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}

Research Team

Richard Ambinder, MD, PhD

Principal Investigator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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 Canada, Japan for the following indications:

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

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Dr. William G. Nelson

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Director since 1992

MD, PhD

Dr. Elizabeth Jaffee

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Chief Medical Officer since 2023

MD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

In a study of 119 adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation, the TBI/Cy conditioning regimen resulted in a median overall survival of 11 months, compared to 6.2 months for the Bu/Cy regimen.

Although both conditioning regimens showed no statistically significant differences in overall survival and disease-free survival, the Bu/Cy regimen was associated with a higher risk of relapse, indicating a potential disadvantage in using this non-TBI approach.

NCBI (Pubmed)

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. Abdelaty, MM., Gawaly, A., Fathy, GM., et al.[2021]

In a study of 79 patients undergoing allogeneic bone marrow transplantation, the combination of etoposide, cyclophosphamide, and fractionated total-body irradiation (TBI) showed a 57% overall survival rate at 3 years for patients with early leukemia, indicating its efficacy as a preparative regimen.

Patients with advanced disease experienced significantly lower survival rates (17%) and higher toxicity, highlighting that this regimen is more effective and safer for those with early-stage hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide, cyclophosphamide, total-body irradiation, and allogeneic bone marrow transplantation for hematologic malignancies. Giralt, SA., LeMaistre, CF., Vriesendorp, HM., et al.[2017]

In a study of 55 patients with acute myeloblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation, a conditioning regimen using busulfan and fludarabine showed promising outcomes with a 1-year overall survival rate of 76% and a 3-year progression-free survival rate of 74%.

The study indicated that this regimen has acceptable levels of toxicity, with only 5.5% treatment-related mortality, and highlighted that the presence of active disease at transplantation negatively impacts survival outcomes.

NCBI (Pubmed)

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. Kasar, M., Asma, S., Kozanoglu, I., et al.[2018]

Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) effectively promotes rapid hematopoietic reconstruction in patients with malignant hematopoietic diseases, with a 17.5% incidence of acute graft-versus-host disease (aGVHD) managed by immunosuppressive therapies.

The study involved 40 patients, with a median follow-up of 13.8 months, showing a transplantation-related mortality (TRM) rate of 17.5% and a relapse rate of 5.0%, indicating that while allo-PBSCT is a promising treatment for leukemia, there are significant risks of complications and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic peripheral blood hematopoietic stem cell transplantation for patients with hematologic malignancies. Xia, L., Fang, J., You, Y., et al.[2019]

In a study of 42 patients undergoing allogeneic hematopoietic stem cell transplantation, the combination of busulfan and fludarabine (BuFlu) resulted in significantly lower rates of mucositis compared to the traditional busulfan and cyclophosphamide (BuCy) regimen.

Both BuFlu and BuCy showed similar efficacy in terms of engraftment time, relapse risk, event-free survival, and overall survival, suggesting that BuFlu is a viable alternative to BuCy for this treatment.

NCBI (Pubmed)

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. Lee, JH., Choi, J., Kwon, KA., et al.[2021]

In a study of 95 patients undergoing allogeneic stem cell transplantation, replacing cyclophosphamide with fludarabine in the conditioning regimen (busulfan+fludarabine) led to faster engraftment and significantly lower rates of acute and chronic graft-versus-host disease (GVHD).

The fludarabine regimen also resulted in better event-free survival and overall survival rates compared to the standard busulfan and cyclophosphamide regimen, indicating it may be a more effective option for myeloablative conditioning in allogeneic SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Chae, YS., Sohn, SK., Kim, JG., et al.[2022]

A novel conditioning regimen for allogeneic hematopoietic stem cell transplantation (SCT) in Fanconi anemia patients showed rapid engraftment and stable donor hemopoiesis with minimal short-term toxic complications, indicating its safety and efficacy.

The conditioning regimen, which avoided irradiation and cyclophosphamide, resulted in low organ toxicity and effective immunosuppression, although some patients experienced mild acute graft-versus-host disease (GVHD).

NCBI (Pubmed)

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. Maschan, AA., Trakhtman, PE., Balashov, DN., et al.[2013]

In a multicenter phase 1-2 study involving 96 patients with severe aplastic anemia, using cyclophosphamide at reduced doses of 50 mg/kg and 100 mg/kg, along with fludarabine, anti-thymocyte globulin, and total body irradiation, resulted in high engraftment rates of 92% and 85% respectively, demonstrating effective conditioning for unrelated donor transplantation.

The study found that lower doses of cyclophosphamide were associated with significantly reduced major regimen-related toxicity, with only 11% experiencing severe side effects at 50 mg/kg compared to 22% at 100 mg/kg, suggesting a safer approach to treatment.

NCBI (Pubmed)

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. Anderlini, P., Wu, J., Gersten, I., et al.[2021]

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

The reduced-intensity conditioning regimen of fludarabine and melphalan was found to be feasible and effective in achieving 100% donor chimerism in 22 patients with metastatic breast cancer and renal cell carcinoma after allogeneic stem cell transplantation.

The treatment resulted in a 45% response rate in terms of tumor regression, with some patients experiencing complete or partial responses, suggesting that the graft-versus-host disease may contribute to the graft-versus-tumor effect.

NCBI (Pubmed)

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. Ueno, NT., Cheng, YC., Rondón, G., et al.[2021]

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]

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

Etoposide, cyclophosphamide, total-body irradiation, and allogeneic bone marrow transplantation for hematologic malignancies. [2017]

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]

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

Allogeneic peripheral blood hematopoietic stem cell transplantation for patients with hematologic malignancies. [2019]

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]

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]

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

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. [2022]

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]

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]

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]

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]