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

18 Years
Open (Enrolling)
Anemia, Hematopoietic/Lymphoid Cancer, Lymphopenia, Neutropenia, Thrombocytopenia

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Trial Information

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

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

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

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.

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)

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Outcome Measure:

Etiologies of post HSCT cytopenias

Outcome Description:

Will be collected and reported descriptively.

Outcome Time Frame:

Up to 8 weeks

Safety Issue:


Principal Investigator

Dolores Grosso, DNP, CRNP

Investigator Role:

Principal Investigator

Investigator Affiliation:

Thomas Jefferson University


United States: Food and Drug Administration

Study ID:




Start Date:

August 2012

Completion Date:

September 2019

Related Keywords:

  • Anemia
  • Hematopoietic/Lymphoid Cancer
  • Lymphopenia
  • Neutropenia
  • Thrombocytopenia
  • Anemia
  • Lymphopenia
  • Neutropenia
  • Thrombocytopenia



Thomas Jefferson University Philadelphia, Pennsylvania  19107-6541