Specialized Blood Cell Transplants for Cancers of the Blood and Bone Marrow
Specialized Blood Cell Transplants for Cancers of the Blood and Bone Marrow
The are a variety of cancerous diseases of the blood and bone marrow that can be potentially
 cured by bone marrow transplantation (BMT). Diseases like leukemia, lymphoma, and multiple
 myeloma are among the conditions that can be treated with BMT.

 Some patients with these diseases can be treated with medical chemotherapy alone. However,
 patients who relapse following chemotherapy are usually not curable with additional
 chemotherapy treatments. The only option known to provide a potential cure if this occurs is
 BMT.

 Allogenic transplants are cells collected from relatives of the patient. The transplant
 requires additional high intensity chemotherapy and radiation in order to destroy cancerous
 cells. In the process, many normal bone marrow cells are also destroyed. This is the reason
 for transplanting stem cells. The stem cells help to build new functioning bone marrow, red
 cells, white cells, and platelets. In addition, the immune cells from the donor are implanted
 into the recipient s body and help to fight off infection and kill remaining cancerous cells.

 Unfortunately, the powerful doses of chemotherapy and radiation therapy associated with
 allogenic BMT have toxic side effects and often make BMTs too dangerous to attempt in many
 patients.

 In order to reduce the complications of BMT, and make it a safer available option for
 patients with cancers of the blood and bone marrow, researchers have developed a new approach
 to the BMT.

 In this study researchers plan to use stem cells collected from the blood stream of patient s
 relatives rather than from the bone marrow (blood progenitor/stem cell transplant). In
 addition, researchers plan to use low doses of chemotherapy and no radiation therapy to
 reduce side effects. The majority of the cancer killing effect will be the responsibility of
 the stem cell transplant rather than the chemotherapy.
Patients with malignant and non-malignant hematologic diseases including severe aplastic
 anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS),
 acute and chronic leukemias, Hodgkin's and non-Hodgkin's lymphoma and multiple myeloma (MM)
 can now be cured by allogeneic bone marrow transplantation (BMT). This curative effect has
 been ascribed to the use of high dose chemo-radiotherapy and the anti-tumor or anti-bone
 marrow effect of the allograft. Dose intensification of conditioning regimens in attempts to
 reduce disease recurrence has been largely unsuccessful because of increased toxicity and
 mortality. Indeed, most evidence now points to donor-derived T-cells as being the principal
 modality leading to the complete eradication of both malignant and non-malignant host
 hematopoietic cells.

 The assumption that successful allogeneic BMT relies on the myeloablative effect of intensive
 but hazardous chemo-radiotherapy has largely restricted this therapeutic modality to patients
 with malignant or life-threatening hematologic disorders under the age of 55 years.
 Treatment-related mortality increases substantially with age, prior intensive treatment with
 chemo-radiotherapy, worsening performance status, and co-morbid medical conditions. An
 unacceptable risk of death from conventional BMT renders many patients ineligible for what
 may otherwise be curative therapy.

 Several in vitro studies have demonstrated the existence of donor-derived CD4 and CD8
 positive lymphocytes with specific reactivity for the patient s leukemia. These cells provide
 a potent graft-versus-leukemia (GVL) effect. This GVL effect is best seen in patients with
 CML relapsing after BMT, where a single infusion of donor lymphocytes has been shown to
 induce complete remission. In addition to the potent anti-leukemia effect of these cells,
 there is now strong evidence that donor T-cells are capable of completely eradicating
 residual host hematopoietic cells in a non-myeloablative transplant setting
 (graft-versus-marrow) leading to successful and complete donor hematopoietic engraftment.

 Non-myeloablative allogenic peripheral blood stem cell transplants are currently being
 investigated in phase I/II trials assessing engraftment efficacy and toxicity at a number of
 transplant centers. Preliminary data, including our own experience with greater than 150
 patients undergoing this type of procedure, have shown a high rate of complete donor
 engraftment with a low toxicity profile. Two recent studies investigating non-myeloablative
 allo-transplantation in standard risk patients revealed an extremely low rate of
 transplant-related complications and mortality.

 The decreased risk of transplant-related complications associated with non-myeloablative
 transplants expands the eligibility of transplant candidates as well as opens the possibility
 to evaluate non-myeloablative regimens in patients at high risk for complications with
 standard transplantation. Besides hematologic malignancies, allogeneic BMT has been shown to
 be curative in a number of debilitating hematologic diseases which may behave in a relatively
 indolent fashion, such as paroxysmal nocturnal hemoglobinuria (PNH) and refractory anemia
 (RA) or refractory anemia with ringed sideroblasts (RARS). However, the 30% risk of
 treatment-related mortality (TRM) with standard myeloablative allotransplantation usually
 precludes these patients from potentially curative therapy, because of concerns about
 shortening life in patients with these disorders. In this protocol we investigate
 non-myeloablative allogeneic peripheral blood stem cell (PBSC) transplantation in two groups
 of subjects where standard allogeneic transplantation is considered to have unacceptable
 toxicity.

 Group A: Subjects with hematologic malignancies with factors putting them at high risk for
 transplant related complications and mortality, including prior intensive chemo-radiotherapy
 and co-morbid diseases.

 Group B: Subjects with hematologic diseases (both clonal and non-clonal) associated with
 reasonable longevity not currently considered for allogeneic BMT because of prohibitive
 procedural mortality with conventional BMT (enrollment closed October 2010).

 In this protocol, eligible subjects are treated with an allogeneic PBSC transplant from an
 HLA identical or single HLA antigen-mismatched family donor, using an intensive
 immunosuppressive regimen without myeloablation in an attempt to decrease the transplant
 related toxicities while preserving the anti-malignancy and/or anti-host marrow effect of the
 graft. The low intensity non-myeloablative conditioning regimen should provide adequate
 immunosuppression to allow stem cell and lymphocyte engraftment. T-cell replete,
 donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized PBSCs will be used to
 establish hematopoietic and lymphoid reconstitution. We will add back lymphocytes in
 recipients with less than 100% donor T-cell chimerism in an attempt to prevent graft
 rejection and enhance a graft-versus-malignancy effect.

 The primary endpoint of this study is transplant related mortality (200 day survival). Other
 end points include engraftment, degree of donor-host chimerism, incidence of acute and
 chronic graft versus host disease (GVHD), transplant related morbidity as well as
 disease-free and overall survival.
-  INCLUSION CRITERIA - Recipients:

 Group A: Subjects at high risk for transplant related complications and mortality as
 defined below:

 Ages 10 to 75 (both inclusive) with a history of one of the following:

 -  Treatment with dose intensive chemotherapy and/or radiotherapy

 -  Previous history of allo/auto transplant

 -  History of multiple myeloma or extramedullary plasmacytoma

 -  Chronic disease or co-morbid medical condition including subjects with symptoms or
 signs of significant pulmonary disease, hepatic disease, kidney disease, cardiac
 disease or disease of other organ systems which would result in increased risk of
 morbidity or death from a standard myeloablative transplant.

 Diseases to be included:

 -  CML chronic phase

 -  Acute lymphoblastic leukemia (ALL), all subjects in complete or partial remission.

 -  AML: AML in first complete or partial remission Exceptions: AML with good risk
 karyotypes: AML M3 t(15:17), AML M4Eo (inv. 16), AML t(8;21). All AML in second or
 subsequent complete remission.

 -  MDS: refractory anemia with excess blasts (RAEB), or chronic myelomonocyte leukemia
 (CMML).

 -  Myeloproliferative diseases associated with either cytopenia or uncontrolled
 proliferation.

 -  CLL or small lymphocytic lymphoma (SLL) with bulky or progressive disease despite
 prior treatment with chemotherapy which includes purine analogs.

 -  NHL

 A) Intermediate or high grade relapsed or progressive despite treatment with standard
 therapy ineligible for autologous PBSC transplant.

 B) NHL intermediate or high grade relapsing despite prior autologous transplant.

 C) Low grade follicular or small lymphocytic lymphoma (1) high risk patients who have
 relapsed following conventional chemotherapy, (2) relapsed following autologous marrow or
 PBSC transplant, or (3) chemo resistant disease.

 D) Mantle cell lymphoma

 E) NHL intermediate or high grade with concurrent BCL2 and MYC translocations who are at
 high risk for relapsed and who have low survival with conventional chemotherapy.

 -  HD, relapsed after prior autologous transplant or after 2 or more combination
 chemotherapy regimens and ineligible for autologous PBSC transplant.

 -  EBV driven lymphoproliferative disorders progressing despite standard therapies.

 -  MM: MM subjects must be between the ages of 8 and 65 (both inclusive)

 -  Mycosis fungoides, which has been shown to be amenable to allogeneic stem cell
 transplants.

 Group B: (Closed to enrollment Oct 2010) Subjects with hematologic diseases associated with
 reasonable longevity, shown to be curable by allogeneic BMT but where concern for a high
 procedural mortality with conventional BMT may delay or prevent such treatment.

 Ages 8 to 80 (both inclusive) with a history of one of the following

 -  PNH associated with either life-threatening thrombosis, cytopenia, transfusion
 dependence or recurrent and debilitating hemolytic crisis.

 -  Aplastic anemia or PRCA (acquired or congenital) in subjects associated with
 transfusion dependence and/or neutropenia who are not candidates for or who have
 failed immunosuppressive therapy

 -  RA or RARS MDS subjects who have associated transfusion dependence and/or neutropenia.

 Ability to comprehend the investigational nature of the study and provide informed consent.
 The procedure will be explained to subjects age 8-17 years with formal consent being
 obtained from parents or legal guardian.

 Availability of HLA identical or single HLA locus mismatched family donor

 INCLUSION CRITERIA - Donor:

 HLA identical or single HLA mismatched family donor

 Age greater than or equal to 2 up to 80 years old

 Weight greater than or equal to 18 kg

 Ability of donor or guardian of donor to comprehend the investigational nature of the study
 and provide informed consent.

 EXCLUSION CRITERIA - Recipient - any of the following:

 Pregnant or lactating

 Group A: age less than 10 or greater than 75 (multiple myeloma age less than 8 or greater
 than 65);

 Group B: Age less than 8 or greater than 80 years.

 ECOG performance status of 3 or more (See NIH Bone and Marrow Consortium Supportive Care
 Guidelines for Allogeneic Hematopoietic Stem Cell Transplant Recipients -
 http://intranet.cc.nih.gov/bmt/_pdf/ECOG_Karnofsky_Lansky_Scales.pdf)

 Psychiatric disorder or mental deficiency severe as to make compliance with the BMT
 treatment unlikely and making informed consent impossible

 Major anticipated illness or organ failure incompatible with survival from PBSC transplant

 Diffusion capacity of carbon monoxide (DLCO) less than 40% predicted.

 Left ventricular ejection fraction: less than 30%.

 Serum creatinine greater than 2.5 mg/dl or creatinine clearance less than 50 cc/min by 24
 hr urine collection

 Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of normal,

 Other malignant diseases liable to relapse or progress within 5 years.

 EXCLUSION CRITERIA - Donor - any of the following:

 Pregnant or lactating

 Donor unfit to receive G-CSF and undergo apheresis (uncontrolled hypertension, history of
 congestive heart failure or unstable angina, thrombocytopenia)

 HIV positive donor. Donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or
 human T-cell lymphotropic virus (HTLV I/II) will be used at the discretion of the
 investigator following counseling and approval from the recipient