Clinical trial NCT01203722: Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies
Official title: Reduced Intensity, Partially HLA Mismatched Allogeneic BMT for Hematologic Malignancies Using Donors Other Than First-degree Relatives
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hematologic Malignancies
Keywords: Reduced intensity
partially HLA mismatched allogeneic BMT
Acute leukemias
Chronic leukemias
Myelodysplasia
Lymphomas
Unrelated or non-first-degree related donors
Peripheral blood stem cell transplant
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-09-16
Enrollment: 89
Sex: ALL
Minimum age (years): 6
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Patient Inclusion Criteria:

1. Patient age 0.5-75 years
2. Absence of a suitable related or unrelated bone marrow donor who is molecularly matched at HLA-A, B, Cw, DRB1, and DQB1.
3. Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor. Donors who are homozygous for the CCR5delta32 polymorphism are given preference.
4. Eligible diagnoses:

   1. Relapsed or refractory acute leukemia in second or subsequent remission, with remission defined as \<5% bone marrow blasts morphologically
   2. Poor-risk acute leukemia in first remission, with remission defined as \<5% bone marrow blasts morphologically:

      * AML with at least one of the following:

        * AML arising from MDS or a myeloproliferative disorder, or secondary AML
        * Presence of Flt3 internal tandem duplications
        * Poor-risk cytogenetics: Complex karyotype \[\> 3 abnormalities\], inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7
        * Primary refractory disease
      * ALL (leukemia and/or lymphoma) with at least one of the following:

        * Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangement
        * Clear evidence of hypodiploidy
        * Primary refractory disease
      * Biphenotypic leukemia
   3. MDS with at least one of the following poor-risk features:

      * Poor-risk cytogenetics (7/7q minus or complex cytogenetics)
      * IPSS score of INT-2 or greater
      * Treatment-related MDS
      * MDS diagnosed before age 21 years
      * Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy
      * Life-threatening cytopenias, including those generally requiring greater than weekly transfusions
   4. Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase.
   5. Philadelphia chromosome negative myeloproliferative disease.
   6. Chronic myelomonocytic leukemia.
   7. Juvenile myelomonocytic leukemia.
   8. Low-grade non-Hodgkin lymphoma (including SLL and CLL) or plasma cell neoplasm that has:

      * progressed after at least two prior therapies (excluding single agent rituximab and single agent steroids), or
      * in the case of lymphoma undergone histologic conversion;
      * patients with transformed lymphomas must have stable disease or better.
   9. Poor-risk CLL or SLL as follows:

      * 11q deletion disease that has progressed after a combination chemotherapy regimen,
      * 17p deletion disease,
      * or histologic conversion;
      * patients with transformed lymphomas must have stable disease or better.
   10. Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or better to last therapy:

       * NK or NK-T cell lymphoma, hepatosplenic T-cell lymphoma, or subcutaneous panniculitic T-cell lymphoma, blastic/ blastoid variant of mantle cell lymphoma
       * Hodgkin or aggressive non Hodgkin lymphoma that has failed at least one multiagent regimen, and the patient is either ineligible for autologous BMT or autologous BMT is not recommended.
       * Eligible subtypes of aggressive non-Hodgkin lymphoma include:

         * mantle cell lymphoma
         * follicular grade 3 lymphoma
         * diffuse large B-cell lymphoma or its subtypes, excluding primary CNS lymphoma
         * primary mediastinal large B-cell lymphoma
         * large B-cell lymphoma, unspecified
         * anaplastic large cell lymphoma, excluding skin-only disease
         * Burkitt's lymphoma or atypical Burkitt's lymphoma (high-grade B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt's), in complete remission
5. Patients with CLL, SLL, or prolymphocytic leukemia must have \< 20% bone marrow involvement by malignancy (to lower risk of graft rejection).
6. One of the following, in order to lower risk of graft rejection:

   * Cytotoxic chemotherapy, an adequate course of 5-azacitidine or decitabine, or alemtuzumab within 3 months prior to start of conditioning; or
   * Previous BMT within 6 months prior to start of conditioning.

   NOTE: Patients who have received treatment outside of these windows may be eligible if it is deemed sufficient to reduce graft rejection risk; this will be decided on a case-by-case basis by the PI or co-PI.
7. Any previous BMT must have occurred at least 3 months prior to start of conditioning.
8. Adequate end-organ function as measured by:

   1. Left ventricular ejection fraction greater than or equal to 35%, or shortening fraction \> 25%, unless cleared by a cardiologist
   2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST \< 5 x ULN
   3. 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
9. ECOG performance status \< 2 or Karnofsky or Lansky score \> 60

Patient Exclusion Criteria:

* Not pregnant or breast-feeding.
* No uncontrolled bacterial, viral, or fungal infection.

  * Note: HIV-infected patients are potentially eligible. Eligibility of HIV-infected patients will be determined on a case-by-case basis.
* No previous allogeneic BMT (syngeneic BMT permissible).
* Active extramedullary leukemia or known active CNS involvement by malignancy. Such disease treated into remission is permitted.

Donor Inclusion Criteria:

1. Potential donors consist of:

   * Unrelated donors
   * Second-degree relatives
   * First cousins
2. The donor and recipient must be identical at at least 5 HLA alleles based on high resolution typing of HLA-A, -B, -Cw, -DRB1, and -DQB1, with at least one allele matched for a HLA class I gene (HLA-A, -B, or -Cw) and at least one allele matched for a class II gene (HLA-DRB1 or -DQB1).
3. Meets institutional selection criteria and medically fit to donate. 4 . Lack of recipient anti-donor HLA antibody. Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors. Pheresis to reduce anti-HLA antibodies is permissible; however eligibility to proceed with the transplant regimen would be contingent upon the result.

Donor Exclusion Criteria:

* Donor must not be HLA identical to the recipient.
* Has not donated blood products to recipient.

Primary outcomes:
measure: Transplant regimen as determined by rates of severe acute graft-versus-host-disease (GVHD)
timeFrame: Study Day 100
measure: Transplant regimen as determined by rates of transplant-related nonrelapse mortality (NRM)
timeFrame: Study Day 100
measure: 6-month probability of survival as assessed by absence of grade III-IV GVHD or evidence of graft failure.
timeFrame: 6 months
Secondary outcomes:
measure: Progression-free survival
timeFrame: 7 years
measure: Event-free survival
timeFrame: 7 years
measure: Overall survival
timeFrame: 7 years
measure: Cumulative incidence of progression or relapse
timeFrame: 7 years
measure: Cumulative incidence of NRM.
timeFrame: 7 years
measure: Cumulative incidence of acute grade II-IV GVHD.
timeFrame: 1 year
measure: Cumulative incidence of acute grade III-IV GVHD
timeFrame: 1 year
measure: Cumulative incidence of chronic GVHD
timeFrame: 1 year
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Richard Ambinder, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rappazzo KC, Zahurak M, Bettinotti M, Ali SA, Ambinder AJ, Bolanos-Meade J, Borrello I, Dezern AE, Gladstone D, Gocke C, Fuchs E, Huff CA, Imus PH, Jain T, Luznik L, Rahmat L, Swinnen LJ, Wagner-Johnston N, Jones RJ, Ambinder RF. Nonmyeloablative, HLA-Mismatched Unrelated Peripheral Blood Transplantation with High-Dose Post-Transplantation Cyclophosphamide. Transplant Cell Ther. 2021 Nov;27(11):909.e1-909.e6. doi: 10.1016/j.jtct.2021.08.013. Epub 2021 Aug 20.
citation: Kasamon YL, Ambinder RF, Fuchs EJ, Zahurak M, Rosner GL, Bolanos-Meade J, Levis MJ, Gladstone DE, Huff CA, Swinnen LJ, Matsui WH, Borrello I, Brodsky RA, Jones RJ, Luznik L. Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide. Blood Adv. 2017;1(4):288-292. doi: 10.1182/bloodadvances.2016002766. Epub 2017 Jan 6.