Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
FLT, Leuprolide, Thymic Renewal, Stem Cell Transplant, Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Brief summary
Background: * One way to treat certain cancers of the blood and immune system is to give a patient stem cells from the bone marrow of a donor whose genes are very similar but not identical to the patients. One problem with these transplants is that the new immune cells may not work as well in the recipient as they did in the donor. The result may be that the immune system will not work as well. This can increase the risk of severe infections and other complications. * Researchers are studying the use of drugs that lower hormone levels and may allow the immune system to recover in a way that improves white blood cell function. In this study they will be looking at the drug leuprolide, a drug that lowers estrogen or testosterone levels, to see if it might improve the function of the newly transplanted cells. Objectives: * To determine whether leuprolide improves immune system function after bone marrow transplant from a donor with similarities in their immune cells (matched to each other). * To evaluate the effectiveness of a nuclear medicine test with a radiotracer drug 3-deoxy-3 18F-fluorothymidine (FLT) in imaging studies. FLT will be used to image the immune system function in patients who have received bone marrow from the donor. Eligibility: * People between 15 (or as young as 9 in those who have gone through puberty) and 55 years of age. These patients must have acute myelogenous leukemia, acute lymphocytic leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or chronic myeloid leukemia. They must also be eligible for a bone marrow transplant. * Genetically similar donors for the patients who are eligible for a transplant. Design: * People taking part in the study will be screened with a physical examination, medical history, blood and urine tests, and imaging studies. Patients who are not in remission or who require a bone marrow donor search may receive chemotherapy first. * Donors will provide bone marrow for transplant according to standard bone marrow transplant (BMT) procedures. * All women and half of the men will receive regular leuprolide doses 2 weeks before BMT to suppress hormone function. * All recipients will receive 4 days of radiation followed by 2-4 days of chemotherapy before the bone marrow transplant (depending on age). Recipients will also receive other drugs to prevent transplant rejection and other complications of transplantation. * Recipients will be monitored in the hospital for 4 weeks after transplant with blood tests and other studies. * Some recipients will have an imaging study with FLT during the protocol. These imaging studies will take place before the transplant, on days 5 and 28 after transplant, and at a later time to be determined by the study researchers. * Following discharge, participants will be monitored closely for up to 6 months, with regular but less frequent followup visits for at least 5 years. Study-related medications, including vaccinations for the new immune system, will be provided by the National Institutes of Health during the hospital stay and after discharge.
Detailed description
Background: * Impaired lymphocyte immune reconstitution is associated with morbidity and mortality following allogeneic bone marrow transplant (BMT). * Data suggest that one of the limitations of immunity after BMT is the lack of thymus recovery and proper B cell development. * Androgen withdrawal has been shown to enhance T and B lymphopoiesis. * Leuprolide is an approved, safe, gonadotropin releasing hormone (GnRH) agonist/antagonist. * Noninvasive imaging modalities to study immune reconstitution would be invaluable to predict optimal or impaired immune recovery permitting early institution of therapies. * FLT is 3-deoxy-3 18F-fluorothymidine, a radiolabeled thymidine analogue that illustrates dividing hematopoietic cells and may predict immune recovery after allogeneic BMT. * FLT has been used safely in patients who have received intensive chemotherapy. Objectives: * Primary: To determine if leuprolide improves B lymphocyte reconstitution after first BMT. * Primary: To assess whether 18F FLT positron emission tomography (PET)/computed tomography (CT) could predict early engraftment/immune reconstitution in marrow and thymus after allogeneic BMT. * Primary: To assess safety of leuprolide after 2nd BMT evaluated in a separate arm. Eligibility: * Patients \> 9 years old and pubertal and/or \>15 year and less than or equal to 55 years, with aggressive leukemia (Acute Myelogenous Leukemia (AML), myelodysplastic syndromes (MDS) with high risk cytogenetics, Acute Lymphocytic Leukemia (ALL), CMML, certain CML) requiring BMT will be enrolled at National Cancer Institute (NCI). * At University of Oklahoma, Age \> 17 years old and less than or equal to 55 years for recipient. * Patients \> 4 and \< 24 years with the above diseases will be enrolled at Children's National Medical Center (CNMC). Design: * This is a prospective pilot study, the primary aims of which are: 1) to assess whether leuprolide enhances lymphocyte recovery after first BMT, 2) whether FLT imaging can be used to predict engraftment/immune reconstitution after first transplant, and 3) whether leuprolide and FLT are tolerable for second HSCT. * At NCI and Univ of Oklahoma, post-pubertal pediatric male patients (\<18 years) will be randomized to receive a 3 month (11.25 mg) injection and adult male patients will be randomized to receive 4-month preparation of leuprolide (30 mg) or placebo two weeks before the preparative regimen for first BMT. Women and all individuals undergoing 2nd BMT will receive leuprolide at these doses per age and be evaluated in the treated cohort. At Children's National Medical Center, the patients will not receive leuprolide outside of the context of clinical care and will receive myeloablative BMT as per standard of care with FLT imaging for engraftment as the only primary endpoint. * A target of 68 evaluable adult patients will be enrolled on this trial, which may necessitate up to 118 patients (118 donors) enrolled to reach this target at NCI and University of Oklahoma. A total of 10 pediatric patients will be enrolled at Children's National Medical Center for FLT imaging only. Sixteen patients will be enrolled to undergo second BMT. * At NCI, adults greater than 18 years old both female and adult male patients undergoing 2nd BMT will receive 4-month preparation of leuprolide (30 mg) two weeks before the preparative regimen. All patients will undergo FLT imaging to evaluate whether this may predict BMT response or failure (relapse). This will be a pilot arm of 16 patients total. * The planned length of this trial is 7 years with interim analyses at day 100 and day 365. * Some of the patients are anticipated to be evaluated using FLT (to include only patients needed for the immunological primary endpoint, not increasing total patient numbers). 23 adult NCI patients in total will undergo FLT PET/CT imaging on day -1, at day +5 or day +9, at 4 weeks, and at a future point to include evidence of graft-versus-host disease (GVHD) relapse, or immune recovery. An estimated 50 patients (including subset of the 23 patients undergoing serial scanning) will be imaged approximately at 1 year for evaluation of thymus reconstitution. The total possible numbers will include no more than 118 patients to achieve the 68 evaluable adults for the immunological primary endpoint. However, all 23 FLT PET/CT imaged NCI patients will undergo a single 1 year FLT for evaluation of thymus reconstitution. Up to 10 pediatric patients at CNMC will undergo FLT PET/CT imaging on Day -1, day+9, and day +28 (if possible). Initial images will be correlated with engraftment and other secondary endpoints.
Interventions
PROCEDUREFirst Allogeneic Bone Marrow Transplant (BMT)
First Allogeneic Bone Marrow Transplant
DRUGLeuprolide
Leuprolide: 30 mg intramuscular injection(for adult) or 11.25 mg (for patients \<18 years) between day -13 and day -20 pre-bone marrow transplant but definitely prior to initiation of preparative regimen as a 4 month intramuscular injection for patients \> 18 years and as a 3 month injection (adult preparation) for patients \< 18 years
DRUG18F FLT
For the first 23 patients undergoing 1st bone marrow transplant (BMT):\[18F\]fluorothymidine (18F FLT): 0.07 mCi/kg with a maximum of 3 mCi On day + 28 (+/- 5 days) For 2nd BMT: 18F FLT: 0.07 mCi/kg with a maximum of 3 mCi On day -1, + 28, day 60 and at relapse (+/- 5 days)
DRUGCyclophosphamide
Cyclophosphamide: 60 mg/kg intravenous (IV) on days -4 and -3 (for Adults \> 22 years) or Cyclophosphamide: cyclophosphamide 50 mg/kg IV, Days -5, -4, -3, -2. (For Pediatric \</= 22 years)
DRUGMethotrexate
Methotrexate:10 mg/m(2) intravenous (IV) on day +1, and 5 mg/m(2) IV Days + 3, 6, 11
DRUGTacrolimus
Tacrolimus:0.02 mg/kg/day continuous intravenous infusion (CIV) on day -1.
RADIATIONTotal Body Irradiation
Total Body Irradiation (TBI) 1200 cGy fractionate twice daily (lung block) Days -8, -7, -6, -5 (adult), -9, -8, -7, -6 (ped)
DRUGBusulfan
Second choice is Busulfan (with goal steady state of 800-1000) with fludarabine or cyclophosphamide at myeloablative dosing or non-myeloablative dosing.
DRUGFludarabine
Given with Busulfan as alternative to cyclophosphamide in second transplant setting only
PROCEDURESecond Allogeneic Bone Marrow Transplantation
Second Allogeneic Bone Marrow Transplantation
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* ELIGIBILITY CRITERIA: INCLUSION CRITERIA: TRANSPLANT RECIPIENT 1. At National Institutes of Health (NIH). Age greater than or equal to 15 years old and/or greater than or equal to 9 years old and pubertal and less than or equal to 55 years for recipient. Pubertal is defined by: prior menses at any time (females), documentation of clinical Tanner stage greater than 2 at some point pre-chemotherapy or at the current visit. (At this point, sex steroids have been produced for a few years which have driven initial pubertal development). Tanner 2 is defined as: breast buds for females with coarse pubic hair, and coarse pubic hair and testes \> 2.5cm for males. 2. At Children's National Medical Center only: age \> 4 years old and \< 24. 3. At University of Oklahoma: Age greater than or equal to 17 years old and less than or equal to 55 years for recipient. 4. A diagnosis of a hematologic malignancy for which stem cell transplant is standard of care: 4.1. Acute Lymphocytic Leukemia (ALL) Adult: (greater than or equal to 22 years) greater than or equal to compete remission 2 (CR2) OR complete remission 1 (CR1) with: * Matched sibling donor for recipient treated on adult leukemia regimen * t(9:22) or bcr-abl+; t(4:11), t(1:19), t(8:14), 11q23 (MLL rearrangements) complex cytogenetics (5 or more chromosomal abnormalities), hypodiploidy (\<44 chromosomes). Note that patients with ALL blast crisis who emerge from chronic myeloid leukemia (CML) are also eligible * Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy * High white blood cell (WBC) (\>30,000 for B-cell ALL and \>100,000 for T-cell ALL) at diagnosis * Persistence of minimal residual disease despite induction chemotherapy Pediatric (\< 22 years): greater than or equal to CR2 OR CR1 with high risk features * Matched sibling donor for recipient treated on adult leukemia regimen * Primary induction failure (M3 (\>25% with greater 200 cells counted) marrow at day 29), M2 (5-25% blasts with greater than 200 cells counted) bone marrow or minimal residual disease (MRD) \> 1% at day 29 who then fail at day 43 with either an M2 or M3 BM or MRD \> 1% * Persistent leukemia and t(9;22) (MRD \>1% day 29 or MRD \> 0.01% end consolidation) * 11q23 (MLL) rearrangements detected by cytogenetic or polymerase chain reaction (PCR) at initial diagnosis who are slow early responders (M2/M3 at day 14 or MRD\> 0.01% at day 29) * Extreme hypodiploidy (\< 44 chromosomes or deoxyribonucleic acid (DNA) index of \<0.81) detected by cytogenetic/ploidy analysis 4.2 Acute Myelogenous Leukemia Adult: (greater than or equal to 22 years) greater than or equal to CR2 OR CR1 with high one of the following risk features -Adverse or intermediate-risk cytogenetics including: 1. Normal cytogenetics 2. complex karyotype (\>2 abnormalities) 3. inv (3) or t (3;3); t(11;19)(q23;p13.1); +13; -17/17p-; -18; -20; (t(6;9); t(6;11); -7, 7q-; -5, 5q-; trisomy 8; t(3;5); t(9:11)(p22q23) 4. monosomy karyotype (presence of an autosomal monosomy in conjunction with at least one other autosomal monosomy or structural abnormality. 5. Any other karyotype EXCEPT t(8;21), t(9;11), inv(16), or t (16;16), and M3 (17; 17) unless ckit mutation present and then eligible. 6. AML emerging from CML (blast crisis) are eligible -Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy * Secondary AML, defined as AML related to antecedent myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), or cytotoxic chemotherapy * Hyperleukocytosis (White blood cell (WBC) \> 100,000 at diagnosis) * Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-LM; FLT-ITDs) * Bilineage or biphenotypic leukemias are high risk features and eligible. Pediatric (\< 22 years): greater than or equal to CR2 OR CR1 with a high risk feature including: -Primary induction failure (greater than or equal to 5% blasts in marrow after induction) * Persistent leukemia (\>15% after first course of chemotherapy) * Complex karyotype, monosomy 7, or -5/-5q, FLT3 ITD-AR (\>0.4) EXCEPT if also inv(16)/t(16;16), t(8,21) * Normal cytogenetics or abnormal cytogenetics EXCEPT if also inv(16)/t(16;16), t(8,21) are eligible for SIBLING transplant only * Bilineage or biphenotypic leukemias are high risk features and eligible. 4.3. Myelodysplastic Syndrome Refractory Anemia with Excess Blasts (RAEB) 1 or 2; cytogenetics showing complex karyotype (3 or more abnormalities), monosomy 7/del(7q), or inv(3)/t(3q)/del(3q); or transfusion dependent. 4.4. Chronic Myelomonocytic Leukemia 4.5. Chronic Myelogenous Leukemia who have failed 2G- tyrosine kinase inhibitors (TKI) 4.6. Standard pediatric indications for myeloablative transplantation for patients undergoing bone marrow transplant at Children's National Medical Center per institutional guidelines 5\. Disease status If patients are found to not be in remission at screening, then the patient may be returned to their primary hematologist/oncologist or may receive chemotherapy as per standard of care for the malignant disease. Patients for whom this would be their first allogeneic transplant must be in remission (\< 5% malignant blasts in marrow and peripheral blood and no evidence of extramedullary disease) for transplant. Patients enrolled on this protocol for their second transplant do not need to have attained remission prior to transplant. 6\. Performance status: Karnofsky or Lansky performance status greater than or equal to 60% AND life expectance of greater than 3 months. 7\. Ability to give informed consent. For recipients and donors \< 18 years of age, their legal guardian must give informed consent. Pediatric patients will be included in an age appropriate discussion in accordance with institutional guidelines. 8 Hepatic function: Patients must have evidence of adequate liver function prior to enrollment defined by total bilirubin \< 2.5 mg/dL (unless documented Gilbert's syndrome) AND transaminases less than or equal to 5 x the upper limit of normal for age appropriate indices. 9\. Renal function: Patients must have evidence of adequate renal function to proceed with stem cell transplant, creatinine clearance \> 60 ml/min/1.73 m(2). Glomerular filtration rate (GFR) may also demonstrate adequate renal function. 10\. Left ventricular ejection fraction greater than or equal to 50% OR shortening fraction of greater than or equal to 27% demonstrated on 2-dimension (2D) echocardiogram or multi-gated acquisition scan (MUGA). 11\. Pulmonary function of Diffusing Capacity of the Lung for Carbon Monoxide (DLC0) adj/alveolar volume (VA) and forced expiratory volume 1 (FEV1) greater than or equal to 60% of normal indices for age and height unless the patient has a likely acute reversible etiology of decline and then DLCO adj/VA greater than or equal to 30% of normal. Pediatric patients unable to complete pulmonary function tests (PFTs) may be enrolled as per enrolling institution Standard Operating Procedure (SOP) for recipient guidelines. 12\. Patients with prior autologous stem cell transplants will be included. Patients with prior allogeneic stem cell transplants will be eligible for 2nd BMT if not previously transplanted with FLT on this study. 13\. Prior experimental systemic therapies must have been completed greater than 2 weeks prior to study entry.
Exclusion criteria
TRANSPLANT RECIPIENT 1. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent. 2. Active infections not responding to therapy. All efforts should be made to clear the infection prior to enrollment. 3. Clinically significant systemic illness with manifestations of significant organ dysfunction which in the judgment principal investigator (PI) or associate investigator (AI) would render the patient unlikely to tolerate the protocol therapy or complete the study. 4. Presence of active malignancy from an organ system other than hematopoietic. 5. Human immunodeficiency virus (HIV) infection. 6. Chronic active hepatitis B infection. Patients may be hepatitis B core antibody positive but must be surface antigen negative and without active evidence of disease. 7. Pregnant or lactating females will be excluded from this trial due to unknown risks to the developing fetus. Patients of child-bearing potential must use an effective form of contraception while on study. 8. Sexually active individuals capable of becoming pregnant who are unable or unwilling to use effective form(s) of contraception during time enrolled on study and for 1 year post-transplant. 9. History of prior Leuprolide intolerance. Note: patients ARE eligible if prior or current leuprolide exposure. INCLUSION CRITERIA: MATCHED RELATED TRANSPLANT DONOR 1. Age greater than or equal to 2 and less than or equal to 60 years old and able to give consent or assent. For donors \< 18 years old, the legal guardian must be able to provide informed consent and an evaluation by a Licensed Social Worker (LSW) or psychiatric personnel will be needed to determine willingness to participate. Pediatric patients will be included in an age appropriate discussion in accordance with institutional guidelines. 2. Human leukocyte antigen (HLA)-matched related donor, excluding identical twins. Donors must be matched at least 7 loci out of 8 at the allele or antigen level excluding antigen DRB1 mismatch. 3. Donor selection will be in accordance with National Institutes of Health (NIH)/Clinical Center (CC) Department of Transfusion Medicine criteria and must be able to medically endure stem cell collection or as per local institutional guidelines. 4. Donors must be HIV negative, human T-cell leukemia-lymphoma virus (HTLV) negative, hepatitis B surface antigen (HBsA) negative. 5. Donors must be physically able to and willing to tolerate marrow harvest collection preferably, or in the absence of this option, able and willing to donate via peripheral blood pheresis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of B Cells at One Year Post-transplant in Participants Who Did/Did Not Receive Leuprolide Following Bone Marrow Transplant (BMT) | after first Bone Marrow Transplant, approximately 12 months post-transplant | B cell percentage is defined as the percentage of lymphocytes that are B cells. |
| Time to Engraftment in First Transplant Recipients Only With Median Thoracic Spine Standardized Uptake Values (SUV) of 1.4 or Greater Than Those Patients With SUV's Less Than 1.4 | 18F FLT scan done between days +5 to +12 and then time from that scan to engraftment measured | 18F-FLT imaging was performed serially on patients post transplant to identify the level of uptake of 18F-FLT at a day +5 to +12 scan and the day at which neutrophils recover to \>500 (i.e., subclinical bone-marrow recovery within 5 days of Bone Marrow Transplantation (BMT infusion)). On each image for each patient, the region of interest was drawn within each thoracic medullary space (n=12), generating the SUV for each space. The mean of these was calculated for each scan. The analysis was the median of the means of the SUV of the thorax values of the day 5-12 scan (averaged the SUV of the thorax for each patient and then took the medians of these). |
| Number of Adverse Events Related to Study Drug Experienced by Participants After Second Bone Marrow Transplant (BMT) | 12 months after second BMT | Serious and non-serious adverse events were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | Date treatment consent signed to date off study, approximately 79 months and 11 days. | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Males That Did Not Receive Leuprolide for 1st Transplant Males undergoing first transplant who did not receive leuprolide. | 12 |
| Males Randomized to Receive Leuprolide for 1st Transplant Males undergoing first transplant who were randomized to receive leuprolide. | 9 |
| Females That Received Leuprolide for 1st Transplant Females undergoing first transplant who all received leuprolide. | 22 |
| Matched Related Donors for Transplant Individuals related to patients and who gave hematopoietic stem cells for patients receiving allogeneic bone marrow transplant on this study. | 31 |
| Recipients of 2nd Transplant Patients receiving second allogeneic Bone Marrow Transplant on this study. | 2 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Disease progression on study | 2 | 1 | 1 | 0 | 0 |
| Overall Study | enrolled on new protocol | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Males That Did Not Receive Leuprolide for 1st Transplant | Males Randomized to Receive Leuprolide for 1st Transplant | Females That Received Leuprolide for 1st Transplant | Matched Related Donors for Transplant | Recipients of 2nd Transplant | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 4 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 9 Participants | 22 Participants | 28 Participants | 2 Participants | 72 Participants |
| Age, Continuous | 33 years STANDARD_DEVIATION 9.3 | 26.77 years STANDARD_DEVIATION 5.71 | 36.05 years STANDARD_DEVIATION 6.1 | 33.86 years STANDARD_DEVIATION 11.49 | 23.05 years STANDARD_DEVIATION 3.61 | 33.61 years STANDARD_DEVIATION 10.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 6 Participants | 15 Participants | 26 Participants | 1 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants | 5 Participants | 1 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 9 Participants | 5 Participants | 15 Participants | 28 Participants | 2 Participants | 59 Participants |
| Region of Enrollment United States | 12 Participants | 9 Participants | 22 Participants | 31 Participants | 2 Participants | 76 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 22 Participants | 17 Participants | 0 Participants | 39 Participants |
| Sex: Female, Male Male | 12 Participants | 9 Participants | 0 Participants | 14 Participants | 2 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 10 | 3 / 8 | 8 / 20 | 0 / 31 | 2 / 2 |
| other Total, other adverse events | 10 / 10 | 8 / 8 | 20 / 20 | 4 / 31 | 2 / 2 |
| serious Total, serious adverse events | 5 / 10 | 6 / 8 | 15 / 20 | 2 / 31 | 2 / 2 |
Outcome results
Primary
Number of Adverse Events Related to Study Drug Experienced by Participants After Second Bone Marrow Transplant (BMT)
Serious and non-serious adverse events were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: 12 months after second BMT
Population: Only the patients in the SG4 group who had a 2nd BMT had a primary endpoint of toxicity requiring leuprolide AE reporting.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Transplant Recipient | Number of Adverse Events Related to Study Drug Experienced by Participants After Second Bone Marrow Transplant (BMT) | 0 Adverse Events |
Primary
Percentage of B Cells at One Year Post-transplant in Participants Who Did/Did Not Receive Leuprolide Following Bone Marrow Transplant (BMT)
B cell percentage is defined as the percentage of lymphocytes that are B cells.
Time frame: after first Bone Marrow Transplant, approximately 12 months post-transplant
Population: Only first BMT patients (SG1-3) with \>1 year of follow-up without relapse were evaluable. Of evaluable patients, 5 males and 9 females received and 7 males did not receive Lupron. Reasons for patients being inevaluable were missing data (2) or insufficient follow-up due to death without relapse (3), relapse (11), or withdrawal (1) before 1 year.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Transplant Recipient | Percentage of B Cells at One Year Post-transplant in Participants Who Did/Did Not Receive Leuprolide Following Bone Marrow Transplant (BMT) | Males that received leuprolide | 22.1 percentage of cells |
| Transplant Recipient | Percentage of B Cells at One Year Post-transplant in Participants Who Did/Did Not Receive Leuprolide Following Bone Marrow Transplant (BMT) | Males that did not receive leuprolide | 21.9 percentage of cells |
| Transplant Recipient | Percentage of B Cells at One Year Post-transplant in Participants Who Did/Did Not Receive Leuprolide Following Bone Marrow Transplant (BMT) | Females who all received leuprolide | 14.3 percentage of cells |
Primary
Time to Engraftment in First Transplant Recipients Only With Median Thoracic Spine Standardized Uptake Values (SUV) of 1.4 or Greater Than Those Patients With SUV's Less Than 1.4
18F-FLT imaging was performed serially on patients post transplant to identify the level of uptake of 18F-FLT at a day +5 to +12 scan and the day at which neutrophils recover to \>500 (i.e., subclinical bone-marrow recovery within 5 days of Bone Marrow Transplantation (BMT infusion)). On each image for each patient, the region of interest was drawn within each thoracic medullary space (n=12), generating the SUV for each space. The mean of these was calculated for each scan. The analysis was the median of the means of the SUV of the thorax values of the day 5-12 scan (averaged the SUV of the thorax for each patient and then took the medians of these).
Time frame: 18F FLT scan done between days +5 to +12 and then time from that scan to engraftment measured
Population: The pre-specified cohort for this endpoint was 23 first BMT recipients. Only 20 of 23 were evaluable due to inability to obtain the early scan (1) or early relapse (2). As pre-specified in the protocol, all 20 patients were analyzed together as the intention was to look at the imaging modality itself and not any effect of leuprolide.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Transplant Recipient | Time to Engraftment in First Transplant Recipients Only With Median Thoracic Spine Standardized Uptake Values (SUV) of 1.4 or Greater Than Those Patients With SUV's Less Than 1.4 | Patients with SUV 1.4 or greater | 5 Days |
| Transplant Recipient | Time to Engraftment in First Transplant Recipients Only With Median Thoracic Spine Standardized Uptake Values (SUV) of 1.4 or Greater Than Those Patients With SUV's Less Than 1.4 | Patients with SUV less than 1.4 | 15 Days |
p-value: 0.0075Wilcoxon's rank sum test
Secondary
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Date treatment consent signed to date off study, approximately 79 months and 11 days.
Population: 40/45 transplant recipients and all 31 donors were evaluable for adverse events as five patients did not proceed to transplant after enrollment due to progression of disease in four cases and enrollment on a new protocol in one case.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant Recipient | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 10 Participants |
| Males Randomized to Receive Leuprolide for 1st Transplant | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 8 Participants |
| Females That Received Leuprolide for 1st Transplant | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 20 Participants |
| Matched Related Donors for Transplant | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 4 Participants |
| Recipients of 2nd Transplant | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 2 Participants |