Donor Stem Cell Boost in Treating Patients With Low Blood Cells After Donor Stem Cell Transplant

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Brief Title

Donor Stem Cell Boost in Treating Patients With Low Blood Cells After Donor Stem Cell Transplant

Official Title

Compassionate Use of the CliniMACS® CD34 Reagent System for Patients Requiring a Post Hematopoietic Stem Cell Transplant Boost of Donor Hematopoietic Stem Cells

Brief Summary

      This clinical trial studies how well donor stem cell boost works in treating patients with
      low blood cells after donor stem cell transplant. Donor stem cell boost may increase low
      blood cell counts caused by hematologic cancer or its treatment.
    

Detailed Description

      Successful engraftment after allogeneic hematopoietic stem cell transplant (HSCT) is defined
      by an actual neutrophil count (ANC) of > 500 10^6/L and a self-sustaining platelet count of
      20 x 10^9/L. ANC recovery usually occurs 14 to 21 days after the infusion of donor HSCs with
      red cell and platelet recovery typically following within the same time frame, although
      resolution of anemia may occur last. Recovery time is dose dependent, but in one report,
      donor HSC aliquots containing 1.9 to 20.5 10^6/kg CD34+ cells resulted in an ANC of > 500
      10^6/L at a median of 12 days and 16 days for patients receiving filgrastim versus those not
      receiving a white cell growth factor. In this trial, self-sustaining platelet counts of 20 x
      10^9/L occurred at median times of 15 to 11 days respectively. The results of another trial
      comparing outcomes between patients receiving mobilized peripheral blood stem cells (PBSCs)
      versus those receiving marrow from their donors showed that median times ANC of > 500 10^6/L
      and self-sustaining platelet counts of 20 x 10^9/L were 16 and 13 days respectively in the
      group receiving PBSCs and 21 and 19 days in those receiving marrow. Similar HSC doses
      associated with successful engraftment in these time frames have been demonstrated in other
      trials.

      Most transplant centers require a minimum dose of 1 to 2 x 10^6 CD34+ cells/kg to achieve
      adequate count recovery in a reasonable time frame post HSCT, although an early trial
      examining recovery after autologous reinfusion of HSCs demonstrated that a threshold of 2.5 x
      10^6/kg of CD 34 cells was associated with consistent and rapid WBC and platelet recovery
      times (18 and 14 days respectively). A later trial assessing autologous PBSC mobilization in
      breast cancer patients showed that HSC doses of ≥ 5 x 10^6 CD34+ cells/kg were associated
      with an 85% probability of WBC and platelet recovery by day 14, but with doses of 2 x 10^6 or
      less, 10% of patients had platelet recovery beyond day +28. While the precise dose of HSCs
      for successful engraftment in the allogeneic setting is not known, patient characteristics
      such as myelofibrosis and/or splenomegaly are likely to cause interpatient variation in the
      minimum number of HSCs needed for successful engraftment. In addition, donor factors such as
      mismatch in size with the recipient and biologic variation in the number of HSCs that can be
      obtained from any individual donor, can create a deficit in the amount of HSCs required for
      robust count recovery in a particular recipient. All of these factors can contribute to a
      poor functional or numeric cell dose and result in pancytopenia after HSCT.

      Drugs required for the prophylaxis and treatment of GVHD and infection have myelotoxic
      effects post HSCT, and unlike their use in solid organ transplantation, the marrow toxic
      effects of these drugs are potentially more severe and longer lasting in the presence of a
      newly reconstituting immune system. While many drugs can have negative effects on marrow
      function after HSCT, mycophenolate mofetil (MMF) and ganciclovir are two of the most commonly
      used agents with the potential to cause cytopenias.

      After hydrolysis to its active form, mycophenolic acid (MPA), MMF inhibits T and B cell
      proliferation making its use valuable in the prevention of graft versus host and host versus
      graft reactions post HSCT, especially in conjunction with a calcineurin inhibitor. Levels of
      MPA are increased in the presence of altered renal function, and other commonly used post
      HSCT drugs including acyclovir, ganciclovir, valaganciclovir, and tacrolimus. A major side
      effect of MMF is pancytopenia, particularly neutropenia, which is exacerbated by high drug
      levels. Due to finding of a wide interpatient variability in drug exposure, it has recently
      been recommended that the monitoring of MPA levels would result in better therapeutic
      outcomes, although MPA drug levels are not commonly obtained as yet in clinical practice.
      Myelotoxicity from the drug is observed after renal transplantation in the presence of a
      non-transplanted immune system demonstrating the potent myelosuppression associated with this
      drug, and the increased toxicity in patients with abnormal renal function. Patients post HSCT
      are treated with multiple drugs that both increase MPA levels and alter creatinine clearance,
      and are thereby highly susceptible to the marrow toxic effects of the drug which can result
      in cytopenias.

      Ganciclovir and valganciclovir, which is rapidly converted to ganciclovir by intestinal
      mucosal cells and hepatocytes to ganciclovir, are inhibitors of DNA synthesis. Ganciclovir is
      a known myelotoxic drug that is effective in prophylaxis and treatment of cytomegalovirus
      (CMV) infections in transplant recipients. Salzberger et al. examined the outcomes between
      engraftment and day +100 post HSCT of 278 patients receiving ganciclovir and found that 41%
      of patients receiving the drug had an ANC less than 1000 10^6/L for at least 2 consecutive
      days. Hyperbilirubinemia during the first 20 days after HSCT, elevated serum creatinine after
      day +21, and low marrow cellularity between days +21 and +28 were significant risk factors
      for neutropenia. Patients with 3 risk factors had a 57% chance of developing neutropenia,
      which was significantly associated with a decreased overall and event free survival. As noted
      above, concomitant use of ganciclovir and MMF increase the serum concentration of both drugs
      exacerbating marrow toxicity. Because CMV is a life-threatening disease post HSCT, it is
      often necessary to use ganciclovir especially in the presence of renal failure which is
      exacerbated with the use of foscarnet, the alternate drug for CMV treatment. Therefore,
      ganciclovir-induced pancytopenia may be unavoidable in certain contexts.

      Other medications with potentially toxic effects on the marrow alone or in combination with
      other commonly used agents which may contribute to the development of post HSCT cytopenias
      include levetiracetam, methotrexate, antibiotics such as linezolid, vancomycin, amoxicillin,
      cephalosporins, cidofovir, and gabapentin.

      In addition to insufficient allogeneic cell doses and medication toxicities, infections post
      HSCT can also result in persistent cytopenias. Reactivation of human herpes virus 6 (HHV-6)
      and CMV in particular are associated with pancytopenia. HHV-6 reactivates at a median of 20
      days post-HSCT and active infection has been shown in almost 50% of patients. The clinical
      syndrome associated with an active HHV-6 infection varies in intensity and may include
      encephalitis, rash, interstitial pneumonitis, and secondary graft failure. A transient,
      clinically insignificant HHV-6 reactivation occurs in many patients and because the symptoms
      of an HHV-6 infection are heterogenous and therefore less recognized, the disease may become
      severe prior to the recognition that the reactivation requires treatment. HHV-6 can become
      chronically active and has been associated not only with secondary graft failure, but pure
      red cell aplasia as well.

      CMV reactivation in the post HSCT period can also be accompanied by an acute syndrome
      manifested by fever, myalgia, and suppressed marrow function. Leukopenia at the start of CMV
      therapy has been associated with a poor response to anti-viral therapy and is a risk factor
      for progression of CMV viremia to CMV disease. While the most serious manifestations of CMV
      disease are related to pulmonary and enteral infections CMV-induced marrow suppression and
      marrow failure has been described, with identification of specific genotypes of CMV highly
      associated with mortality from pancytopenia. Because CMV and the treatment for CMV can both
      be associated with post HSCT cytopenias, it is often difficult to distinguish which of the
      two is the major etiological factor.

      Although the pathophysiology is unclear, persistent cytopenias post HSCT have also been
      associated with acute and chronic GVHD, bacterial and fungal infections, and impaired hepatic
      and renal function. Because failure of hematopoietic recovery after HSCT is associated with
      compromised patient survival, this protocol was developed to provide patients with persistent
      cytopenias post HSCT a boost of their original donors' HSCs to improve peripheral blood
      counts.
    


Study Type

Interventional


Primary Outcome

Etiologies of post HSCT cytopenias


Condition

Anemia

Intervention

Allogeneic hematopoietic stem cell transplantation

Study Arms / Comparison Groups

 Supportive care (allogeneic PBSCT boost)
Description:  Patients undergo allogeneic PBSCT boost from cells selected for CD34+ using the CliniMACS CD34 Reagent System.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

0

Start Date

August 2012

Completion Date

December 2014

Primary Completion Date

December 2014

Eligibility Criteria

        Inclusion Criteria:

          1. No evidence of active disease as measured by staging studies pertinent to the
             particular diagnosis within 1 month of the CD 34+ boost

          2. Full donor chimerism as manifested by a ≥ 90% donor peripheral blood total, MNC, and T
             cell chimerism result on the last two studies prior to the planned CD 34+ boost, with
             the second study performed within 1 month of the infusion.

          3. HHV-6 and CMV negative by PCR for at least 1 month prior to the CD 34+ boost as
             measured by at least 2 assays within the month timeframe

          4. ANC of < 1000 10^6/L or maintenance of an ANC ≥ 1000 10^6/L only with white cell
             growth factor support

          5. Requirement for red cell transfusion to maintain a hemoglobin of ≥ 9.0 g/dL

          6. Requirement for red cell transfusion to avoid symptomatic anemia in patients with
             hemoglobin values of ≤ 11.0 g/dL

          7. Requirement for platelet transfusion to maintain a platelet count of ≥ 20 10^9/L

          8. Requirement for platelet transfusion to avoid bleeding in patients with platelet
             counts ≤ 50 109/L

          9. No signs of active acute GVHD (excluding stages I-II skin GVHD)
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Dolores Grosso, DNP, CRNP, , 



Administrative Informations


NCT ID

NCT01660347

Organization ID

12D.214

Secondary IDs

2012-35

Responsible Party

Sponsor

Study Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University


Study Sponsor

Dolores Grosso, DNP, CRNP, Principal Investigator, Thomas Jefferson University


Verification Date

October 2016