Bone Marrow Transplant for Blood Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Richard Ambinder, MD, PhD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Sirolimus

Disqualifiers: Pregnancy, Uncontrolled infections, Active CNS leukemia, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

If transplantation using mismatched unrelated donors or non-first-degree relatives could be performed with an acceptable toxicity profile, an important unmet need would be served. Towards this goal, the current study extends our platform of nonmyeloablative, partially HLA-mismatched bone marrow transplant (BMT) and Peripheral Blood Stem Cell Transplant (PBSCT) to the use of such donors, investigating up to several postgrafting immunosuppression regimens that incorporate high-dose Cy. Of central interest is the incorporation of sirolimus into this postgrafting immunosuppression regimen. The primary goal for phase 1 is to identify a transplant regimen associated with acceptable rates of severe acute GVHD and NRM by Day 100 and for phase 2 estimate the 6-month probability of survival without having had acute grade III- IV GVHD or graft failure.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Allogeneic Blood or Marrow Transplant for blood cancer?

Research shows that allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for blood cancers like acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). Studies indicate that using conditioning regimens with drugs like cyclophosphamide and fludarabine, along with total body irradiation (TBI), can lead to successful outcomes, including hematopoietic reconstruction and reduced relapse rates. ^{1 2 3 4 5}

Is bone marrow transplant generally safe for humans?

Research shows that bone marrow transplants, using fludarabine-based regimens, are generally safe with low organ toxicity and effective for stable engraftment in patients with conditions like Fanconi anemia and acute leukemia. However, there are risks of complications such as graft-versus-host disease (GVHD) and infections, which vary depending on the specific regimen and patient condition. ^{3 4 6 7 8}

How does the Bone Marrow Transplant for Blood Cancer treatment differ from other treatments?

This treatment is unique because it combines fludarabine and cyclophosphamide with total body irradiation to prepare the body for an allogeneic stem cell transplant, which can be more effective and less toxic than traditional regimens that use higher doses of cyclophosphamide. This approach aims to reduce organ toxicity while maintaining successful engraftment and survival rates. ^{3 7 9 10 11}

Eligibility Criteria

This trial is for people aged 0.5-75 with certain blood cancers or tumors who've had at least two prior treatments, or specific poor-risk features. They must have acceptable organ function and performance status, no suitable HLA-matched donor, and not be pregnant or breastfeeding. HIV-positive individuals may be considered on a case-by-case basis.

Inclusion Criteria

Adequate end-organ function as measured by: Left ventricular ejection fraction greater than or equal to 35%, or shortening fraction > 25%, unless cleared by a cardiologist, Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST < 5 x ULN, FEV1 and FVC > 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation >92% on room air, ECOG performance status < 2 or Karnofsky or Lansky score > 60

I am between 6 months and 75 years old.

I don't have a matching bone marrow donor.

Exclusion Criteria

Not pregnant or breast-feeding

I do not have any untreated infections.

I have not had a bone marrow transplant from another person.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Transplant Conditioning

Participants receive Fludarabine, Cytoxan, and Total Body Irradiation (TBI) as conditioning before transplantation

5 days

Daily visits for administration

Transplantation

Participants undergo allogeneic blood or marrow transplantation (BMT) or Peripheral Blood Stem Cell Transplant (PBSCT)

1 day

1 visit (in-patient)

Post-Transplantation Immunosuppression

Participants receive high-dose Cytoxan, Sirolimus, and Mycophenolate Mofetil (MMF) for immunosuppression

6 months

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of GVHD and survival

6 months

Regular follow-up visits

Long-term Follow-up

Participants are tracked for event-free survival, overall survival, and incidence of chronic GVHD

7 years

Treatment Details

Interventions

• Allogeneic Blood or Marrow Transplant (Procedure)
• Cytoxan (Alkylating agents)
• Fludarabine (Alkylating agents)
• Mycophenolate Mofetil (Other)
• Peripheral Blood Stem Cell Transplant (Procedure)
• Sirolimus (Immunosuppressant)
• Tacrolimus (Immunosuppressant)
• Total Body Irradiation (Radiation)

Trial Overview The study tests a bone marrow transplant (BMT) from partially matched donors using nonmyeloablative conditioning to treat hematologic malignancies. It explores postgrafting immunosuppression regimens incorporating high-dose Cytoxan and sirolimus to manage graft-versus-host disease (GVHD) and non-relapse mortality.

Participant Groups

Group I: REGIMEN B Active Control 6 Interventions

Pre-BMT : * Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV * Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV * Day -1: 400 cGy total body irradiation (TBI) administered in a single fraction Day 0: Allogeneic blood or marrow transplantation (BMT) Post-Transplantation Immunosuppression Consisting of: * Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV * Day 5: Sirolimus loading dose 6 mg PO once * Day 5 thru Day 35: Mycophenolate Mofetil (MMF) 15 mg/kg PO TID (maximum daily dose 3 g/day) * Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL

Group II: REGIMEN B2 Active Control 6 Interventions

Pre-PBSCT: * Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV * Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV * Day -1: 400 cGy TBI administered in a single fraction Day 0: Peripheral Blood Stem Cell Transplant (PBSCT) Post-Transplantation Immunosuppression Consisting of: * Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV * Day 5: Sirolimus loading dose 6 mg PO once * Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) * Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL

Group III: REGIMEN C Active Control 6 Interventions

Pre-BMT: * Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV * Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV * Day -1: 400 cGy TBI administered in a single fraction Day 0: BMT Post-Transplantation Immunosuppression Consisting of: * Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV * Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) * Day 5 thru Day 180: Tacrolimus 1 mg administered IV QD

Group IV: REGIMEN B3: HIV patients with CCRd32 homozygous donors Active Control 6 Interventions

Pre-PBSCT: * Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV * Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV * Day -1: 400 cGy TBI administered in a single fraction Day 0: Peripheral Blood Stem Cell Transplant (PBSCT) Post-Transplantation Immunosuppression Consisting of: * Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV * Day 5: Sirolimus loading dose 6 mg PO once * Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) * Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL

Allogeneic Blood or Marrow Transplant is already approved in European Union, United States, Canada, Japan for the following indications:

🇪🇺 Approved in European Union as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Acute Leukemia
• Chronic Leukemia
• Lymphoma
• Multiple Myeloma
• Myelodysplastic Syndromes

🇺🇸 Approved in United States as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Acute Leukemia
• Chronic Leukemia
• Lymphoma
• Multiple Myeloma
• Myelodysplastic Syndromes

🇨🇦 Approved in Canada as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Acute Leukemia
• Chronic Leukemia
• Lymphoma
• Multiple Myeloma
• Myelodysplastic Syndromes

🇯🇵 Approved in Japan as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Acute Leukemia
• Chronic Leukemia
• Lymphoma
• Multiple Myeloma
• Myelodysplastic Syndromes

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, MD

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Lead Sponsor

National Cancer Institute (NCI) Collaborator

References

1. England pubmed.ncbi.nlm.nih.gov

Irradiation free conditioning regimen is associated with high relapse rate in Egyptian patients with acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation. [2021] Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for adult patients with acute lymphoblastic leukemia (ALL). Cyclophosphamide plus total body irradiation (TBI/Cy) or plus busulfan (Bu/Cy) is a widely used pre-transplant conditioning regimen for ALL. We retrospectively compared the overall survival (OS), disease-free survival (DFS), and other transplant outcomes of allo-HSCT in 119 adult patients with ALL who received an HLA-matched sibling allo-HSCT using TBI-based versus non-TBI-based conditioning regimens. Patients were divided into two groups by their conditioning regimen: TBI/Cy or Bu/Cy.

2. United States pubmed.ncbi.nlm.nih.gov

Etoposide, cyclophosphamide, total-body irradiation, and allogeneic bone marrow transplantation for hematologic malignancies. [2017] To determine the efficacy and toxicity of etoposide, cyclophosphamide, and fractionated total-body irradiation (TBI) as the conditioning regimen for allogeneic bone marrow transplantation (BMT) in patients with hematologic malignancies.

3. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of fludarabine- and busulfan-based conditioning regimens in patients with acute myeloblastic leukemia: 8-year experience in a single center. [2018] Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for acute myeloblastic leukemia (AML). Because the conditioning regimen of busulfan plus cyclophosphamide carries significant risks of toxicity, we evaluated the factors affecting survival after fludarabine replacement instead of cyclophosphamide.

4. China pubmed.ncbi.nlm.nih.gov

Allogeneic peripheral blood hematopoietic stem cell transplantation for patients with hematologic malignancies. [2019] To investigate the therapeutic effects and associated complications of allogeneic peripheral blood stem cell transplantation (allo-PBSCT). 40 patients with various malignant hematopoietic diseases received allo-PBSCT. The preparative regimens were based on BUCY2 or modified BUCY2. The acute graft-versus host disease (aGVHD) was prevented by cyclosporin A and short-term MTX regimen in all patients. Two patients from donors with one fully mismatched HLA on DRB1 locus and 4 from unrelated donor also administered Zenapox (CD25 MAb) at dosage of 1 mg/kg every day on the day before transplantation and day 4 after transplantation. These 6 patients were also treated with mycophenolate mofetil (MMF). Transfusion of the donor cells: The median of the transfused nucleated cells was 5.38 x 10(8)/kg and that of the CD34+ cells was 7.8 x 10(6)/kg respectively. All the patients gained hematopoietic reconstruction except one who died of infection before engraftment. Seven patients got II degrees-IV degrees aGVHI) and the incidence was 17.5%. Fourteen patients got cGVHD and the incidence was 53.8% in the patients who survived over 6 months. Twenty-eight patients had fever or other characteristics of infection. The median follow-up time was 13.8 months. The incidence of transplantation related mortality (TRM) was 17.5% and 2 patients relapsed (5.0%). It was concluded that allo-PBSCT can reconstruct hematopoiesis quickly and is a favorable therapeutic method for leukemia.

5. United States pubmed.ncbi.nlm.nih.gov

Fludarabine, busulfan, and low-dose TBI conditioning versus cyclophosphamide and TBI in allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia. [2020] The optimal conditioning regimen for adults undergoing transplantation for acute lymphoblastic leukemia (ALL) remains undetermined. Cyclophosphamide and total body irradiation (Cy/TBI) has emerged as a standard myeloablative regimen but is associated with significant toxicity. We compared outcomes between patients undergoing transplant for ALL at centers using Cy/TBI as standard of care and another center using fludarabine, busulfan, and low-dose TBI (400 cGy) in combination with anti-thymocyte globulin as its standard. Among 146 patients (74 Cy/TBI and 72 Flu/Bu/TBI) there were no significant differences in overall or progression-free survival between groups. Non-relapse mortality was similar (12% vs. 16.7% for Cy/TBI and Flu/Bu/TBI, respectively, p = .62) despite the Flu/Bu/TBI group having significantly worse performance status. Flu/Bu/TBI resulted in significantly lower cumulative incidence of relapse compared with Cy/TBI (2-year point estimate 18.5% vs. 31.5%, p = .05). These results demonstrate similar outcomes for patients receiving Flu/Bu/TBI versus Cy/TBI. Flu/Bu/TBI may allow the possibility of providing myeloablative conditioning to patients with poor performance status.

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide. [2021] A combination of busulfan (Bu) and cyclophosphamide (Cy) has been used as a standard myeloablative regimen for allogeneic hematopoietic stem cell transplantation (HSCT). Recent studies postulate that fludarabine (Flu) is a less toxic substitute for Cy.

7. England pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. [2022] A regimen of busulfan and cyclophosphamide (BuCy2) is regarded as the standard myeloablative regimen for SCT. This study evaluated the hypothesis that fludarabine can replace cyclophosphamide for myeloablative allogeneic SCT. Ninety-five patients underwent allogeneic SCT from HLA-identical donors, following BuCy2 (n=55) or busulfan+fludarabine (BF, n=40). The efficacy of fludarabine compared to cyclophosphamide was retrospectively evaluated. The BF group exhibited a shorter duration until engraftment (P=0.001), lower incidence of acute and chronic GVHD (P

8. England pubmed.ncbi.nlm.nih.gov

Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors. [2013] Allogeneic hematopoietic stem cell transplantation (SCT) from unaffected donors remains the only modality for the correction of hematological abnormalities in Fanconi anemia (FA) patients. We performed four HLA-matched related donor SCT using a novel irradiation and cyclophosphamide-free conditioning regimen. The protocol included fludarabine 150 mg/m(2), busulfan 4 mg/kg, and antithymocyte globulin 90 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A, MTX, and daclizumab. The engraftment and occurrence of full stable donor hemopoiesis was rapid in all cases with minimal short-term toxic complications. There were no infections or febrile episodes during the inpatient phase. Three patients developed acute GVHD grade I-II involving gut and skin and one patient progressed to extensive chronic GVHD. The preparative conditioning regimen is safe and associated with low organ toxicity and effective immunosupression for the stable engraftment in FA patients undergoing SCT with matched related donors.

9. England pubmed.ncbi.nlm.nih.gov

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. [2021] The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts.

10. England pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. [2013] Conditioning including total body/lymphoid irradiation is widely used to prevent graft rejection in patients with refractory severe aplastic anemia (SAA) undergoing hemopoietic cell transplantation (HCT) from alternative donors and or after graft manipulation. To reduce regimen-related toxicity we transplanted three children with refractory SAA after conditioning with radiotherapy-free regimens. Conditioning included fludarabine 175-180 mg/m2 in all patients. In addition, patient 1 (failing two previous grafts) received thiotepa 10 mg/kg and Campath-1H 60 mg/m2; patient 2 cyclophosphamide 120 mg/kg, thiotepa 15 mg/kg and OKT-3 0.1 mg/kg/day for 4 weeks; and patient 3 cyclophosphamide 120 and ATG 90 mg/kg. Stem cell source was unmanipulated marrow from the same unrelated donor as for the two previous transplantations in patient 1 and CD34+-purified peripheral blood stem cells from an HLA-matched unrelated donor and from the haploidentical mother in patients 2 and 3. Only patient 1 received graft-versus-host disease (GVHD) prophylaxis with cyclosporine A and mycophenolate mofetil. Follow-up is now 30, 51, and 15 months. None of the patients developed GVHD. All patients have normal counts with complete donor chimerism. Fludarabine-based conditioning is powerfully immunosuppressive and may be used for children with refractory SAA undergoing HCT from alternative donors even after rejection following previous HCT.

11. United States pubmed.ncbi.nlm.nih.gov

Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. [2021] We evaluated the feasibility and efficacy of a reduced-intensity conditioning (RIC) regimen of fludarabine and melphalan to achieve rapid complete donor chimerism after allogeneic stem cell transplantation (SCT) in patients with metastatic solid tumors. Between January 1999 and January 2003, 8 patients with metastatic breast cancer (BC) and 15 with metastatic renal cell carcinoma (RCC) underwent allogeneic SCT after an RIC regimen of 5 days of fludarabine and 2 days of melphalan. Filgrastim-mobilized stem cells from HLA-identical related or unrelated donors were infused. Prophylaxis for graft-versus-host disease (GVHD) consisted of tacrolimus and methotrexate. All 22 evaluable patients had 100% donor chimerism at day 30 and at all measurement times thereafter. One patient died 19 days after SCT. Nine patients (39%) had grades II to IV acute GVHD and 10 patients (43%) had chronic GVHD. Five patients (22%) died of nonrelapse treatment-related complications. Treatment-related disease response was seen in 10 patients (45%), with 3 complete responses, 2 partial responses, and 5 minor responses. Fludarabine-melphalan is a feasible and effective RIC regimen for allogeneic SCT in metastatic BC and RCC. It induces rapid complete donor chimerism without the need for donor lymphocyte infusion. Tumor regression associated with GVHD is consistent with graft-versus-tumor effect.