Bone Marrow Transplant + GVHD Prophylaxis for Blood Cancer in HIV/AIDS Patients

Overseen By Mustafa A Hyder, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Antiretrovirals

Must not be taking: Investigational agents

Disqualifiers: Pregnancy, Uncontrolled illness, Active psychiatric disorder, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

265 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: People living with HIV(PLWH) are at a higher risk for cancers that may be curable with a bone marrow transplant. HIV infection itself is no longer a reason to not get a transplant, for patients who otherwise have a standard reason to need transplant. Objective: This study is being done to see if a new combination of drugs (cyclophosphamide, maraviroc, and bortezomib) is both safe and effective at protecting against graft-versus-host disease after bone marrow transplant. The study will also test the transplant s impact on your survival and control of your cancer. Eligibility: People aged 18 years and older living with HIV and a blood cancer that is eligible for a transplant. Healthy family members aged 12 or older who are half matched to transplant recipients are also needed to donate bone marrow. Design: The study will be done in 2 phases. The first phase will be to see if we can safely use a new combination of drugs to prevent GVHD. If the combination is safe in the first phase, the study will proceed to the second phase. In the second phase, we will see if this new combination can better protect against GVHD after transplant. Participants will be screened. Their diagnoses, organ function and eligibility will be confirmed. Participants will have a catheter inserted into a vein in their chest or neck. Medications and transfusions will be given through the catheter; blood will be drawn from it. Participants will be in the hospital for 6 weeks or longer. They will receive various drugs for 2 weeks to prep their body for the transplant. The transplant cells will be administered through the catheter. Participants will continue to receive drug treatments after the transplant. Blood transfusions may also be needed. Participants will return 1-2 times per week for follow-up visits for 3 months after discharge. Participants will have visits 6, 12, 18, 24 months after transplant, then once a year for 5 years.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, changes to your HIV medication may be needed to avoid interactions with the study drugs, but these changes are not part of the study.

What data supports the effectiveness of the treatment for bone marrow transplant with GVHD prophylaxis in HIV/AIDS patients?

Research shows that reduced-intensity conditioning (RIC) regimens, which are part of the treatment, are associated with a slightly higher survival rate compared to more intense regimens in patients with HIV undergoing bone marrow transplants. Additionally, RIC allows for successful engraftment with minimal early mortality, and the graft-versus-tumor effect can be achieved with an acceptable risk of complications. ^{1 2 3 4 5}

Is reduced-intensity conditioning (RIC) for bone marrow transplants generally safe for humans?

Reduced-intensity conditioning (RIC) for bone marrow transplants is generally considered safe, with lower early toxicity compared to traditional methods. However, there is a significant risk of developing chronic graft-versus-host disease (GVHD), which affects a notable proportion of patients. ^{5 6 7 8 9}

How is the treatment RIC for blood cancer in HIV/AIDS patients different from other treatments?

The RIC treatment for blood cancer in HIV/AIDS patients is unique because it uses a less intense conditioning regimen before a bone marrow transplant, which reduces the risk of severe side effects while still allowing the transplant to work effectively. This approach is particularly beneficial for patients with HIV, as it helps manage the cancer without overwhelming their immune system. ^{1 2 3 4 10}

Research Team

Mustafa A Hyder, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for adults over 18 with HIV and blood cancer needing a bone marrow transplant. Eligible patients must have specific types of leukemia, lymphoma, or myeloma in remission or partially responsive to treatment. They need a half-matched family donor aged 12+, good organ function, and controlled HIV with an undetectable viral load.

Inclusion Criteria

You have been diagnosed with a type of blood cancer that requires a stem cell transplant. Your cancer must meet specific criteria, such as being in remission or having certain genetic mutations. You must have a potential donor who is a close relative and willing to donate. You must also meet certain health requirements, such as having good organ function and not being pregnant or planning to become pregnant. Finally, you must understand and agree to participate by signing a consent form.

Exclusion Criteria

Participants who are receiving any other investigational agents that cannot be discontinued/completed at least 2 weeks prior to the date of beginning conditioning, Poorly controlled malignant indication for transplantation, defined as: Leukemia not having achieved morphologic remission (i.e. bone marrow blasts >5% or active extramedullary disease), Lymphoma not having achieved at least a partial response to prior chemotherapy or radiation by clinical and/or radiologic assessment, Multiple myeloma not in complete remission, as determined by negative immunofixation in serum and urine and disappearance of any soft tissue plasmacytomas and <= 5% plasma cells in the bone marrow, Uncontrolled intercurrent illness that in the opinion of the PI would make it unsafe to proceed with transplantation, Study team is unable to identify an adequate antiretroviral regimen to adequately suppress the HIV viral load <400 copies/mL that is compatible with study drugs, Pregnancy, For lactating women: unwilling to discontinue lactation prior to the start of study treatment on day -14, Prohibitive allergy to a study drug or to compounds of similar chemical or biologic composition of the agents (eATG, steroids, cyclophosphamide, busulfan, pentostatin, maraviroc, bortezomib, plerixafor (dose level 3 only)) used in the study, Lack of central access potential sufficient for transplant, Active psychiatric disorder which is deemed by the PI to have significant risk of compromising compliance with the transplant protocol and/or antiretroviral therapy, Grade 3-4 motor or sensory neuropathy per CTCAE version 5.0, Failure to qualify per institutional Standard Policies

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplant Preparation

Participants receive various drugs to prepare their body for the transplant, including eATG, pentostatin, cyclophosphamide, and busulfan.

2 weeks

Transplantation and Initial Treatment

Transplant cells are administered, followed by GVHD prophylaxis with cyclophosphamide, bortezomib, and maraviroc.

6 weeks or longer

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits 1-2 times per week for 3 months after discharge.

3 months

1-2 visits per week

Long-term Follow-up

Participants have visits at 6, 12, 18, 24 months after transplant, then once a year for 5 years to monitor overall survival and other outcomes.

5 years

Treatment Details

Interventions

• Bortezomib
• Cyclophosphamide
• Maraviroc
• RIC

Trial Overview The study tests if cyclophosphamide, maraviroc, and bortezomib can prevent graft-versus-host disease after bone marrow transplants in people with HIV. It's done in two phases: first ensuring safety of the drug combo, then assessing its effectiveness against GVHD.

Participant Groups

Group I: 2/Recipient Arm 2 Experimental Treatment 5 Interventions

RIC+alloHCT+GVHD prophylaxis per RP2D

Group II: 1/Recipient Arm 1 Experimental Treatment 5 Interventions

RIC+alloHCT+GVHD prophylaxis per dose levels 1, 2, and

Group III: 3/Donor Arm Active Control 1 Intervention

Collection of research samples on hematopoietic donors

RIC is already approved in United States, European Union for the following indications:

Approved in United States as RIC for:

• Hematologic malignancies in HIV-positive patients

Approved in European Union as RIC for:

• Hematologic malignancies in HIV-positive patients

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Allogeneic hematopoietic cell transplantation (allo-HCT) shows promising outcomes for people living with HIV, with an overall survival rate of 81.6% at 6 months and 56.6% at 12 months, indicating that their clinical outcomes are comparable to those of patients without HIV.

Reduced-intensity conditioning (RIC) regimens appear to offer a slight survival advantage over myeloablative conditioning (MAC) regimens, suggesting that RIC may be a preferable option for these patients, although further prospective trials are needed to optimize treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies in Patients with HIV Infection. Arslan, S., Litzow, MR., Cummins, NW., et al.[2021]

In a study of 101 high-risk patients undergoing reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation, the incidence of acute graft-versus-host disease (aGVHD) was found to be 36%, and chronic graft-versus-host disease (cGVHD) was 43% at 2 years, indicating a significant risk of these complications.

The study revealed that aGVHD was significantly associated with the dose of antithymocyte globulin (ATG) used, while using peripheral blood as a stem cell source was linked to a higher risk of cGVHD; however, the presence of GVHD correlated with a lower risk of disease progression or relapse, suggesting a beneficial graft-versus-tumor effect without increasing transplantation-related mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Mohty, M., Bay, JO., Faucher, C., et al.[2021]

Nonmyeloablative allogeneic transplantation appears to be a safe and effective treatment for patients with HIV and refractory hematologic malignancies, as demonstrated by two case studies with minimal toxicity and complete remissions achieved in both patients.

Patient 1, who received genetically modified cells, remains in complete remission with undetectable HIV levels and rising CD4 counts over two years post-transplant, indicating potential long-term benefits of this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Kang, EM., de Witte, M., Malech, H., et al.[2021]

In a phase II trial involving 17 HIV-positive patients undergoing allogeneic hematopoietic cell transplant, there was no nonrelapse mortality at 100 days, indicating a promising safety profile for this treatment approach.

At one year, the overall survival rate was 59%, and in patients who achieved complete chimerism, HIV DNA and infectious virus were undetectable in the blood, suggesting effective viral control post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies: The BMT CTN-0903/AMC-080 Trial. Ambinder, RF., Wu, J., Logan, B., et al.[2021]

In a study of 292 patients with hematologic malignancies undergoing reduced-intensity conditioning (RIC) followed by allogeneic hematopoietic cell transplantation, the 5-year overall survival rates varied significantly by disease type, with the highest at 78% for indolent non-Hodgkin lymphoma and the lowest at 14% for myeloproliferative neoplasms.

The study found that recipient cytomegalovirus (CMV) positivity was associated with lower relapse rates, particularly when paired with a CMV-positive donor, highlighting the importance of donor-recipient matching in improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-Intensity Conditioning Followed by Related and Unrelated Allografts for Hematologic Malignancies: Expanded Analysis and Long-Term Follow-Up. Warlick, ED., DeFor, TE., Bejanyan, N., et al.[2020]

Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation resulted in low early toxicity and stable donor stem cell engraftment, with a 1-year overall survival rate of 60% among 76 patients studied.

While the risk of developing acute graft-versus-host disease (GVHD) was relatively low at 32%, chronic extensive GVHD occurred in 43% of patients, indicating a need for ongoing monitoring and management post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study. Martino, R., Caballero, MD., Canals, C., et al.[2019]

In a study involving 111 patients with lymphoid and myeloid malignancies, a reduced-intensity conditioning regimen using total lymphoid irradiation and antithymocyte globulin led to durable chimerism in 97% of patients, indicating effective engraftment.

The regimen resulted in low rates of acute graft-versus-host disease (GVHD) (2% for related donors and 10% for unrelated donors) and a nonrelapse mortality rate of less than 4% at one year, suggesting a safe and effective approach for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Kohrt, HE., Turnbull, BB., Heydari, K., et al.[2021]

Children undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-AlloHSCT) experienced significantly lower rates of acute toxicities, such as mucositis and infections, compared to those receiving myeloablative conditioning (MAC-AlloHSCT), based on a study of 86 patients.

RIC-AlloHSCT also resulted in a lower 100-day transplantation-related mortality (TRM), indicating it may be a safer option for pediatric patients undergoing stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic stem cell transplantation in pediatric patients and subsequent supportive care. Barrell, C., Dietzen, D., Jin, Z., et al.[2012]

In a study of 93 patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), reduced-intensity conditioning (RIC) allo-SCT using fludarabine and busulfan showed promising long-term outcomes, with 4-year disease-free survival (DFS) and overall survival (OS) rates of 43% and 45%, respectively.

The development of chronic graft-versus-host disease (GVHD) was associated with lower relapse rates and improved DFS and OS, highlighting its potential role in enhancing the efficacy of RIC allo-SCT for patients who cannot undergo conventional high-dose conditioning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. Valcárcel, D., Martino, R., Caballero, D., et al.[2013]

In a study of 11 patients with relapsed and refractory lymphoid malignancies, a non-myeloablative allo-SCT regimen using fludarabine and low-dose busulfan allowed for successful engraftment with minimal toxicity, demonstrating a potent graft-versus-tumor (GVT) effect.

Despite the benefits, 72% of patients experienced spontaneous acute graft-versus-host disease (GVHD), but 45% achieved complete remission, indicating that while GVHD is a significant risk, it may be associated with effective tumor response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity conditioning: enhanced graft-versus-tumor effect following dose-reduced conditioning and allogeneic transplantation for refractory lymphoid malignancies after high-dose therapy. Mohty, M., Fegueux, N., Exbrayat, C., et al.[2004]

References

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

Risks and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies in Patients with HIV Infection. [2021]

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

Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. [2021]

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

Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. [2021]

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

Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies: The BMT CTN-0903/AMC-080 Trial. [2021]

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

Reduced-Intensity Conditioning Followed by Related and Unrelated Allografts for Hematologic Malignancies: Expanded Analysis and Long-Term Follow-Up. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study. [2019]

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

TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. [2021]

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

Reduced-intensity conditioning allogeneic stem cell transplantation in pediatric patients and subsequent supportive care. [2012]

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

Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. [2013]

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

Reduced intensity conditioning: enhanced graft-versus-tumor effect following dose-reduced conditioning and allogeneic transplantation for refractory lymphoid malignancies after high-dose therapy. [2004]