloid leukemia (AML). To date, 23 patients with a platelets > 100,000/µL17 27 (18–90) median age of 33 years have been treated. Seventeen patients Chimerism* median % (range) were in first CR, and 6 were in second CR. Twenty-one patients Day +30 27 95 (0–100) had an HLA-identical sibling donor, and the remainder a related Day +90 23 83 (0–100) donor who was a single-locus mismatch. Acute GVHD was a Day +360 7 100 (0–100) common problem with an incidence of 52% while patients were taking CSA and increasing to 78% once CSA was withdrawn after *Chimerism assessment was performed on bone marrow aspirates engraftment. The overall survival (OS) at one year was 48% and the disease-free survival (DFS) at one year was 46%. which was directly related to the status of disease at the time of transplant. For patients in first or second remission at the time of Results in patients with CML were also presented. Twenty-one transplant the OS was 64% with a median follow up of over patients with CML in first chronic phase, median age of 35 years, 18 months. For patients not in remission the OS was received NST – 16 from HLA-matched siblings and 5 from approximately 30% (Figure 1). Many of the patients who relapsed matched unrelated donors. The interval between diagnosis and were successfully salvaged using a reduced-intensity regimen NST was a median of 9 months. The median time posttransplant such as fludarabine + melphalan. DLI were not routinely given. to full hematopoietic engraftment was 21 days. Acute GVHD was These results are considered encouraging enough to warrant a again common in this patient population, 57% while taking CSA randomized trial comparing this approach with conventional BMT. rising to 87% after CSA was discontinued following engraftment. The overall incidence of chronic GVHD was 60% after 15 months of follow-up. The addition of posttransplant methotrexate had no effect on the incidence of acute or chronic GVHD. 1.0

0.8 These data indicate that consistent and durable engraftment of OS/remission donor hematopoietic stem cells and immunocompetent 0.6 lymphocytes can be achieved following NST, with rapid PFS/remission replacement of host with donor cells. This initial experience 0.4 OS/not in remission supports the potential for NST to replace conventional BMT in 0.2 PFS/not in remission some settings, potentially by reducing transplantation-related proportionCumulative toxicity and mortality. Although associated with a low treatment 0.0 related mortality, acute and chronic GVHD remain common 051015 2025 30 35 40 complications that need to be addressed in future studies. Larger Months post-BMT cohorts of patients and longer follow-up are required to assess the overall potential benefits of NST, which may be further Figure 1. Survival, according to remission status at BMT, of AML/MDS improved by more effective and selective immunotherapy with patients treated with FLAG-Ida-based NST: OS, overall survival; PFS, progression-free survival specific immune donor lymphocytes. In time, randomized controlled trials will be required to definitively determine the place of NST in the management of these diseases. Flag-Ida was also used as the preparative regimen pre-NST for 13 patients with CML. The patients had a median age of 56 years The M.D. Anderson Cancer Center experience in (range 42–72 years) and the median time from diagnosis to myeloid leukemia transplant was 30 months. At the time of transplant 7 patients were in first chronic phase and 6 had more advanced disease. Sergio Giralt reviewed the MDACC experience with two NST Of the 7 chronic phase patients, 4 achieved 100% donor cell regimens, FLAG-Ida and fludarabine + melphalan, in myeloid engraftment, 2 patients reached 15% donor cell engraftment with malignancies. In one study AML and MDS patients were treated if subsequent autologous reconstitution and 1 patient did not have they were ineligible for a conventional allogeneic transplant due to any evidence of donor engraftment. Thus, although in the setting age or comorbid disease. In all, 32 patients with a median age of of chronic phase CML it is possible to achieve donor cell 62 years (range 28–75) were treated. Twenty-six patients had engraftment with FLAG-Ida in some patients with a low incidence AML and 6 a myelodysplastic syndrome (MDS). The median time of non-relapse mortality, this approach is not sufficiently from primary diagnosis to treatment was 10 months (range 1–49). immunosuppressive to facilitate unrelated donor cell engraftment. Patients received the FLAG-Ida (fludarabine, high-dose The approximately 20% incidence of secondary autologous cytarabine, idarubicin, G-CSF) preparative regimen pretransplant reconstitution in the related setting using FLAG-Ida also suggests as previously reported.4 At the time of transplant 9 patients were that other non-ablative or reduced intensity conditioning regimens in first CR, 3 were in untreated first relapse, 4 were in second CR, should be explored. and 16 had more advanced relapsed or refractory disease. As summarized in Table 1, the degree and rate of engraftment were Since 1996, a reduced-intensity regimen consisting of fludarabine similar to that seen with conventional allogeneic transplants. (25–30 mg/m2/day x 4–5 days) and melphalan (70–90 mg/m2/day There were 4 cases of primary graft failure and 2 of late graft x 2 days) (FM) has been studied in patients with AML or MDS. failure, all resulting in autologous reconstitution. The results are summarized in Table 2.

Toxicity was limited, with 1 treatment-related death and 2 acute The incidence of graft failure was low with no cases of secondary GVHD-related deaths. The major problem was relapse, the rate of autologous reconstitution. Non-relapse mortality (NRM) was

5 Table 2. Outcome of patients with AML/MDS undergoing reduced intensity starting shortly. The FLAG-Ida regimen in CML is less successful, conditioning with fludarabine and melphalan at MDACC from with graft failure being a major problem. The fludarabine + 2/96 through 9/00 melphalan regimen in patients with myeloid leukemias holds more 6/6 HLA-matched 6/6 HLA-matched promise, producing good engraftment and disease control in sibling unrelated donor these initial studies. GVHD and relapse remain the main n = 31 n = 34 problems associated with this transplantation technique.

Median age, years (range) 53 (36-75) 55 (22-64) The M.D. Anderson Cancer Center experience in lymphoid leukemias Median time to treatment, months (range) 13 (1-38) 12 (2-176) Issa Khouri presented data on NST studies in patients with Reason for NST * lymphoid leukemias at the MDACC. Patients were eligible for NST Advanced age 12 15 Extensive prior Rx 13 11 if they were > 50 years with or without comorbid disease and had Poor organ function 10 13 disease beyond first remission. For patients with large-cell lymphoma, NST was given if a poor outcome was expected with Median days to ANC > 0.5 x 109/L 14 16 autologous BMT or if they had failed prior autologous transplant. Different conditioning regimens were used for aggressive and Graft failure primary/secondary 1 / 0 1 / 0 indolent lymphomas. Patients with aggressive NHL were conditioned with cisplatin 25 mg/m2/day ci x 4 days (Days –6 to Mean % donor chimerism 93.5 (n = 21) / 93.5 (n = 21) / –3), fludarabine 30 mg/m2/day x 2 days (Days –4 and –3) and day 30 / day 100 100 (n = 10) 100 (n = 13) cytarabine 1 g/m2/day x 2 days (Days –4 and –3). Patients with

Report on the second iwNST meeting Acute GVHD II–IV / III–IV 19% / 10% 57% / 33% indolent NHL received fludarabine 30 mg/m2/day x 3 days (Days Chronic GVHD 44% 64% –5 to –3), cyclophosphamide 750 mg/m2/day x 3 days (Days –5 to Non-relapse mortality –3) and rituximab 375 mg/m2 on Day –13 and 1000 mg/m2 on @ 100 days / @ 365 days 17% / 23% 41% / 48% Days –6, +1, and +8.

OS / PFS at 18 months 36% / 34% 37% / 33% To date 57 patients with a median age of 55 years (range 21–73 years) have been treated including 5 patients who had received a OS / PFS at 18 months All patients If in remission at BMT 90% / 90% prior autologous transplant. Twenty-five patients with aggressive If not in remission at BMT 26% / 23% histologies (13 DLCL, 5 mantle cell, 4 CLL with Richter’s transformation and 3 others) and 32 with indolent B-cell disorders * Patients may have more than one reason for NST (20 FL/SLL and 12 CLL) were transplanted. The chemosensitivity ANC, absolute neutrophil count; OS, overall survival; PFS, progression free of the patients at the time of transplant is shown in Table 3. survival

Table 3. Chemosensitivity of lymphoid malignancy patients at transplant moderate though reasonable for this older population of patients. NRM was low in patients in remission at the time of transplant. Aggressive NHL FL/SLL CLL GVHD was the single most important complication in the n (%) n (%) n (%) unrelated-donor group. Grade 3–4 GVHD occurred in 33% of Refractory 9 (36) 1 (5) 8 (67) these patients. This degree of GVHD was a relatively rare Sensitive 15 (60) 17 (67) 4 (33) occurrence in the patients with matched related donors (about Untested 1 (4) 2 (10) 0 (0) 10%). As seen in other disease types the OS and progression- free survival (PFS) were directly related to the disease status at the time of transplant. To further improve results the anti-CD33 Of the 57 patients, 2 experienced primary and 2 secondary graft monoclonal antibody gemtuzumab ozogamicin (Mylotarg) has failure. Thirty days posttransplant, the median percentage of been added to the preparative regimen, and rapid donor cells in the bone marrow was 50% (range 30–100%). immunosuppressive withdrawal followed by DLI has been applied Grade II–IV acute GVHD was seen in 10 patients (17.5%). in patients who do not develop GVHD by 90–180 days Twenty patients (35%) developed chronic GVHD that was posttransplant and who were not in remission at the time of extensive in 12 patients (6 post-DLI) and limited in 8 patients. The transplant. 100-day mortality was approximately 3.5% (2 patients with follicular lymphoma died: 1 from GVHD and the other from The FM preparative regimen has also been studied in 39 patients infection at Day 35). After a median follow-up of 6 months (range with CML. Most of the patients had transformed disease, and the 1–50 months), the OS was 63% and DFS was 54%. median age was 51 years. Thirty-six patients engrafted donor cells, 2 had autologous recovery and 1 patient did not recover Predictors of a good response were chemosensitive disease, their counts. Early or late mixed chimerism was a rare event, with early stage disease, and age < 55 years and no acute GVHD. All most patients being 100% donor at 30 days and 6 months post- 5 patients who had previously received an autologous transplant transplant. The study is continuing for patients in chronic phase. A were alive in remission 12 to 24 months post-BMT. The presence phase I study using fludarabine + busulfan in patients with of the bcl-2 rearrangement was studied pre- and posttransplant advanced disease is being considered. using PCR in 6 patients with follicular lymphoma. The patients were followed periodically, and all are now PCR negative These first generation studies have shown that the FLAG-Ida NST (Figure 2). The transition from PCR positivity to negativity does approach is feasible in older patients with AML, and in fact these not necessarily relate to the presence of 100% donor cells, and studies do not have an upper age limit as part of the entry criteria. the response can be gradual, taking up to a year. These results The results have been encouraging in patients who were in led to the decision to base DLI administration not on mixed remission at the time of transplant, and a phase III study will be chimerism but on disease response. If patients are continuing to

6 • Volume 8 • Issue 1 • August 2001 •

Report on the second iwNST meeting recipients of MUD grafts and is therefore an attractive option for CML patients with unrelated donors. Further studies to confirm these initial results are required.

Our initial experience with haploidentical NST holds promise that this approach could successfully be applied to high-risk patients who do not have a matched sibling or MUD. As with other types of stem cell transplantation, the outcome is influenced by disease status, type of disease (non-malignant > CML > AML > ALL), age, cell dose, and immune factors. Transplant-related mortality is still high because mismatched transplants are usually reserved exclusively for high-risk cases. We are optimistic that by using such innovative, Figure 2. PCR status, for bcl-2 rearrangement, and chimerism in 6 patients who received fludarabine-based transplantation NST for follicular lymphoma procedures, the success rate may be increased to about 50% in young patients transplanted in good have disease response they are followed without initiating DLI. performance status, but this will need to be demonstrated in It was agreed that for future studies that, as with traditional subsequent studies. In parallel with better patient selection, a transplants, results need to be presented grouped by disease, as focus of future research should be on developing strategies to the response to NST varies between diagnostic groups. improve post-grafting immune reconstitution, as late infectious or immune deficiency-related complications (e.g. second cancers) Hadassah experience with NST in unrelated and may become the critical factor for long-term success, after mismatched transplants overcoming the rejection barrier and GVHD.

Only 20–30% of patients have an HLA-identical sibling. Mismatched family or unrelated donors are a potential alternative Protocol development sessions although these approaches are currently limited by graft rejection and a high incidence and severity of GVHD. Intensified doses of The future development of NST relies on the coordination of large are generally used in the unrelated setting to multicenter cooperative clinical trials to define the proper role for facilitate engraftment. The intensified conditioning results in a high this approach. It also remains important for pilot studies testing frequency of transplant-related complications. It has been new concepts to be carried out, but studies investigating minor previously demonstrated that it is possible to achieve rapid and stable engraftment and low transplant-related organ toxicity with variations in preparative regimens should not be pursued. fludarabine + ATG based NST with matched related donors. This Strategies to separate the GVH and HVG reactions are important approach minimizes the intensity of the conditioning regimen and should focus on non-alloreactive transplants, specific while maximizing short-term immunosuppression and the GVL immunotherapy, and enhancement of immune reconstitution. effect. We have treated 33 patients, median age 24 years with Phase III studies are required to prove the efficacy of NST and mismatched related or unrelated donors using the same regimen. should be carried out in larger numbers of patients, have longer Diagnoses were CML 11, AML 8, ALL 5, MDS 5, lymphoma 3 and follow-up, and provide disease-specific results. Randomized solid tumor 1. Most patients (88%) achieved stable full chimerism. phase II studies should be initiated to test alternative NST Toxicity was lower than is usually observed in patients receiving strategies while definitive phase III trials of non-ablative conventional transplants from matched related or unrelated approaches versus standard therapy (ablative transplants or donors. Nine patients (27%) experienced Grade III–IV acute non-transplant treatments depending on the disease) should be GVHD, and 3 developed severe and extensive GVHD. The pursued based on the most promising phase II results. In order to 42-month estimated OS was 45%, and the DFS was 40% with a move the field forward as efficiently as possible, all patients median follow-up of 20 months. Fifteen patients died: 5 from receiving NST should do so on well designed clinical trials and all relapse, 4 from GVHD, 3 from organ toxicity, 2 from infections and patients should be reported to one of the international blood and 1 from graft rejection. Engraftment and rates of full chimerism bone marrow transplant registries (IBMTR or EBMT). The ultimate were similar to what is seen with traditional ablative allogeneic transplants from matched unrelated donors. aim of NST is to achieve engraftment, immune reconstitution and separation of GVH and graft-versus-malignancy reactions that will For CML, the most common indication for matched unrelated enable this novel approach to result in more patients being cured donor (MUD) transplant, the course of MUD transplants following of their disease. This could be achieved by developing cellular fludarabine-based non-myeloablative conditioning does not immunotherapy specific for antigens of the target malignancy and appear to differ from that of transplants from fully ablative major infections, and devoid of potential for GVHD. The HLA-matched sibling donors. Fludarabine-based NST seems to consensus on useful studies that should be carried out presently enable engraftment with low transplant-related toxicity in CML is summarized below.

7 GVHD prophylaxis – The role for CAMPATH-1H either pre- or followed by NST would be useful. There was no interest in post-transplant needs to be elucidated. A pilot study using comparing different NST regimens in this setting at this time. CAMPATH-1H pre-transplant as a strategy to reduce the Solid tumors – There is a need for a series of phase II studies in incidence of acute GVHD is required. a number of malignancies, as the data available to date are still Myeloid leukemia – A study comparing the fludarabine and relatively preliminary. busulfan regimen to fludarabine, busulfan and CAMPATH-1H (replacing ATG to reduce the incidence of GVHD) was of interest. Participants were identified to lead the further development of In addition a comparison of fludarabine and cyclophosphamide these ideas with the goal of having two or more accruing (FC) versus fludarabine and busulfan could demonstrate whether multicenter trials in the area of NST by the time of the third iwNST there is a difference in effectiveness of these two regimens in the meeting in 2002. NST setting. There was significant interest in a trial of NST versus standard care in elderly patients with AML. The accrual of CML References patients onto transplant studies may be affected for the foreseeable future by the increasing use of imatinib mesylate 1. Prigozhina TB, Gurevitch O, Zhu J, Slavin S. Permanent and (STI571, Gleevec) in this indication. specific transplantation tolerance induced by a non- Lymphoid malignancies – FC + rituximab should be studied as myeloablative treatment to a wide variety of allogeneic tissues: conditioning prior to transplant in patients with indolent I. Induction of tolerance by a short course of total lymphoid lymphomas or CLL beyond first remission. Large-cell lymphoma is irradiation and selective elimination of the donor-specific host currently a more difficult indication to evaluate. Only pilot data lymphocytes. Transplantation 1997; 63(10): 1394–9. exist, and more phase II data are needed before a consensus on 2. Giralt S, Slavin S (eds). Non-myeloablative stem cell the best approach can be reached. In Hodgkin disease the EBMT transplantation (NST). Darwin Scientific Publishing, UK, 2000. Report on the second iwNST meeting is active in investigating a number of preparative regimens. The 3. Slavin S, Nagler A, Varadi G, Or R. Graft vs autoimmunity results from these trials can be compared with historical controls following allogeneic non-myeloablative blood stem cell to determine the potential of NST in this disease. Indolent B-cell transplantation in a patient with chronic myelogenous leukemia disorders were also identified as an appropriate setting within and severe systemic psoriasis and psoriatic polyarthritis. Exp which to compare existing different approaches to NST. Hematol 2000; 28(7): 853–7. Non-malignant diseases – There was interest in investigating 4. Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini the use of fludarabine + busulfan for genetic diseases P, O’Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, (considering higher doses of busulfan in pediatric patients), FC for Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, severe aplastic anemia, or fludarabine + low-dose cyclo- Körbling M, Keating M, Kantarjian H and Champlin R. phosphamide for Fanconi’s anemia. Again, a study ± CAMPATH Engraftment of allogeneic hematopoietic progenitor cells with would provide data on the possibility of reducing GVHD. purine analog-containing chemotherapy: harnessing graft- Multiple myeloma – There was interest in comparing autologous versus-leukemia without myeloablative therapy. Blood 1997; transplantation with the tandem autologous–NST approach. A 89(12): 4531–6. study comparing high-dose melphalan with high-dose melphalan

Non-myeloablative stem cell transplant trials at the IBMTR The IBMTR has undertaken the coordination of two multicenter trials in in the randomized phase II trial above. For patients deemed at higher non-myeloablative stem cell transplantation. Dr. Robert Collins of Texas risk of relapse / disease progression, immunosuppression is tapered by Southwestern University and Dr. Christopher Bredeson of the IBMTR day +90 and DLI can be initiated for failure to achieve a CR. One are co-PIs on the two trials, which are being conducted at approximately hundred patients in five disease groups are to be entered by the a dozen centers in the USA and Canada. participating institutions* over the next year.

The first trial, “A phase ll multicenter randomized study of two non- Centers interested in referring patients for consideration or learning myeloablative stem cell strategies for low-grade lymphoma and chronic more about the trials can contact either Dr. Robert Collins lymphocytic leukemia” randomizes patients to either fludarabine 30 mg/ ([email protected]) or m2/day x 3 days + 200 cGy TBI with cyclosporine and mycophenolate Dr. Christopher Bredeson ([email protected]). mofetil (MMF) as posttransplant immunosuppression, or fludarabine 25 mg/m2/day x 5 days + cyclophosphamide 1 g/m2/day x 2 days with * The following investigators and sites are participating in one or both of FK506 and methotrexate as posttransplant immunosuppression. DLI in the above trials: Dr. Robert Collins, University of Texas Southwestern escalating doses is reserved for patients experiencing disease Medical Center, Dallas, Texas; Dr. Christopher Bredeson, Medical progression posttransplant. The goal of this trial is to identify which College of Wisconsin, Milwaukee, Wisconsin; Dr. Steven Goldstein, regimen to bring into phase III trials against traditional myeloablative H. Lee Moffitt Cancer Center, Tampa, Florida; Dr. J.J. Ifthikharuddin, allogeneic transplants for this patient population. One hundred patients Strong Memorial Hospital, Rochester, NY; Dr. Richard Maziarz, Oregon are to be randomized over the next year at the participating institutions.* Health Sciences University, Portland, Oregon; Dr. Scott Rowley, The trial is being supported by Schering AG, Amgen and Roche. Hackensack University, Hackensack, New Jersey; Dr. Mark Juckett, University of Wisconsin, Madison, Wisconsin; Dr. Thomas Kiss, The second trial, “Low dose TBI and fludarabine followed by HLA Princess Margaret Hospital, Toronto, Ontario; Dr. Margarida Silverman, matched allogeneic stem cell transplantation for hematologic University of Iowa Hospitals and Clinics, Iowa City, Iowa; Dr. Madhuri malignancies – a multicenter study”, uses the same fludarabine + TBI Vusirikala, Vanderbilt University Medical Center, Nashville, Tennessee; regimen approach of the randomized phase II trial but has different Dr. Neal Flomenberg, Thomas Jefferson University Hospital, schedules for the tapering of posttransplant immunosuppression based Philadelphia, Pennsylvania; Dr. Robert Rifkin, Rocky Mountain BMT on the perceived risk of relapse / disease progression of the different Program, Denver, Colorado; Dr. John Edwards, Walt Disney Memorial eligible disease groups. In low risk disease groups, immunosuppression Cancer Institute, Orlando, Florida. Dr. Lothar Huebsch, University of is tapered by day +180 and DLI is reserved for disease progression as Ottawa, Ottawa.

8 • Volume 8 • Issue 1 • August 2001 •

Forbeck Forum discusses recommendations for clinical trials in hematopoietic stem cell transplantation

hile laboratory advances have Martin (Fred Hutchinson Cancer Research The Committee on Reporting of Adverse Wincreased fundamental knowledge Center, Seattle) and Dr. Mary Horowitz Event Data in Transplant proposed a more of transplantation and tumor biology and (IBMTR/ABMTR Statistical Center, efficient and effective method for reporting suggested strategies for improving Milwaukee). adverse event data in autologous or transplant results, implementing and allogeneic marrow or peripheral blood completing clinical trials that definitively The Forum was quite successful in hematopoietic stem cell transplant clinical test the efficacy of new transplant achieving its objectives, which included trials. The Committee’s recommendations approaches has proven difficult. reviewing the current state of clinical trials included: (1) adoption of a standardized Regulatory and funding agencies, in hematopoietic stem cell transplantation template of organ-specific severity scales, pharmaceutical companies and transplant (HSCT) and the major obstacles to with allowances for ad hoc additions and physicians often have divergent implementing and completing trials in a modifications as needed for specific study perspectives and objectives that hinder timely manner. Participants discussed drugs; (2) standardized definitions of achieving consensus on optimal clinical trial designs most likely to be causality relationships between study drug approaches. successful in HSCT; streamlined systems administration and adverse events; (3) for reporting adverse events that ensure modifications in the criteria for the The Forum on Planning and Conducting patient safety but do not impose an definition of a severe adverse event; (4) Clinical Trials in Hematopoietic Stem Cell excessive burden on clinical investigators; calibrating the level of detail and time Transplantation held immediately following and strategies for achieving consensus on window in reporting adverse event data to the recent Tandem BMT Meetings in diagnosis and grading transplant-specific the severity of the adverse event and its February attempted to address these outcomes, particularly engraftment and perceived relationship to study drug; (5) issues and provide recommendations for graft-versus-host disease. These encouraging investigators to report clinical trial design, adverse event recommendations for clinical trial design, adverse events as diseases or reporting and analysis of transplant- adverse event reporting and analysis of syndromes, wherever possible, instead of specific outcomes. The Forum was transplant-specific outcomes will be reporting individual component symptoms, sponsored by the William Guy Forbeck summarized by sub-committees organized signs, laboratory abnormalities and Research Foundation, which funds to address each topic and submitted for sequelae; and (6) exempting certain opportunities for small groups of leading publication. A short summary follows. adverse events from mandatory reporting. scientists from a variety of disciplines to participate in an environment where they Recommendations from the Committee on The Committee on Reporting Transplant- can freely exchange ideas and build on Designing Clinical Trials in Hematopoietic Specific Outcomes reviewed the current Stem Cell Transplantation included: (1) each other’s knowledge, experience and state of the art in diagnosis and grading of enrolling patients as close to start of insight, in the hope that they might shorten major transplant-related outcomes transplant therapy as possible to avoid the cancer research timetable. Invited high early drop-out rates; (2) striving for including engraftment, acute graft-versus participants and observers at the February relatively homogeneous study populations host disease (GVHD), chronic GVHD, and forum included representatives from the to avoid unanticipated imbalances; (3) relapse. Deficiencies in current systems academic transplant community, the US prospective planning for covariate were discussed and specific studies Food and Drug Administration, the US adjustment and judicious use of proposed, particularly in the areas of National Institutes of Health, the American stratification; (4) appropriate use of non- GVHD. The Committee also Society for Blood and Marrow randomized controls in certain situations; recommended proposed changes to Transplantation, the Foundation for the (5) avoiding overly restrictive requirements existing cell product standards. It was Accreditation of Hematopoietic Cell for supportive care strategies not clearly agreed that a series of future meetings, Therapy, the International Society of related to the primary outcome; (6) each focused on specific transplant- Hematotherapy and Graft Engineering, the stratification on center and appropriate related outcomes, would be beneficial. National Marrow Donor Program, the strategies for detecting and adjusting for International Bone Marrow Transplant center effects; (7) use of appropriate and, Plans are underway for future forums, the Registry, and the Autologous Blood and often, multiple statistical techniques and first to focus on diagnosing and grading Marrow Transplant Registry. It was monitoring strategies, that can acute and chronic GVHD. organized by Dr. James Gajewski (M.D. accommodate competing risks, time- Anderson Cancer Center, Houston), Dr. dependent effects and other Stephen Litwin (FDA, Rockville), Dr. Paul posttransplant events.

Committee on Designing Clinical Trials Charles Peterson, MD, US National Heart, Lung, Committee on Reporting of Transplant- Addressing Issues in Hematopoietic Stem and Blood Institute, Bethesda, MD Specific Outcomes Cell Transplantation Julie Vose, MD, University of Nebraska, Omaha, James Gajewski, MD, M.D. Anderson Cancer Mary M. Horowitz, MD, MS, IBMTR/ABMTR NE Center, Houston, TX Statistical Center, Milwaukee, WI (Chair) Andy Gilman, MD, Children’s Mercy Hospital, Don Berry, PhD, M.D. Anderson Cancer Center, Committee on Reporting of Adverse Event Kansas City, MO Houston, TX Data in Hematopoietic Stem Cell Transplant Liana Harvath, PhD, US National Heart, Lung, Karl Blume, MD, Stanford University Medical Clinical Trials and Blood Institute, Bethesda, MD Center, Stanford, CA Paul Martin, MD, Fred Hutchinson Cancer Stephanie Lee, MD, Dana-Farber Cancer Marian Ewell, ScD, EMMES Corporation, Research Center, Seattle, WA (Chair) Institute, Boston, MA Potomac, MD Joseph Antin, MD, Dana Farber Cancer Institute, John McMannis, PhD, M.D. Anderson Cancer John Klein, PhD, IBMTR/ABMTR Statistical Boston, MA Center, Houston, TX Center, Milwaukee, WI Patricia Keegan, MD, Center for Biologics Annemarie Moseley, MD, PhD, Osiris Steve Litwin, MD, US Food and Drug Evaluation Research, Rockville, MD Therapeutics, Inc., Baltimore, MD Administration, Rockville, MD Virginia Paton, PharmD, Cerus Corporation, John Wagner, MD, University of Minnesota, Joyce Niland, PhD, City of Hope Cancer Center, Concord, CA Minneapolis, MN Duarte, CA Daniel Weisdorf, MD, University of Minnesota, Minneapolis, MN 9 Recent peer-reviewed publications from the IBMTR/ABMTR

Davies SM, Ramsay NKC, Klein JP, Champlin RE, Passweg JR, Zhang MJ, MJ, Edwards JR, Fasth A, Gale RP, Weisdorf DJ, Bolwell B, Cahn J-Y, Camitta Rowlings PA, Pelz CJ, Atkinson KA, Junker A, Kamani NR, Loechelt BJ, BM, Gale RP, Giralt S, Heilmann C, Barrett AJ, Cahn JY, Drobyski WR, Gale Pietryga DW, Ringdén O, Vowels M, Henslee-Downey PJ, Herzig RH, RP, Goldman JM, Gratwohl A, Gordon- Hegland J, Williams AV, Klein JP, Hutchinson R, Keating A, Lazarus HM, Smith EC, Henslee-Downey PJ, Herzig Sobocinski KA, Rowlings PA, Horowitz Milone GA, Neudorf S, Perez WS, Powles RH, Klein JP, Marmont AM, O’Reilly RJ, MM. Impact of donor type on outcome of RL, Prentice HG, Schiller G, Socié G, Ringdén O, Slavin S, Sobocinski KA, bone marrow transplantation for Wiskott- Vowels M, Wiley J, Yeager A, Horowitz Speck B, Weiner RS, Horowitz MM. T-cell Aldrich syndrome by donor type: MM. Comparison of preparative regimens depletion of bone marrow transplants for collaborative study of the International in transplants for children with acute leukemia from donors other than HLA- Bone Marrow Transplant Registry and the lymphoblastic leukemia. J Clin Oncol identical siblings: advantage of T-cell National Marrow Donor Program. Blood 18:340–347, 2000. antibodies with narrow specificities. Blood 97:1598–1603, 2001. 95:3996–4003, 2000. Socié G, Curtis RE, Deeg HJ, Sobocinski Vose JM, Zhang MJ, Rowlings PA, KA, Filipovich AH, Travis LB, Sullivan KM, Klein JP, Keiding N, Shu Y, Szydlo RM, Lazarus HM, Bolwell BJ, Freytes CO, Rowlings PA, Kingma DW, Banks PM, Goldman JM. Summary curves for Pavlovsky S, Keating A, Yanes B, van Travis WD, Witherspoon RP, Sanders J, patients transplanted for chronic myeloid Besien K, Armitage JO, Horowitz MM and Jaffe ES, Horowitz MM. New malignant leukemia salvaged by a donor lymphocyte others of the ABMTR Lymphoma Working diseases after allogeneic marrow infusion: the current leukemia free survival Committee. Autologous transplantation for transplantation for childhood acute curve. Br J Haematol 109:148–152, 2000. diffuse aggressive non-Hodgkin’s leukemia. J Clin Oncol 18:348–357, 2000. lymphoma in patients never achieving Craddock C, Szydlo RA, Klein JP, Dazzi F, remission: a report from the Autologous Giralt S, Szydlo R, Goldman JM, Veum Olavarria E, van Rhee EF, Pocock C, Blood and Marrow Transplant Registry JS, Biggs JC, Herzig RH, Klein JP, Cwynarski K, Apperley JF, Goldman JM. (ABMTR). J Clin Oncol 19:406–413, McGlave PB, Schiller G, Gale RP, Estimating leukemia-free survival after 2001. Rowlings PA, Horowitz MM. Effect of allografting for chronic myeloid leukemia: short-term interferon therapy on the a new method that takes account of Lazarus HM, Loberiza FR, Jr., Zhang MJ, outcome of HLA-identical sibling bone patients who relapse and are restored to Armitage JO, Ballen KK, Bashey A, marrow transplantation for chronic complete remission. Blood 96:86–90, Bolwell BJ, Burns LJ, Freytes C, Gale RP, myelogenous leukemia: an analysis from 2000. Gibson J, Herzig RH, LeMaistre CF, the International Bone Marrow Transplant Marks D, Mason J, Miller AM, Milone GA, Registry. Blood 95:410–415, 2000. Klein JP, Szydlo RA, Craddock C, Pavlovsky S, Reece DE, Rizzo, JD, Goldman JM. Estimation of current van Besien K, Vose JM, Horowitz MM. Rocha V, Wagner JE, Sobocinski KA, leukemia-free survival following donor Autotransplants for Hodgkin’s disease in Klein JP, Zhang MJ, Horowitz MM, lymphocyte infusion therapy for patients first relapse or second remission: a report Gluckman E and other members of the with leukemia who relapse after from the Autologous Blood and Marrow Eurocord and the IBMTR Working allografting: application of a multistate Transplant Registry (ABMTR). Bone Committee on Alternative Donor and Stem model. Statistics in Medicine 19:3005– Marrow Transplant 27:387–396, 2001. Cell Sources. Comparison of graft versus 3016, 2000. host disease in children transplanted with Scheike TH, Zhang MJ. An additive- HLA-identical sibling umbilical cord blood Stiff PJ, Veum-Stone J, Lazarus HM, multiplicative Cox-Aalen regression model. versus bone marrow hematopoietic stem Ayash L, Edwards JR, Keating A, Klein JP, Scand J Statistics, 2001. In press. sells. N Engl J Med 342:1846–1854, Oblon DJ, Shea TC, Thomé S, Horowitz 2000. MM. High dose chemotherapy and nbmtLINK patient care video autologous hematopoietic stem cell available Champlin RE, Schmitz N, Horowitz MM, transplantation for ovarian carcinoma in Chapuis B, Chopra R, Cornelissen JJ, North America: a report from the The National Bone Marrow Transplant Gale RP, Goldman JM, Loberiza FR Jr, Autologous Blood and Marrow Transplant Link, a non-profit organization committed Hertenstein B, Klein JP, Montserrat E, Registry. Ann Intern Med 133:504–515, to reducing the burdens of those Zhang MJ, Ringdén O, Tomany SC, 2000. challenged by bone marrow / stem cell Rowlings PA, Van Hoef MEHM, Gratwohl transplantation through education and A, on behalf of the IBMTR Tallman MS, Rowlings PA, Milone G, support, has created a video to help Histocompatibility & Stem Cell Sources Zhang MJ, Perez WS, Weisdorf D, prepare patients for what they will face Working Committee and the European Keating A, Gale RP, Geller RB, Laughlin when undergoing transplantation. The film, Group for Blood and Marrow MJ, Lazarus HM, Luger S, McCarthy PL, The New Normal, comes from the voices Transplantation (EBMT). Blood stem cells Rowe JM, Saez RA, Vowels MR, Horowitz of six transplant survivors ranging in age compared with bone marrow as a source MM. Effect of postremission of hematopoietic cells for allogeneic chemotherapy before human leukocyte and background, and from 2 to 10 years transplantation. Blood 95:3702–3709, antigen-identical sibling transplantation for posttransplant. The New Normal hopes to 2000. acute myelogenous leukemia in first help overcome patients’ fears by giving complete remission. Blood 96:1254– them an idea of what to expect and Barrett AJ, Ringdén O, Zhang MJ, Bashey 1258, 2000. provides information, inspiration and hope A, Cahn JY, Cairo MS, Gale RP, Gratwohl to patients and their caregivers. For more A, Locatelli F, Martino R, Schultz KR, Collins R, Goldstein S, Giralt S, Levine J, information on this complimentary video, Tiberghien P and the GVHD/GVL Working Porter D, Drobyski W, Barrett AJ, Horowitz please contact the National Bone Marrow Committee of the International Bone MM, Parker, P. Donor leukocyte infusions Transplant Link at 20411 W. 12 Mile Road, Marrow Transplant Registry. Effect of in acute lymphocytic leukemia. Bone nucleated marrow cell dose on relapse Marrow Transplant 26:511–516, 2000. Suite 108, Southfield, Michigan 48076, and survival in identical twin bone marrow USA; telephone: 1-800-LINK-BMT transplants for leukemia. Blood 95:3323– Filipovich AH, Murphy SC, Ireland M, (1-800-546-5268) or 248-932-8483; 3327, 2000. Kollman C, Pelz CJ, Casper JT, Cowan e-mail: [email protected].

10 • Volume 8 • Issue 1 • August 2001 •

Foundation and corporate support of the IBMTR/ABMTR

Thanks to the many contributors who have joined our international collaboration for research in blood and marrow transplantation. We gratefully acknowledge the support of the Medical College of Wisconsin; the National Cancer Institute; the National Institute of and Infectious Disease; the National Heart, Lung and Blood Institute; the Department of Defense; and the generosity of the following supporters:

Non-federal support listing for the IBMTR/ABMTR

(Grant awards since 1999)

Abgenix, Inc. * Fujisawa Healthcare, Inc. Mutual of Omaha * AmCell Corporation * Gambro BCT, Inc. NeoRx American Cancer Society * Genentech, Inc. * Nexell Therapeutics, Inc. American Society of Clinical Oncology GeneScreen, Inc. Novartis Pharmaceuticals, Inc. Amgen, Inc. Genetic Therapy, Inc. / Systemix, Inc., * Orphan Medical, Inc. Anonymous Novartis Companies * Ortho Biotech, Inc. *Aventis Pharmaceuticals * GlaxoSmithKline, Inc. John Oster Family Foundation * Berlex Laboratories * Human Genome Sciences Pall Medical BioTransplant, Inc. Hunter’s Hope Foundation Pfizer US Pharmaceuticals * BlueCross and BlueShield Association * ICN Pharmaceuticals, Inc. Pharmacia Corporation The Lynde and Harry Bradley * IDEC Pharmaceuticals Corporation * Principal Life Insurance Company Foundation * Immunex Corporation Protide Pharmaceuticals, Inc. * Bristol-Myers Squibb Oncology IMPATH, Inc. * Response Oncology, Inc. Cambridge University Press * IntraBiotics Pharmaceuticals, Inc. RGK Foundation Celgene Corporation Kaiser Permanente Roche Laboratories Cell Therapeutics, Inc. The Kettering Family Foundation SangStat Center for Advanced Studies in * Kirin Brewery Company (Japan) * Schering AG (Berlin) Leukemia Robert J. Kleberg, Jr. & Helen C. * Schering Oncology/Biotech * Cerus Corporation Kleberg Foundation Stackner Family Foundation * Chimeric Therapies, Inc. * Life Trac/Allianz Life The Starr Foundation * Chiron Therapeutics Ligand Pharmaceuticals, Inc. StemCell Technologies, Inc. Cincinnati Transplant Institute * The Liposome Company, Inc. StemSoft Software, Inc. Corixa Nada and Herbert P. Mahler Charities * SuperGen Darwin Medical Communications, Ltd. * Market Certitude, LLC Therakos, a Johnson & Johnson Co. Edwards Lifesciences/RMI * MedImmune, Inc. * TheraTechnologies, Inc. Eleanor Naylor Dana Charitable Trust * Merck & Company * Unicare Life & Health Insurance Deborah J. Dearholt Memorial Fund * Milliman & Robertson, Inc. United Resource Networks Eligix Milstein Family Foundation US Oncology * Empire Blue Cross Blue Shield Miltenyi Biotec ViraCor William Guy Forbeck Research The Milwaukee Foundation / Elsa *Wyeth/Genetics Institute Foundation Schoeneich Medical Research Fund

* Corporate member

IBMTR/ABMTR Corporate Membership Program

Several corporations have joined the IBMTR/ABMTR Corporate IBMTR/ABMTR Summary Slides on the State-of-the-Art in Blood Membership Program (see above). The annual membership and Marrow Transplantation as well as invitations to our meetings program provides member organizations with informational and educational forums and access to the IBMTR/ABMTR materials on blood and bone marrow transplantation developed databases for simple analyses. These resources are useful for by the IBMTR/ABMTR Information Resource Service. marketing managers, medical directors, research directors, product managers, case managers or transplant coordinators. The program includes subscriptions to the Statistical Center Report on Survival Statistics for Blood and Marrow Transplants, For additional information on the Corporate Membership Program, IBMTR/ABMTR Newsletters, the worldwide IBMTR/ABMTR please contact Lisa Schneider, Associate Director of Development, Directory of Blood and Marrow Transplant Physicians, and the Tel (414) 456-8363, Fax (414) 456-6530.

11 ABMTR Executive Committee members IBMTR Executive Committee members

Julie M. Vose, MD Elizabeth C. Reed, MD Alexandra H. Filipovich, MD Mary M. Horowitz, MD, MS University of Nebraska Medical Center, University of Nebraska Medical Center, Children’s Hospital Medical Center, Medical College of Wisconsin, Omaha, NE, USA (Chair) Omaha, NE, USA Cincinnati, OH, USA (Chair) Milwaukee, WI, USA

Richard E. Champlin, MD Thomas C. Shea, MD Olle Ringdén, MD, PhD John P. Klein, PhD M.D. Anderson Cancer Center, Houston, TX, University of North Carolina, Chapel Hill, NC, Huddinge University Hospital, Huddinge, Medical College of Wisconsin, USA (Chair-Elect) USA Sweden (Chair-Elect) Milwaukee, WI, USA

Mary M. Horowitz, MD, MS Patrick J. Stiff, MD Sergio A. Giralt, MD H. Grant Prentice, MD Medical College of Wisconsin, Milwaukee, Loyola Marymount University Medical Center, M.D. Anderson Cancer Center, Houston, TX, Royal Free Hospital, London, UK WI, USA Maywood, IL, USA USA Gérard Socié, MD, PhD Armand Keating, MD Koen van Beisen, MD John M. Goldman, DM Hôpital St. Louis, Paris, France University of Toronto, Toronto, Ontario, University of Chicago Medical Center, Imperial College of Medicine, London, UK (Secretary-Treasurer) Canada (Past Chair) Chicago, IL, USA (Past Chair) (Secretary-Treasurer) L. Bik To, MD, FRACP, FRCPA John P. Klein, PhD Mine Harada, MD Hansen Center for Cancer Research, Medical College of Wisconsin, Milwaukee, Daniel J. Weisdorf, MD Okayama University Medical School, Adelaide, Australia WI, USA University of Minnesota, Minneapolis, MN, Okayama, Japan USA Axel R. Zander, MD, PhD Hillard M. Lazarus, MD P. Jean Henslee-Downey, MD University Hospital Eppendorf, Hamburg, Case Western Reserve University, Steven N. Wolff, MD Indiana Blood and Marrow Transplantation, Germany Cleveland, OH, USA Aastrom Biosciences Inc., Ann Arbor, MI, USA Indianapolis, IN, USA

Statistical Mary M. Horowitz, MD, MS Mary Eapen, MD, MS Mei-Jie Zhang, PhD Scientific Director Assistant Scientific Director, Pediatrics Associate Professor / Center John P. Klein, PhD Fausto R. Loberiza, Jr, MD, MS Biostatistician Statistical Director Assistant Scientific Director Personnel Christopher N. Bredeson, J. Douglas Rizzo, MD MD, MSc Assistant Scientific Director Assistant Scientific Director This issue of the IBMTR/ABMTR Newsletter is supported by an Claudia A. Abel Amie M. Lalor Linda M. Schneider unrestricted educational Data Coordinator Clinical Research Coordinator Desktop Publishing Specialist grant from Kavita P. Bhavsar Barbara B. Liu, MS Lisa J. Schneider Schering AG Data Entry Assistant Manager, Information Systems Associate Director of Development Jane Gulla Bernardo E. Mayorga Sherry L. Simpson Data Entry Assistant Data Entry Assistant Clinical Research Coordinator Please address correspondence to: Scott S. Huntley Barbara A. McGary, BS Kathleen A. Sobocinski, MS IBMTR/ABMTR Statistical Center Administrative Coordinator II Manager of Information Systems Associate Statistical Director Medical College of Wisconsin Jennifer Kennedy Sharon K. Nell Sandra J. Sobotka 8701 Watertown Plank Road PO Box 26509 Data Entry Assistant Clinical Research Coordinator Administrative Assistant Milwaukee WI 53226, USA Kim R. Jackson Melodee L. Nugent, MA Tim Sobotka Administrative Assistant Information Specialist / Biostatistician Staff Assistant Telephone: (414) 456-8325 Fax: (414) 456-6530 Thomas Joshua Mita A. Patani Hongyu Tian E-mail: [email protected] Data Entry Assistant Data Entry Assistant Database Analyst Diane J. Knutson, BS Ann G. Pereles Patricia A. Vespalec Please contact the IBMTR/ABMTR Statistical Center with any address Senior Research Associate Data Entry Assistant Communications Specialist updates, or if a colleague would also Kathleen P. Kovatovic, RPh Waleska S. Pèrez, MPH D’Etta Waldoch, CMP like to receive the Newsletter. We also welcome your suggestions and Audit Coordinator Research Scientist Associate Director, International comments. Angela S. Kummerow Jane E. Rebro Programs Data Coordinator Communications Coordinator Published for and on behalf of the IBMTR/ABMTR by

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12