Bone Marrow Transplant for Blood Cancer

Overseen By Richard Ambinder, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Sirolimus

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests bone marrow and stem cell transplants for various blood cancers using donors who are not perfect genetic matches. The goal is to determine if this approach can be safe and effective, with a focus on reducing severe side effects like graft-versus-host disease, where donor cells attack the patient's body. The trial involves different treatment plans and medications, such as Cytoxan (a chemotherapy drug) and sirolimus (an immunosuppressant), to support the body after the transplant. Individuals with certain types of blood cancer, like leukemia or lymphoma, without a perfect donor match might be suitable for this trial. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering a chance to contribute to groundbreaking advancements in blood cancer treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that bone marrow and peripheral blood stem cell transplants are usually well-tolerated but carry some risks. Studies have found that patients might develop long-term health issues after these transplants. For example, one study noted a higher risk of chronic graft-versus-host disease (GVHD), where donor cells attack the recipient's body, following a peripheral blood stem cell transplant. However, no significant differences in overall survival rates were found between the two types of transplants.

The safety of using Cytoxan (cyclophosphamide) and Fludarabine in these procedures has been studied. High doses of Cytoxan often prevent severe GVHD, and research indicates it is generally safe with careful monitoring. Fludarabine helps reduce the immune system's response, smoothing the transplant process.

Sirolimus, a drug that suppresses the immune system, lowers the risk of GVHD. While sirolimus is usually well-tolerated, it requires careful dosing to balance effectiveness with potential side effects.

In summary, while these treatments have some risks, they are generally considered safe when managed carefully. The aim is always to reduce complications like GVHD and improve survival rates after the transplant. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for blood cancer, which often rely on chemotherapy and radiation alone, the treatments in this trial combine allogeneic blood or marrow transplants with innovative immunosuppressive protocols. Researchers are excited about these treatments because they utilize a combination of drugs like Fludarabine and Cytoxan before and after transplantation to prepare the body and help manage the immune system. Additionally, the use of high-dose Cytoxan post-transplantation, along with Sirolimus or Tacrolimus, aims to reduce complications such as graft-versus-host disease. These approaches strive to improve patient outcomes by enhancing the effectiveness of the transplant and reducing potential side effects.

What evidence suggests that this trial's treatments could be effective for blood cancer?

Studies have shown that stem cell transplants from donors can effectively treat blood cancers. In this trial, participants will receive different transplant regimens. Some will undergo Allogeneic Blood or Marrow Transplant (BMT), while others will receive Peripheral Blood Stem Cell Transplant (PBSCT). Research indicates that these transplants can potentially cure the disease, even in patients over 70. However, they carry risks such as infection and cancer recurrence. PBSCT, one of the options in this trial, helps patients recover their blood cell levels faster than bone marrow transplants. It is also associated with lower chances of cancer returning and better survival rates in patients with advanced blood cancer. Early evidence suggests that adding sirolimus, a drug that weakens the immune system, might help manage complications after the transplant. ^{6 7 8 9 10}

Who Is on the Research Team?

Richard Ambinder, MD, PhD

Principal Investigator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic Blood or Marrow Transplant
• Cytoxan
• Fludarabine
• Mycophenolate Mofetil
• Peripheral Blood Stem Cell Transplant
• Sirolimus
• Tacrolimus
• Total Body Irradiation

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.

How Is the Trial Designed?

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

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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 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]

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]

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 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]

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 146 adults with acute lymphoblastic leukemia undergoing transplantation, both conditioning regimens (Cyclophosphamide/Total Body Irradiation vs. Fludarabine/Busulfan/Low-dose TBI) showed similar overall and progression-free survival rates, indicating comparable efficacy.

However, the Fludarabine/Busulfan/Low-dose TBI regimen resulted in a significantly lower relapse rate (18.5% vs. 31.5% for Cy/TBI), suggesting it may be a safer option, especially for patients with poorer performance status.

NCBI (Pubmed)

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. Speziali, C., Daly, A., Abuhaleeqa, M., et al.[2020]

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 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]

Citations

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nature.com

nature.com/articles/s41408-023-00900-z

Long-term outcomes of allogeneic stem cell transplant in ...

Allogeneic stem cell transplant (allo SCT) for multiple myeloma (MM) is potentially curative in some, while toxic in many others.

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pmc.ncbi.nlm.nih.gov

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Outcome of Allogeneic Hematopoietic Stem Cell ...

Allogeneic stem cell transplantation is an effective treatment option in patients with hematological malignancies. Our outcomes are comparable ...

3.

astctjournal.org

astctjournal.org/article/S2666-6367(24)00842-X/fulltext

Outcomes of Allogeneic Hematopoietic Stem Cell ...

Allo-HCT offers curative potential for patients aged 70 and above with hematologic malignancies. •. Post-transplant relapse and infection remain the leading ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S2666636725012205

Long-Term Outcomes After Allogeneic Hematopoietic Stem ...

At present, 95 patients (33.3%) are long-term survivors in continuous CR at 5-22 yr since transplant. Despite pronounced toxicity, allo-HSCT is effective in ...

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ashpublications.org

ashpublications.org/blood/article/144/Supplement%201/7436/528851/Treatment-Trends-and-Outcomes-of-Allogeneic

Treatment Trends and Outcomes of Allogeneic ...

Allogeneic Hematopoietic Cell Transplantation Can Cure Some Patients with Acute Leukemia in Relapse or Primary Induction Failure: A CIBMTR Study ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10130410/

Long-term health outcomes of allogeneic hematopoietic stem ...

Long-term survivors of HCT may have numerous chronic health conditions related to the transplant. In a multicenter retrospective study of HCT ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5345733/

Safety and efficacy of allogeneic hematopoietic stem cell ...

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

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sciencedirect.com

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OUTCOMES OF ALLOGENEIC STEM CELL ...

This study presents data on allogeneic HSCT procedures performed in our transplant center for AML patients.

9.

nature.com

nature.com/articles/s41375-024-02318-3

How risky is a second allogeneic stem cell transplantation?

Outcomes at two years after second alloSCT were: NRM 22%, relapse incidence 50%, overall survival 38%, and progression-free survival 28%.

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mayoclinic.org

mayoclinic.org/tests-procedures/bone-marrow-transplant/about/pac-20384854

Bone marrow transplant

A bone marrow transplant is a procedure that infuses healthy blood-forming stem cells into your body to replace bone marrow that's not producing enough healthy ...